FN Clarivate Analytics Web of Science
VR 1.0
PT J
AU Barnette, DN
   VandeKopple, M
   Wu, YG
   Willoughby, DA
   Lincoln, J
AF Barnette, Damien N.
   VandeKopple, Matthew
   Wu, Yonggan
   Willoughby, David A.
   Lincoln, Joy
TI RNA-Seq Analysis to Identify Novel Roles of Scleraxis during Embryonic
   Mouse Heart Valve Remodeling
SO PLOS ONE
LA English
DT Article
ID GENE-EXPRESSION; DISEASE; DIFFERENTIATION; TENDONS; CHICKEN; DOMAIN
AB Heart valve disease affects up to 30% of the population and has been shown to have origins during embryonic development. Valvulogenesis begins with formation of endocardial cushions in the atrioventricular canal and outflow tract regions. Subsequently, endocardial cushions remodel, elongate and progressively form mature valve structures composed of a highly organized connective tissue that provides the necessary biomechanical function throughout life. While endocardial cushion formation has been well studied, the processes required for valve remodeling are less well understood. The transcription factor Scleraxis (Scx) is detected in mouse valves from E15.5 during initial stages of remodeling, and expression remains high until birth when formation of the highly organized mature structure is complete. Heart valves from Scx(-/-) mice are abnormally thick and develop fibrotic phenotypes similar to human disease by juvenile stages. These phenotypes begin around E15.5 and are associated with defects in connective tissue organization and valve interstitial cell differentiation. In order to understand the etiology of this phenotype, we analyzed the transcriptome of remodeling valves isolated from E15.5 Scx(-/-) embryos using RNA-seq. From this, we have identified a profile of protein and non-protein mRNAs that are dependent on Scx function and using bioinformatics we can predict the molecular functions and biological processes affected by these genes. These include processes and functions associated with gene regulation (methyltransferase activity, DNA binding, Notch signaling), vitamin A metabolism (retinoic acid biosynthesis) and cellular development (cell morphology, cell assembly and organization). In addition, several mRNAs are affected by alternative splicing events in the absence of Scx, suggesting additional roles in post-transcriptional modification. In summary, our findings have identified transcriptome profiles from abnormal heart valves isolated from E15.5 Scx(-/-) embryos that could be used in the future to understand mechanisms of heart valve disease in the human population.
C1 [Barnette, Damien N.] Leonard M Miller Sch Med, Mol & Cellular Pharmacol Grad Program, Miami, FL USA.
   [Barnette, Damien N.; VandeKopple, Matthew; Lincoln, Joy] Nationwide Childrens Hosp, Res Inst, Ctr Cardiovasc & Pulm Res, Columbus, OH 43210 USA.
   [Barnette, Damien N.; VandeKopple, Matthew; Lincoln, Joy] Nationwide Childrens Hosp, Res Inst, Ctr Heart, Columbus, OH USA.
   [VandeKopple, Matthew] Ohio State Univ, Mol Cellular & Dev Biol Grad Program, Columbus, OH 43210 USA.
   [Wu, Yonggan; Willoughby, David A.] Ocean Ridge Biosci LLC, Palm Beach Gardens, FL USA.
   [Lincoln, Joy] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA.
C3 University System of Ohio; Ohio State University; Nationwide Childrens
   Hospital; Research Institute at Nationwide Children's Hospital; Center
   for Cardiovascular & Pulmonary Research; University System of Ohio; Ohio
   State University; Nationwide Childrens Hospital; Research Institute at
   Nationwide Children's Hospital; Center for Cardiovascular & Pulmonary
   Research; University System of Ohio; Ohio State University; University
   System of Ohio; Ohio State University
RP Lincoln, J (corresponding author), Nationwide Childrens Hosp, Res Inst, Ctr Cardiovasc & Pulm Res, Columbus, OH 43210 USA.
EM joy.lincoln@nationwidechildrens.org
OI Lincoln, Joy/0000-0003-1517-6888
FU NIH [NHLBI R01HL091878]; American Heart Association [PRE16270014]; Ocean
   Ridge Biosciences LLC
FX This work was supported by NIH (NHLBI R01HL091878 (JL)) and The American
   Heart Association (PRE16270014 (DNB)). The funders had no role in study
   design, data collection and analysis, decision to publish, or
   preparation of the manuscript. Ocean Ridge Biosciences LLC provided
   support in the form of salaries for authors Yonggan Wu and David A.
   Willoughby, but did not have any additional role in the study design,
   data collection and analysis, decision to publish, or preparation of the
   manuscript. The specific roles of these authors is articulated in the
   'author contributions' section.
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NR 26
TC 10
Z9 13
U1 0
U2 6
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD JUL 1
PY 2014
VL 9
IS 7
AR e101425
DI 10.1371/journal.pone.0101425
PG 10
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA AM1UX
UT WOS:000339635000105
PM 24983472
OA Green Published, Green Submitted, gold
DA 2025-04-10
ER

PT J
AU Wagner, M
   Miles, K
   Siddiqui, MAQ
AF Wagner, M
   Miles, K
   Siddiqui, MAQ
TI Early developmental expression pattern of retinoblastoma tumor
   suppressor mRNA indicates a role in the epithelial-to-mesenchyme
   transformation of endocardial cushion cells
SO DEVELOPMENTAL DYNAMICS
LA English
DT Article
DE retinoblastoma tumor suppressor; cardiac septation; endocardial cushion
   cells; epithelial-to-mesenchyme transformation; epicardium; somitic
   myotome; alternative splicing of RNA; cyclins and cyclin-dependent
   kinases; hepatocyte growth factor/scatter factor
ID SUBEPICARDIAL MESENCHYME; CYCLE MACHINERY; CHICK-EMBRYOS; PROTEIN; GENE;
   RAS; IDENTIFICATION; MORPHOGENESIS; RECEPTOR; HGF/SF
AB The earliest stages of embryonic development are characterized by the generation of precursor cell populations that differentiate and coalesce into tissue and organ primordia, To provide sufficient numbers of differentiated cells for tissue and organ formation, the differentiative as well as the proliferative processes of cells must be controlled and coordinated. Potential regulators of the proliferative process include molecules that control the cell cycle, in particular, the tumor suppressor proteins. To bean to understand the role such molecules can play in development, we have studied the expression of the retinoblastoma tumor suppressor (Rb) gene in early chicken development. Our studies in early chicken embryos show that Rb is encoded by a single gene that gives rise to several Rb mRNA isoforms through alternative splicing of a primary transcript. These mRNA isoforms potentially encode Rb proteins that differ with respect to the number of sequence motifs known to target cyclin-dependent kinases to Rb, suggesting dynamic control of Rb phosphorylation and function during development. This complex expression pattern of Rb mRNA begins as early as the blastoderm stage of chicken development (stage 3) and continues through stage 18, the latest stage examined. Despite this early embryonic expression of Rb mRNA as detected by reverse transcription polymerase chain reaction, Rb mRNA levels sufficient to be detected by in situ hybridization were not expressed until after stage 14 of development. Rb mRNA was found to be localized to cells of the endocardial cushions of the early heart tube, cells of the epicardium, and myogenic cells of the semitic myotome. Interestingly, each of these cell types undergoes an epithelial-to-mesenchyme transformation to form a migratory and/or invasive population of mesenchymal cells. We have focused our studies on the expression of Rb mRNA in endocardial cells of the early heart tube, because the transition of these cells to mesenchyme initiates the important process of septation, an early step in the formation of heart valves. (C) 2001 Wiley-Liss, Inc.
C1 SUNY Hlth Sci Ctr, Dept Anat & Cell Biol, Ctr Cardiovasc & Muscle Res, Brooklyn, NY 11203 USA.
C3 State University of New York (SUNY) System; SUNY Downstate Health
   Sciences University
RP Wagner, M (corresponding author), SUNY Hlth Sci Ctr, Dept Anat & Cell Biol, Ctr Cardiovasc & Muscle Res, 450 Clarkson Ave,Box 5, Brooklyn, NY 11203 USA.
FU NHLBI NIH HHS [HL 53573] Funding Source: Medline
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NR 37
TC 5
Z9 5
U1 0
U2 1
PU WILEY-LISS
PI NEW YORK
PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA
SN 1058-8388
J9 DEV DYNAM
JI Dev. Dyn.
PD MAR
PY 2001
VL 220
IS 3
BP 198
EP 211
DI 10.1002/1097-0177(20010301)220:3<198::AID-DVDY1103>3.0.CO;2-T
PG 14
WC Anatomy & Morphology; Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Anatomy & Morphology; Developmental Biology
GA 404YY
UT WOS:000167131400002
PM 11241829
OA Bronze
DA 2025-04-10
ER

PT J
AU Raja, A
   Ganta, V
AF Raja, Adarshini
   Ganta, Vijay
TI Synthetic Antiangiogenic Vascular Endothelial Growth Factor-A Splice
   Variant Revascularizes Ischemic Muscle in Peripheral Artery Disease
SO JOURNAL OF THE AMERICAN HEART ASSOCIATION
LA English
DT Article
DE alternative splicing; growth factors; ischemia; phospho-proteome arrays;
   signal transduction
ID THERAPEUTIC ANGIOGENESIS; CELL-MIGRATION; MOUSE MODEL; VEGF; VEGF(165)B;
   ACTIVATION; ISOFORM; PATHWAY; KINASE; RECEPTOR
AB Background Alternative splicing in the eighth exon C-terminus of VEGF-A (vascular endothelial growth factor-A) results in the formation of proangiogenic VEGF(165)a and antiangiogenic VEGF(165)b isoforms. The only known difference between these 2 isoform families is a 6-amino acid switch from CDKPRR (in VEGF(165)a) to SLTRKD (in VEGF(165)b). We have recently shown that VEGF(165)b can induce VEGFR2-activation but fails to induce VEGFR1 (VEGF receptor 1)-activation. The molecular mechanisms that regulate VEGF(165)b's ability toward differential VEGFR2 versus VEGFR1 activation/inhibition are not yet clear. Methods and Results Hypoxia serum starvation was used as an in vitro peripheral artery disease model. Unilateral single ligation of the femoral artery was used as a preclinical peripheral artery disease model. VEGFR1 activating ligands have 2 arginine (RR) residues in their eighth exon C-terminus, that were replaced by lysine-aspartic acid (KD) in VEGF(165)b. A synthetic anti-angiogenic VEGF(165)b splice variant in which the KD residues were switched to RR (VEGF(165)b(KD -> RR)) activated both VEGFR1- and VEGFR2-signaling pathways to induce ischemic-endothelial cell angiogenic capacity in vitro and enhance perfusion recovery in a severe experimental-peripheral artery disease model significantly higher than VEGF(165)a. Phosphoproteome arrays showed that the therapeutic efficacy of VEGF(165)b(KD -> RR) over VEGF(165)a is due to its ability to induce P38-activation in ischemic endothelial cells. Conclusions Our data shows that the KD residues regulate VEGF(165)b's VEGFR1 inhibitory property but not VEGFR2. Switching these KD residues to RR resulted in the formation of a synthetic/recombinant VEGF(165)b(KD -> RR) isoform that has the ability to activate both VEGFR1- and VEGFR2-signaling and induce ischemic-endothelial cell angiogenic and proliferative capacity that matched the angiogenic requirement necessary to achieve perfusion recovery in a severe experimental-peripheral artery disease model.
C1 [Raja, Adarshini] Augusta Univ, Med Coll Georgia, Augusta, GA USA.
   [Ganta, Vijay] Augusta Univ, Vasc Biol Ctr, Augusta, GA 30912 USA.
   [Ganta, Vijay] Augusta Univ, Dept Med, Augusta, GA USA.
C3 University System of Georgia; Augusta University; University System of
   Georgia; Augusta University; University System of Georgia; Augusta
   University
RP Ganta, V (corresponding author), Augusta Univ, Vasc Biol Ctr, Augusta, GA 30912 USA.
EM vganta@augusta.edu
OI Ganta, Vijay/0000-0002-2967-8320
FU National Institutes of Health [7R01HL146673-02]
FX This work was supported by National Institutes of Health
   -7R01HL146673-02 to V.C.G.
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NR 55
TC 2
Z9 2
U1 0
U2 0
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
EI 2047-9980
J9 J AM HEART ASSOC
JI J. Am. Heart Assoc.
PD OCT 15
PY 2024
VL 13
IS 20
AR e034304
DI 10.1161/JAHA.124.034304
PG 18
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA I8K7D
UT WOS:001332695300028
PM 39392159
DA 2025-04-10
ER

PT J
AU Hsu, PY
   Hsi, E
   Wang, TM
   Lin, RT
   Liao, YC
   Juo, SHH
AF Hsu, Po-Yuan
   Hsi, Edward
   Wang, Tzu-Ming
   Lin, Ruey-Tay
   Liao, Yi-Chu
   Juo, Suh-Hang H.
TI MicroRNA let-7g possesses a therapeutic potential for peripheral artery
   disease
SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
LA English
DT Article
DE microRNA let-7g; vascular endothelial growth factor-A; endothelial
   progenitor cells; peripheral artery disease; angiogenesis
ID ANGIOGENESIS; E2F1; NEOVASCULARIZATION; CONTRIBUTES; MODEL; P53
AB Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis and conveys a significant health burden globally. Critical limb ischaemia encompasses the most severe consequence of PAD. Our previous studies indicate that microRNA let-7g prevents atherosclerosis and improves endothelial functions. This study aimed to investigate whether and how let-7g therapy may improve blood flow to ischaemic limbs. The present study shows that let-7g has multiple pro-angiogenic effects on mouse ischaemic limb model and could be a potential therapeutic agent for PAD. Mice receiving intramuscular injection of let-7g had more neovascularization, better local perfusion and increased recruitment of endothelial progenitor cells after hindlimb ischaemia. The therapeutic effects of let-7g's on angiogenesis are mediated by multiple regulatory machinery. First, let-7g increased expression of vascular endothelial growth factor-A (VEGF-A) and VEGF receptor-2 (VEGFR-2) through targeting their upstream regulators HIF-3a and TP53. In addition, let-7g affected the splicing factor SC35 which subsequently enhanced the alternative splicing of VEGF-A from the anti- angiogenic isoform VEGF-A165b towards the pro-angiogenic isoform VEGF-A164a. The pleiotropic effects of let-7g on angiogenesis imply that let-7g may possess a therapeutic potential in ischaemic diseases.
C1 [Hsu, Po-Yuan; Hsi, Edward; Wang, Tzu-Ming; Juo, Suh-Hang H.] China Med Univ Hosp, Dept Med Res, Taichung, Taiwan.
   [Lin, Ruey-Tay; Juo, Suh-Hang H.] Kaohsiung Med Univ, Dept Neurol, Kaohsiung, Taiwan.
   [Liao, Yi-Chu] Natl Yang Ming Univ, Sch Med, Dept Neurol, Taipei, Taiwan.
   [Liao, Yi-Chu] Taipei Vet Gen Hosp, Dept Neurol, Taipei, Taiwan.
   [Juo, Suh-Hang H.] China Med Univ, Grad Inst Biomed Sci, Taichung, Taiwan.
C3 China Medical University Taiwan; China Medical University Hospital -
   Taiwan; Kaohsiung Medical University; National Yang Ming Chiao Tung
   University; Taipei Veterans General Hospital; China Medical University
   Taiwan
RP Juo, SHH (corresponding author), China Med Univ Hosp, Dept Med Res, Taichung, Taiwan.; Juo, SHH (corresponding author), Kaohsiung Med Univ, Dept Neurol, Kaohsiung, Taiwan.; Liao, YC (corresponding author), Natl Yang Ming Univ, Sch Med, Dept Neurol, Taipei, Taiwan.; Liao, YC (corresponding author), Taipei Vet Gen Hosp, Dept Neurol, Taipei, Taiwan.; Juo, SHH (corresponding author), China Med Univ, Grad Inst Biomed Sci, Taichung, Taiwan.
EM ycliao5@vghtpe.gov.tw; hjuo@mail.cmu.edu.tw
RI Hsi, Edward/A-1356-2013; Juo, Suh-Hang/C-9545-2009; Lin,
   Reuy-Tay/D-5288-2009
OI Liao, Yi-Chu/0000-0002-9644-2086
FU Ministry of Science and Technology (Taiwan, R.O.C.)
   [NSC102-2314-B-037-047-MY3, MOST103-2314-B-037-026-MY3,
   MOST103-2314-B-037-027-MY2, MOST103-2314-B-075076-MY3]; National Health
   Research Institutes (Taiwan, R.O.C.) [NHRI-Ex101-10107PI]
FX This work was supported by the following funding: Ministry of Science
   and Technology (Taiwan, R.O.C. NSC102-2314-B-037-047-MY3,
   MOST103-2314-B-037-026-MY3, MOST103-2314-B-037-027-MY2,
   MOST103-2314-B-075076-MY3), National Health Research Institutes (Taiwan,
   R.O.C. NHRI-Ex101-10107PI). In this manuscript, Hsu PY designed the
   research study, conducted experiments and prepared manuscript. His E
   performed the bioinformatics analysis. Wang TM helped experiments. Lin
   RT and Liao YC performed the data interpretation and manuscript
   preparation. Juo SH designed the study, supervised the progress,
   coordinated the experiments, interpreted the data and finalized
   manuscript.
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NR 29
TC 19
Z9 19
U1 0
U2 5
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1582-1838
EI 1582-4934
J9 J CELL MOL MED
JI J. Cell. Mol. Med.
PD MAR
PY 2017
VL 21
IS 3
BP 519
EP 529
DI 10.1111/jcmm.12997
PG 11
WC Cell Biology; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Research & Experimental Medicine
GA EP5KP
UT WOS:000397417700010
PM 27696675
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Ganta, VC
   Choi, M
   Kutateladze, A
   Annex, BH
AF Ganta, Vijay Chaitanya
   Choi, Min
   Kutateladze, Anna
   Annex, Brian H.
TI VEGF165b Modulates Endothelial VEGFR1-STAT3 Signaling Pathway
   and Angiogenesis in Human and Experimental Peripheral Arterial Disease
SO CIRCULATION RESEARCH
LA English
DT Article
DE alternative splicing; amputation; anti-angiogenic VEGF-A isoforms;
   ischemia; peripheral artery disease
ID GROWTH-FACTOR RECEPTOR-1; SKELETAL-MUSCLE; THERAPEUTIC ANGIOGENESIS;
   REGIONAL ANGIOGENESIS; PERFUSION RECOVERY; INHIBITORY ISOFORM; VEGF
   RECEPTOR-2; SPLICE VARIANT; BONE-MARROW; FACTOR-A
AB Rationale: Atherosclerotic-arterial occlusions decrease tissue perfusion causing ischemia to lower limbs in patients with peripheral arterial disease (PAD). Ischemia in muscle induces an angiogenic response, but the magnitude of this response is frequently inadequate to meet tissue perfusion requirements. Alternate splicing in the exon-8 of vascular endothelial growth factor (VEGF)-A results in production of proangiogenic VEGF(xxx)a isoforms (VEGF(165)a, 165 for the 165 amino acid product) and antiangiogenic VEGF(xxx)b (VEGF(165)b) isoforms.
   Objective: The antiangiogenic VEGF(xxx)b isoforms are thought to antagonize VEGF(xxx)a isoforms and decrease activation of VEGF receptor-2 (VEGFR2), hereunto considered the dominant receptor in postnatal angiogenesis in PAD. Our data will show that VEGF(165)b inhibits VEGFR1 signal transducer and activator of transcription (STAT)-3 signaling to decrease angiogenesis in human and experimental PAD.
   Methods and Results: In human PAD versus control muscle biopsies, VEGF(165)b: (1) is elevated, (2) is bound higher (versus VEGF(165)a) to VEGFR1 not VEGFR2, and (3) levels correlated with decreased VEGFR1, not VEGFR2, activation. In experimental PAD, delivery of an isoform-specific monoclonal antibody to VEGF(165)b versus control antibody enhanced perfusion in animal model of severe PAD (Balb/c strain) without activating VEGFR2 signaling but with increased VEGFR1 activation. Receptor pull-down experiments demonstrate that VEGF(165)b inhibition versus control increased VEGFR1-STAT3 binding and STAT3 activation, independent of Janus-activated kinase-1)/Janus-activated kinase-2. Using VEGFR1(+/-) mice that could not increase VEGFR1 after ischemia, we confirm that VEGF(165)b decreases VEGFR1-STAT3 signaling to decrease perfusion.
   Conclusions: Our results indicate that VEGF(165)b prevents activation of VEGFR1-STAT3 signaling by VEGF(165)a and hence inhibits angiogenesis and perfusion recovery in PAD muscle.
C1 [Ganta, Vijay Chaitanya; Choi, Min; Annex, Brian H.] Univ Virginia, Cardiovasc Res Ctr, Charlottesville, VA USA.
   [Kutateladze, Anna] Univ Virginia, Dept Biol, Charlottesville, VA USA.
   [Annex, Brian H.] Univ Virginia, Dept Cardiovasc Med, Charlottesville, VA USA.
C3 University of Virginia; University of Virginia; University of Virginia
RP Annex, BH (corresponding author), Univ Virginia Hlth Syst, Div Cardiovasc Med, Cardiovasc Res Ctr, POB 800158, Charlottesville, VA 22908 USA.
EM annex@virginia.edu
FU American Heart Association [16SDG30340002];  [1R01 HL116455];  [1R01
   HL121635];  [2R01 HL101200]; American Heart Association (AHA)
   [16SDG30340002] Funding Source: American Heart Association (AHA)
FX B.H. Annex is supported by 1R01 HL116455, 1R01 HL121635, and 2R01
   HL101200. V.C. Ganta thanks American Heart Association for scientist
   development grant 16SDG30340002.
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NR 55
TC 70
Z9 74
U1 0
U2 14
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7330
EI 1524-4571
J9 CIRC RES
JI Circ.Res.
PD JAN 20
PY 2017
VL 120
IS 2
BP 282
EP +
DI 10.1161/CIRCRESAHA.116.309516
PG 37
WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Hematology
GA EI1GY
UT WOS:000392226200012
PM 27974423
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Ganta, VC
   Choi, M
   Farber, CR
   Annex, BH
AF Ganta, Vijay Chaitanya
   Choi, Min
   Farber, Charles R.
   Annex, Brian H.
TI Antiangiogenic VEGF165b Regulates Macrophage Polarization via
   S100A8/S100A9 in Peripheral Artery Disease
SO CIRCULATION
LA English
DT Article
DE alternative splicing; intercellular signaling peptides and proteins;
   therapeutics; angiogenesis inducing agents; autocrine communication;
   paracrine communication; cell communication
ID ENDOTHELIAL GROWTH-FACTOR; THERAPEUTIC ANGIOGENESIS; REGIONAL
   ANGIOGENESIS; SKELETAL-MUSCLE; SPLICE VARIANT; FACTOR-A; VEGF; ISOFORM;
   S100A8/A9; PATHWAY
AB Background: Atherosclerotic occlusions decrease blood flow to the lower limbs, causing ischemia and tissue loss in patients with peripheral artery disease (PAD). No effective medical therapies are currently available to induce angiogenesis and promote perfusion recovery in patients with severe PAD. Clinical trials aimed at inducing vascular endothelial growth factor (VEGF)-A levels, a potent proangiogenic growth factor to induce angiogenesis, and perfusion recovery were not successful. Alternate splicing in the exon-8 of VEGF-A results in the formation of VEGFxxxa (VEGF(165)a) and VEGFxxxb (VEGF(165)b) isoforms with existing literature focusing on VEGF(165)b's role in inhibiting vascular endothelial growth factor receptor 2-dependent angiogenesis. However, we have recently shown that VEGF(165)b blocks VEGF-A-induced endothelial vascular endothelial growth factor receptor 1 (VEGFR1) activation in ischemic muscle to impair perfusion recovery. Because macrophage-secreted VEGF(165)b has been shown to decrease angiogenesis in peripheral artery disease, and macrophages were well known to play important roles in regulating ischemic muscle vascular remodeling, we examined the role of VEGF(165)b in regulating macrophage function in PAD.
   Methods: Femoral artery ligation and resection were used as an in vivo preclinical PAD model, and hypoxia serum starvation was used as an in vitro model for PAD. Experiments including laser-Doppler perfusion imaging, adoptive cell transfer to ischemic muscle, immunoblot analysis, ELISAs, immunostainings, flow cytometry, quantitative polymerase chain reaction analysis, and RNA sequencing were performed to determine a role of VEGF(165)b in regulating macrophage phenotype and function in PAD.
   Results: First, we found increased VEGF(165)b expression with increased M1-like macrophages in PAD versus non-PAD (controls) muscle biopsies. Next, using in vitro hypoxia serum starvation, in vivo preclinical PAD models, and adoptive transfer of VEGF(165)b-expressing bone marrow-derived macrophages or VEGFR1(+/-) bone marrow-derived macrophages (M1-like phenotype), we demonstrate that VEGF(165)b inhibits VEGFR1 activation to induce an M1-like phenotype that impairs ischemic muscle neovascularization. Subsequently, we found S100A8/S100A9 as VEGFR1 downstream regulators of macrophage polarization by RNA-Seq analysis of hypoxia serum starvation-VEGFR1(+/+) versus hypoxia serum starvation-VEGFR1(+/-) bone marrow-derived macrophages.
   Conclusions: In our current study, we demonstrate that increased VEGF(165)b expression in macrophages induces an antiangiogenic M1-like phenotype that directly impairs angiogenesis. VEGFR1 inhibition by VEGF(165)b results in S100A8/S100A9-mediated calcium influx to induce an M1-like phenotype that impairs ischemic muscle revascularization and perfusion recovery.
C1 [Ganta, Vijay Chaitanya; Choi, Min; Annex, Brian H.] Univ Virginia, Robert M Berne Cardiovasc Res Ctr, Charlottesville, VA USA.
   [Farber, Charles R.] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA.
   [Ganta, Vijay Chaitanya; Annex, Brian H.] Univ Virginia, Dept Med, Div Cardiovasc Med, Charlottesville, VA 22908 USA.
C3 University of Virginia; University of Virginia; University of Virginia
RP Ganta, VC (corresponding author), Univ Virginia, Dept Med, Div Cardiovasc Med, Charlottesville, VA 22908 USA.
EM vg6u@virginia.edu
FU American Heart Association Scientist Development Grant [16SDG30340002];
   National Institutes of Health [1R01 HL116455, 1R01 HL121635, 2R01
   HL101200]; American Heart Association (AHA) [16SDG30340002] Funding
   Source: American Heart Association (AHA)
FX This study was supported by an American Heart Association Scientist
   Development Grant 16SDG30340002 (to Dr Ganta) and National Institutes of
   Health grants 1R01 HL116455, 1R01 HL121635, and 2R01 HL101200 (to Dr
   Annex).
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NR 49
TC 77
Z9 82
U1 2
U2 21
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7322
EI 1524-4539
J9 CIRCULATION
JI Circulation
PD JAN 8
PY 2019
VL 139
IS 2
BP 226
EP 242
DI 10.1161/CIRCULATIONAHA.118.034165
PG 17
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA HM4FI
UT WOS:000459428700013
PM 30586702
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Nordon, I
   Brar, R
   Hinchliffe, R
   Cockerill, G
   Loftus, I
   Thompson, M
AF Nordon, Ian
   Brar, Ranjeet
   Hinchliffe, Robert
   Cockerill, Gillian
   Loftus, Ian
   Thompson, Matt
TI The role of proteomic research in vascular disease
SO JOURNAL OF VASCULAR SURGERY
LA English
DT Review
ID ABDOMINAL AORTIC-ANEURYSM; DIFFERENTIAL PROTEIN EXPRESSION; HUMAN
   ATHEROSCLEROTIC PLAQUES; PERIPHERAL ARTERIAL-DISEASE; ACUTE
   MYOCARDIAL-INFARCTION; HIGH-ABUNDANCE PROTEINS; SMOOTH-MUSCLE PROTEINS;
   INFLAMMATORY MARKERS; CARDIOVASCULAR-DISEASE; OVARIAN-CANCER
AB Introduction: Arterial diseases including atherosclerosis, intimal hyperplasia and aneurysms have been shown to be a product of genotype and environment. Gene expression pathways rely on protein translation to generate target effects. As a result of alternative splicing and post-translational modifications, one gene does not code for a single protein but for many. Proteomic studies allow quantification of these proteins in a biological system and determination of altered protein expression in disease. Proteomics is a powerful and expanding field of investigation which in combination with other 'omics may enhance understanding of disease pathophysiology and/or identify biomarkers of vascular disease. This review describes the methodology of protein mining and provides an insight into the valuable contributions already made by proteomics to vascular surgery.
   Methods. MEDLINE and EMBASE databases were searched for relevant articles.
   Results. 118 relevant articles were identified. These were subdivided into categories based on the aspect of protein research they reported. The subheadings include methodology, atherosclerosis, intimal hyperplasia, aortic disease and biomarkers.
   Conclusions: Disease processes classified as genetic are functionally proteomic. Equally disease pathophysiology is the result of, or leads to alterriate protein expression. Understanding the proteome will clarify the pathophysiology of disease. The translation of these findings to clinical practice impacts diagnosis, staging and treatment of disease processes. Biomarker discovery will enable earlier diagnosis of unstable atherosclerotic plaques, it will allow identification of aneurysms more likely to rupture and stratify risk. Proteomic research has enormous potential to modulate many aspects of patient care. (J Vasc Surg 2009;49:1602-12.)
C1 [Nordon, Ian; Brar, Ranjeet; Hinchliffe, Robert; Cockerill, Gillian; Loftus, Ian; Thompson, Matt] Univ London St Georges Hosp, St Georges Vasc Inst, London SW17 0QT, England.
C3 City St Georges, University of London; St Georges University London
RP Nordon, I (corresponding author), Univ London St Georges Hosp, St Georges Vasc Inst, 4th Floor,Blackshaw Rd, London SW17 0QT, England.
EM inordon@sgul.ac.uk
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NR 117
TC 19
Z9 20
U1 0
U2 8
PU MOSBY-ELSEVIER
PI NEW YORK
PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA
SN 0741-5214
J9 J VASC SURG
JI J. Vasc. Surg.
PD JUN
PY 2009
VL 49
IS 6
BP 1602
EP 1612
DI 10.1016/j.jvs.2009.02.242
PG 11
WC Surgery; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Surgery; Cardiovascular System & Cardiology
GA 454KO
UT WOS:000266681000037
PM 19497525
OA Bronze
DA 2025-04-10
ER

PT J
AU Stevens, M
   Star, E
   Lee, M
   Innes, E
   Li, L
   Bowler, E
   Harper, S
   Bates, DO
   Oltean, S
AF Stevens, M.
   Star, E.
   Lee, M.
   Innes, E.
   Li, L.
   Bowler, E.
   Harper, S.
   Bates, D. O.
   Oltean, S.
TI The VEGF-A exon 8 splicing-sensitive fluorescent reporter mouse is a
   novel tool to assess the effects of splicing regulatory compounds in
   vivo
SO RNA BIOLOGY
LA English
DT Article
DE Alternative splicing; vascular endothelial growth factor-A;
   splicing-sensitive fluorescent reporter; angiogenesis; mouse model
ID ENDOTHELIAL GROWTH-FACTOR; SRPK1 INHIBITORS; VEGF(165)B;
   VASCULARIZATION; FACTOR-A(165)B; PERMEABILITY; VEGF-A(165)B; ISOFORMS;
   BINDING; VARIANT
AB Vascular endothelial growth factor (VEGF)-A is differentially spliced to give two functionally different isoform families; pro-angiogenic, pro-permeability VEGF-A(xxx) and anti-angiogenic, anti-permeability VEGF-A(xxx)b. VEGF-A splicing is dysregulated in several pathologies, including cancer, diabetes, and peripheral arterial disease. The bichromatic VEGF-A splicing-sensitive fluorescent reporter harboured in a transgenic mouse is a novel approach to investigate the splicing patterns of VEGF-A in vivo. We generated a transgenic mouse harbouring a splicing-sensitive fluorescent reporter designed to mimic VEGF-A terminal exon splicing (VEGF8ab) by insertion into the ROSA26 genomic locus. dsRED expression denotes proximal splice site selection (VEGF-A(xxx)) and eGFP expression denotes distal splice site selection (VEGF-A(xxx)b). We investigated the tissue-specific expression patterns in the eye, skeletal muscle, cardiac muscle, kidney, and pancreas, and determined whether the splicing pattern could be manipulated in the same manner as endogenous VEGF-A by treatment with the SRPK1 inhibitor SPHINX 31. We confirmed expression of both dsRED and eGFP in the eye, skeletal muscle, cardiac muscle, kidney, and pancreas, with the highest expression of both fluorescent proteins observed in the exocrine pancreas. The ratio of dsRED and eGFP matched that of endogenous VEGF-A(xxx) and VEGF-A(xxx)b. Treatment of the VEGF8ab mice with SPHINX 31 increased the mRNA and protein eGFP/dsRED ratio in the exocrine pancreas, mimicking endogenous VEGF-A splicing. The VEGF-A exon 8 splicing-sensitive fluorescent reporter mouse is a novel tool to assess splicing regulation in the individual cell-types and tissues, which provides a useful screening process for potentially therapeutic splicing regulatory compounds in vivo
C1 [Stevens, M.; Innes, E.; Li, L.; Bowler, E.; Harper, S.; Oltean, S.] Univ Exeter, Inst Biomed & Clin Sci, Sch Med, Coll Med & Hlth, Exeter, Devon, England.
   [Star, E.; Lee, M.] Univ Bristol, Bristol Renal, Sch Clin Sci, Bristol, Avon, England.
   [Harper, S.] Univ Bristol, Sch Physiol Pharmacol & Neurosci, Bristol, Avon, England.
   [Bates, D. O.] Univ Nottingham, Canc Biol, Div Canc & Stem Cells, Sch Med, Nottingham, England.
C3 University of Exeter; University of Bristol; University of Bristol;
   University of Nottingham
RP Oltean, S (corresponding author), Univ Exeter, Inst Biomed & Clin Sci, Sch Med, Coll Med & Hlth, Exeter, Devon, England.
EM s.oltean@exeter.ac.uk
RI sTEVENS, Megan/GPT-0543-2022
OI Bates, David/0000-0003-4850-2360; stevens, megan/0000-0002-7474-6759;
   Oltean, Sebastian/0000-0001-7890-8439
FU BBSRC [BB/J007293/2]; British Heart Foundation [PG/15/53/31371];
   Diabetes UK [17/0005668]; Richard Bright VEGF Research Trust; BBSRC
   [BB/J007293/2, BB/P012035/1, BB/J007293/1] Funding Source: UKRI
FX Funding for this study was supported by grants to SO: BBSRC
   (BB/J007293/2), British Heart Foundation (PG/15/53/31371), Diabetes UK
   (17/0005668) and Richard Bright VEGF Research Trust.
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NR 33
TC 5
Z9 6
U1 0
U2 5
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 1547-6286
EI 1555-8584
J9 RNA BIOL
JI RNA Biol.
PD DEC 2
PY 2019
VL 16
IS 12
BP 1672
EP 1681
DI 10.1080/15476286.2019.1652522
EA AUG 2019
PG 10
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA JI4VQ
UT WOS:000482534400001
PM 31432737
OA hybrid, Green Published
DA 2025-04-10
ER

PT J
AU Enzmann, FK
   Metzger, P
   San Martin, JE
   Dabernig, W
   Akhavan, F
   Hölzenbein, T
   Nierlich, P
AF Enzmann, Florian K.
   Metzger, Peter
   Martin, Julio Ellacuriaga San
   Dabernig, Werner
   Akhavan, Fatema
   Holzenbein, Thomas
   Nierlich, Patrick
TI The Upper-Arm Basilic-Cephalic Loop: A Valueable Alternative for
   Below-Knee Arterial Reconstruction
SO VASCULAR AND ENDOVASCULAR SURGERY
LA English
DT Article
DE peripheral vein bypass; alternative vein bypass; arm vein; peripheral
   artery disease
AB Introduction:
   Despite advances of endovascular interventions, bypass surgery remains the gold standard for treatment of long and complex arterial occlusions in the lower limb. Autologous vein is regarded superior to other options. As the graft of first choice, the great saphenous vein (GSV) is often not available due to previous bypass, stripping or poor quality. Other options like arm veins (AV) are important alternatives. As forearm portions of AVs are often unusable, a graft created from the upper arm basilic and cephalic veins provides a valuable alternative.
   Patients and Methods:
   We analyzed consecutive patients treated at an academic tertiary referral center between 01/1998 and 07/2018 using arm veins as the main peripheral bypass graft. Study endpoints were primary patency, secondary patency, limb salvage and survival.
   Results:
   In the observed time period 2702 bypass procedures were performed at our institution for below-knee arterial reconstructions. Vein grafts used included the ipsilateral GSV (iGSV; n = 1937/71.7%), contralateral GSV (cGSV; 192/7.1%), small saphenous vein (SSV; 133/4.9%), prosthetic conduits (61/2.3%) and different configurations of AV (379/14%). In the majority of patients receiving AV grafts a complete continuous cephalic or basilic vein (CAV) was used (n = 292/77%). If it was not possible to use major parts of these 2 veins, either spliced arm vein grafts (SAV) (42/11%) or an upper arm basilic-cephalic loop graft (45/12%) were used. Median follow-up was 27 (interquartile range: 8-50) months. After 3 years secondary patency (CAV: 85%; SAV: 62%; loop: 66%; p = 0.125) and limb salvage rates (CAV: 79%, SAV: 68%; loop: 79%; p = 0.346) were similar between the 3 bypass options.
   Conclusion:
   The encouraging results of alternative AV configurations highlight their value in case the basilic or cephalic veins are not useable in continuity. Especially for infragenual redo-bypass procedures, these techniques should be considered to offer patients durable revascularization options.
C1 [Enzmann, Florian K.; Metzger, Peter; Martin, Julio Ellacuriaga San; Dabernig, Werner; Akhavan, Fatema; Holzenbein, Thomas; Nierlich, Patrick] Paracelsus Med Univ, Univ Hosp Salzburg, Dept Vasc & Endovasc Surg, Salzburg, Austria.
   [Metzger, Peter] Ao Bezirkskrankenhaus St Johan, Tyrol, Austria.
   [Holzenbein, Thomas] Sozialmed Zentrum Ost Donauspital, Dept Surg, Vienna, Austria.
   [Nierlich, Patrick] Med Univ Vienna, Hosp St John God, Dept Surg, Johannes von Gott Pl 1, A-1020 Vienna, Austria.
C3 Paracelsus Private Medical University; Donauspital; Medical University
   of Vienna
RP Nierlich, P (corresponding author), Med Univ Vienna, Hosp St John God, Dept Surg, Johannes von Gott Pl 1, A-1020 Vienna, Austria.
EM patrick.nierlich@meduniwien.ac.at
RI Enzmann, Florian K./U-6884-2019
OI Enzmann, Florian K./0000-0002-7200-4145
CR Aboyans V, 2018, REV ESP CARDIOL, V71, P111, DOI 10.1016/j.rec.2017.12.014
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NR 30
TC 0
Z9 0
U1 0
U2 0
PU SAGE PUBLICATIONS INC
PI THOUSAND OAKS
PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA
SN 1538-5744
EI 1938-9116
J9 VASC ENDOVASC SURG
JI Vasc. Endovasc. Surg.
PD MAY
PY 2021
VL 55
IS 4
BP 348
EP 354
AR 1538574420980610
DI 10.1177/1538574420980610
EA JAN 2021
PG 7
WC Surgery; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Surgery; Cardiovascular System & Cardiology
GA RL0OO
UT WOS:000628944400001
PM 33478360
DA 2025-04-10
ER

PT J
AU Joyce, W
   He, K
   Zhang, MD
   Ogunsola, S
   Wu, XN
   Joseph, KT
   Bogomolny, D
   Yu, WH
   Springer, MS
   Xie, JY
   Signore, AV
   Campbell, KL
AF Joyce, William
   He, Kai
   Zhang, Mengdie
   Ogunsola, Samuel
   Wu, Xini
   Joseph, Kelvin T.
   Bogomolny, David
   Yu, Wenhua
   Springer, Mark S.
   Xie, Jiuyong
   Signore, Anthony V.
   Campbell, Kevin L.
TI Genetic excision of the regulatory cardiac troponin I extension in
   high-heart rate mammal clades
SO SCIENCE
LA English
DT Article
ID N-TERMINAL EXTENSION; STRIATED-MUSCLE; PHOSPHORYLATION; METABOLISM;
   PROTEINS; BINDING; MOLE; TEMPERATURE; SENSITIVITY; MYOCARDIUM
AB Mammalian cardiac troponin I (cTnI) contains a highly conserved amino-terminal extension harboring protein kinase A targets [serine-23 and -24 (Ser(23/24))] that are phosphorylated during beta-adrenergic stimulation to defend diastolic filling by means of an increased cardiomyocyte relaxation rate. In this work, we show that the Ser(23/24)-encoding exon 3 of TNNI3 was pseudoexonized multiple times in shrews and moles to mimic Ser(23/24) phosphorylation without adrenergic stimulation, facilitating the evolution of exceptionally high resting heart rates (similar to 1000 beats per minute). We further reveal alternative exon 3 splicing in distantly related bat families and confirm that both cTnI splice variants are incorporated into cardiac myofibrils. Because exon 3 of human TNNI3 exhibits a relatively low splice strength score, our findings offer an evolutionarily informed strategy to excise this exon to improve diastolic function during heart failure.
C1 [Joyce, William] Aarhus Univ, Dept Biol Zoophysiol, DK-8000 Aarhus C, Denmark.
   [Joyce, William] Univ Manchester, Div Cardiovasc Sci, Fac Biol Med & Hlth, Manchester M13 9PL, England.
   [He, Kai; Zhang, Mengdie; Wu, Xini; Yu, Wenhua] Guangzhou Univ, Sch Life Sci, Key Lab Conservat & Applicat Biodivers South China, Guangzhou 510006, Guangdong, Peoples R China.
   [Ogunsola, Samuel; Xie, Jiuyong] Univ Manitoba, Dept Physiol & Pathophysiol, Winnipeg, MB R3E 0J9, Canada.
   [Joseph, Kelvin T.; Bogomolny, David; Signore, Anthony V.; Campbell, Kevin L.] Univ Manitoba, Dept Biol Sci, Winnipeg, MB R3T 2N2, Canada.
   [Springer, Mark S.] Univ Calif Riverside, Dept Evolut Ecol & Organismal Biol, Riverside, CA 92521 USA.
   [Joyce, William] Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid 28029, Spain.
   [Signore, Anthony V.] Natl Ctr Foreign Anim Dis, Winnipeg, MB R3E 3M4, Canada.
C3 Aarhus University; University of Manchester; Guangzhou University;
   University of Manitoba; University of Manitoba; University of California
   System; University of California Riverside; Centro Nacional de
   Investigaciones Cardiovasculares (CNIC)
RP Joyce, W (corresponding author), Aarhus Univ, Dept Biol Zoophysiol, DK-8000 Aarhus C, Denmark.; Joyce, W (corresponding author), Univ Manchester, Div Cardiovasc Sci, Fac Biol Med & Hlth, Manchester M13 9PL, England.; Campbell, KL (corresponding author), Univ Manitoba, Dept Biol Sci, Winnipeg, MB R3T 2N2, Canada.; Joyce, W (corresponding author), Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid 28029, Spain.
EM william.joyce@bio.au.dk; kevin.campbell@umanitoba.ca
RI Joyce, William/U-7093-2019; Xie, Jiuyong/D-2899-2013
OI Signore, Anthony/0000-0002-0664-0864; Joyce,
   William/0000-0002-3782-1641; Xie, Jiuyong/0000-0003-2909-1033; Yu,
   Wenhua/0000-0001-5226-7725
FU Novo Nordisk Foundation [NNF19OC0055842]; Guangdong Natural Science
   Funds for Distinguished Young Scholars [2022B1515020033]; National
   Natural Science Foundation of China [32170452]; University of Manitoba
   Faculty of Science Undergraduate Research Award; Vanier Canada Graduate
   Scholarship [FRN-CGV-186989]; National Sciences and Engineering Research
   Council (NSERC) of Canada Discovery [RGPIN-2022-05023]; NSERC of Canada
   Discovery [RGPIN-2016-06562]
FX This work was funded by Novo Nordisk Foundation grant NNF19OC0055842
   (W.J.), Guangdong Natural Science Funds for Distinguished Young Scholars
   2022B1515020033 (K.H.), National Natural Science Foundation of China
   grant 32170452 (K.H.), a University of Manitoba Faculty of Science
   Undergraduate Research Award (D.B., K.T.J.), Vanier Canada Graduate
   Scholarship FRN-CGV-186989 (S.O.), National Sciences and Engineering
   Research Council (NSERC) of Canada Discovery grant RGPIN-2022-05023
   (J.X.), and NSERC of Canada Discovery grant RGPIN-2016-06562 (K.L.C.).
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NR 90
TC 2
Z9 2
U1 20
U2 22
PU AMER ASSOC ADVANCEMENT SCIENCE
PI WASHINGTON
PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA
SN 0036-8075
EI 1095-9203
J9 SCIENCE
JI Science
PD SEP 27
PY 2024
VL 385
IS 6716
BP 1466
EP 1471
DI 10.1126/science.adi8146
PG 6
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA Y6W1Q
UT WOS:001433491400006
PM 39325895
DA 2025-04-10
ER

PT J
AU Kim, Y
   Loanzon, RS
   Southerland, KW
   Long, CA
   Williams, ZF
   Mohapatra, A
AF Kim, Young
   Loanzon, Roberto S.
   Southerland, Kevin W.
   Long, Chandler A.
   Williams, Zachary F.
   Mohapatra, Abhisekh
TI Prosthetic Conduit Use Does Not Adversely Impact Outcomes after Open
   Repair of Popliteal Artery Aneurysms
SO ANNALS OF VASCULAR SURGERY
LA English
DT Article
ID REVERSED VEIN BYPASS; SAPHENOUS-VEIN; ISCHEMIA; DISEASE
AB Background: Single segment, greater saphenous vein (GSV) conduit is considered the optimal bypass conduit among patients undergoing bypass surgery for peripheral artery disease (PAD). While this data has been extrapolated to patients undergoing bypass for popliteal artery aneurysms (PAAs), the pathophysiology of PAA is inherently different when compared to PAD, and the impact of conduit type on long-term outcomes after open repair of PAA remains unclear.Methods: A multicenter database of five regional hospitals was retrospectively reviewed for all patients with PAA undergoing open surgical repair. Data were collected on demographic information, operative details, medications, and postoperative outcomes. Kaplan-Meier curves were used to compare freedom from major adverse limb events (MALE) following GSV versus prosthetic bypass. Cox proportional hazards model was used to identify patient-level characteristics associated with MALE, which was defined as major ipsilateral limb amputation or reintervention for graft patency.Results: From 1999 to 2020, a total of 101 patients with PAA underwent open exclusion and bypass surgery. Median follow-up period was 4.2 years (interquartile range, 1.3-7.4 years), and complete data were available for 99 (98.0%) patients. The majority of patients were male (99.0%) and Caucasian (93.9%). Only 11.1% of procedures were emergent, with the remainder (88.9%) being elective. All patients underwent medial exposure with a below-knee popliteal bypass target (100%). Bypass conduits included GSV (69.7%), prosthetic conduit (28.3%), and 2 (2.0%) alternative conduits (one spliced arm vein, one cryopreserved vein). Patients undergoing prosthetic bypass were older (72 vs. 66 years, P = 0.001) and had similar rates of medical comorbidities. Compared with the GSV group, patients with prosthetic conduits were more frequently placed on postoperative anticoagulation (60.7% vs. 23.2%, P < 0.001). Conduit type did not impact postoperative complication rates (P = NS each). MALE rates were low overall (19.2% at 2 years), and similar when stratified by conduit type (log rank P = 0.47). On multivariable analysis, emergent bypass was associated with MALE (hazard ratio [HR] 5.73, 95% confidence interval [CI] 2.07-15.85, P < 0.001). Prosthetic conduit usage (HR 1.00, 95% CI, 0.402.51, P = 0.99) and postoperative anticoagulation (HR 1.02, 95% CI 0.42-2.50, P = 0.97) were not associated with MALE.Conclusions: Open repair of PAA is associated with excellent long-term outcomes. Prosthetic bypass is a comparable alternative to autogenous conduit for below-knee popliteal bypass tar-gets, and lack of suitable GSV should not prohibit open surgical repair when indicated.
C1 [Kim, Young; Loanzon, Roberto S.; Southerland, Kevin W.; Long, Chandler A.; Williams, Zachary F.] Duke Univ, Dept Surg, Div Vasc & Endovasc Surg, Durham, NC USA.
   [Mohapatra, Abhisekh] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Div Vasc & Endovasc Surg, Boston, MA USA.
   [Kim, Young] Duke Univ, Div Vasc & Endovasc Surg, Surg, Med Ctr, 2301 Erwin Rd, Durham, NC 27710 USA.
C3 Duke University; Harvard University; Harvard University Medical
   Affiliates; Massachusetts General Hospital; Harvard Medical School; Duke
   University
RP Kim, Y (corresponding author), Duke Univ, Div Vasc & Endovasc Surg, Surg, Med Ctr, 2301 Erwin Rd, Durham, NC 27710 USA.
EM y.kim@duke.edu
RI Chen, Jerry/KMX-1547-2024; Mohapatra, Abhisekh/ABD-5171-2020
OI Kim, Young/0000-0001-8763-8813
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NR 23
TC 0
Z9 0
U1 1
U2 1
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA STE 800, 230 PARK AVE, NEW YORK, NY 10169 USA
SN 0890-5096
EI 1615-5947
J9 ANN VASC SURG
JI Ann. Vasc. Surg.
PD JAN
PY 2024
VL 98
BP 124
EP 130
DI 10.1016/j.avsg.2023.08.041
EA DEC 2023
PG 7
WC Surgery; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Surgery; Cardiovascular System & Cardiology
GA DZ4M5
UT WOS:001135903400001
PM 37858670
DA 2025-04-10
ER

PT J
AU Nelson, OL
   Robbins, CT
   Wu, YM
   Granzier, H
AF Nelson, O. Lynne
   Robbins, Charles T.
   Wu, Yiming
   Granzier, Henk
TI Titin isoform switching is a major cardiac adaptive response in
   hibernating grizzly bears
SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
LA English
DT Article
DE collagen; bradycardia; diastolic function; echocardiography
ID DILATED CARDIOMYOPATHY; MYOCARDIAL STIFFNESS; COLLAGEN-METABOLISM;
   DIASTOLIC FUNCTION; GROUND-SQUIRREL; MUSCLE; HEART; EXPRESSION; BLOCK;
   RATS
AB The hibernation phenomenon captures biological as well as clinical interests to understand how organs adapt. Here we studied how hibernating grizzly bears (Ursus arctos horribilis) tolerate extremely low heart rates without developing cardiac chamber dilation. We evaluated cardiac filling function in unanesthetized grizzly bears by echocardiography during the active and hibernating period. Because both collagen and titin are involved in altering diastolic function, we investigated both in the myocardium of active and hibernating grizzly bears. Heart rates were reduced from 84 beats/min in active bears to 19 beats/min in hibernating bears. Diastolic volume, stroke volume, and left ventricular ejection fraction were not different. However, left ventricular muscle mass was significantly lower (300 +/- 12 compared with 402 +/- 14 g; P = 0.003) in the hibernating bears, and as a result the diastolic volume-to-left ventricular muscle mass ratio was significantly greater. Early ventricular filling deceleration times (106.4 +/- 14 compared with 143.2 +/- 20 ms; P = 0.002) were shorter during hibernation, suggesting increased ventricular stiffness. Restrictive pulmonary venous flow patterns supported this conclusion. Collagen type I and III comparisons did not reveal differences between the two groups of bears. In contrast, the expression of titin was altered by a significant upregulation of the stiffer N2B isoform at the expense of the more compliant N2BA isoform. The mean ratio of N2BA to N2B titin was 0.73 +/- 0.07 in the active bears and decreased to 0.42 +/- 0.03 (P = 0.006) in the hibernating bears. The upregulation of stiff N2B cardiac titin is a likely explanation for the increased ventricular stiffness that was revealed by echocardiography, and we propose that it plays a role in preventing chamber dilation in hibernating grizzly bears. Thus our work identified changes in the alternative splicing of cardiac titin as a major adaptive response in hibernating grizzly bears.
C1 [Nelson, O. Lynne] Washington State Univ, Diplomate ACVIM Internal Med & Cardiol, Coll Vet Med, Pullman, WA 99164 USA.
   [Robbins, Charles T.] Washington State Univ, Sch Biol Sci, Pullman, WA 99164 USA.
   [Robbins, Charles T.] Washington State Univ, Dept Nat Resource Sci, Pullman, WA 99164 USA.
   [Granzier, Henk] Univ Arizona, Dept Mol & Cellular Biol, Mol Cardiovasc Res Program, Tucson, AZ 85721 USA.
C3 Washington State University; Washington State University; Washington
   State University; University of Arizona
RP Nelson, OL (corresponding author), Washington State Univ, Diplomate ACVIM Internal Med & Cardiol, Coll Vet Med, 100 Grimes Way,Rm 17, Pullman, WA 99164 USA.
EM olnelson@vetmed.wsu.edu
FU NHLBI NIH HHS [HL-062881] Funding Source: Medline
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NR 45
TC 37
Z9 43
U1 0
U2 11
PU AMER PHYSIOLOGICAL SOC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0363-6135
J9 AM J PHYSIOL-HEART C
JI Am. J. Physiol.-Heart Circul. Physiol.
PD JUL
PY 2008
VL 295
IS 1
BP H366
EP H371
DI 10.1152/ajpheart.00234.2008
PG 6
WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Physiology
GA 325MU
UT WOS:000257593800044
PM 18502907
OA Green Published
DA 2025-04-10
ER

PT J
AU Mehta, Z
   Touma, M
AF Mehta, Zubin
   Touma, Marlin
TI Post-Transcriptional Modification by Alternative Splicing and Pathogenic
   Splicing Variants in Cardiovascular Development and Congenital Heart
   Defects
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Review
DE posttranscriptional modification; alternative splicing; congenital heart
   defects; transcriptome; splicing variants; genome
ID RNA-BINDING PROTEINS; GENE; SWITCH; RBM24; EXON; IDENTIFICATION;
   TRANSCRIPTOME; EXPRESSION; MECHANISM; TITIN
AB Advancements in genomics, bioinformatics, and genome editing have uncovered new dimensions in gene regulation. Post-transcriptional modifications by the alternative splicing of mRNA transcripts are critical regulatory mechanisms of mammalian gene expression. In the heart, there is an expanding interest in elucidating the role of alternative splicing in transcriptome regulation. Substantial efforts were directed toward investigating this process in heart development and failure. However, few studies shed light on alternative splicing products and their dysregulation in congenital heart defects (CHDs). While elegant reports showed the crucial roles of RNA binding proteins (RBPs) in orchestrating splicing transitions during heart development and failure, the impact of RBPs dysregulation or genetic variation on CHDs has not been fully addressed. Herein, we review the current understanding of alternative splicing and RBPs' roles in heart development and CHDs. Wediscuss the impact of perinatal splicing transition and its dysregulation in CHDs. We further summarize the discoveries made of causal splicing variants in key transcription factors that are implicated in CHDs. An improved understanding of the roles of alternative splicing in heart development and CHDs may potentially inform novel preventive and therapeutic advancements for newborn infants with CHDs.
C1 [Mehta, Zubin; Touma, Marlin] Univ Calif Los Angeles, David Geffen Sch Med, Neonatal Congenital Heart Lab, Los Angeles, CA 90095 USA.
   [Mehta, Zubin; Touma, Marlin] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA.
   [Mehta, Zubin; Touma, Marlin] Univ Calif Los Angeles, Childrens Discovery & Innovat Inst, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA.
   [Mehta, Zubin; Touma, Marlin] Univ Calif Los Angeles, Eli & Edythe Broad Stem Cell Res Ctr, David Geffen Sch Med, Los Angeles, CA 90095 USA.
C3 University of California System; University of California Los Angeles;
   University of California Los Angeles Medical Center; David Geffen School
   of Medicine at UCLA; University of California System; University of
   California Los Angeles; University of California Los Angeles Medical
   Center; David Geffen School of Medicine at UCLA; University of
   California System; University of California Los Angeles; University of
   California Los Angeles Medical Center; David Geffen School of Medicine
   at UCLA; University of California System; University of California Los
   Angeles; University of California Los Angeles Medical Center; David
   Geffen School of Medicine at UCLA
RP Touma, M (corresponding author), Univ Calif Los Angeles, David Geffen Sch Med, Neonatal Congenital Heart Lab, Los Angeles, CA 90095 USA.; Touma, M (corresponding author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA.; Touma, M (corresponding author), Univ Calif Los Angeles, Childrens Discovery & Innovat Inst, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA.; Touma, M (corresponding author), Univ Calif Los Angeles, Eli & Edythe Broad Stem Cell Res Ctr, David Geffen Sch Med, Los Angeles, CA 90095 USA.
EM mtouma@mednet.ucla.edu
OI Touma, MD, PhD, Marlin/0000-0002-2827-4068
FU NIH/NHLBI [1R01 HL153853-01]; Department of Defense-Congressionally
   Directed Medical Research Programs [W81XWH-18-1-0164]; 2022 UCLA
   Academic Senate Faculty Research Fund; 2021 UCLA Broad Stem Cell
   Research Center (BSCRC) T32 Training grant; National Heart Lung and
   Blood Institute [R01HL153853] Funding Source: NIH RePORTER
FX This work was supported by the 2021 UCLA Broad Stem Cell Research Center
   (BSCRC) T32 Training grant (Z.M.) and grants from NIH/NHLBI 1R01
   HL153853-01 (M.T.), the Department of Defense-Congressionally Directed
   Medical Research Programs W81XWH-18-1-0164 (M.T.), and the 2022 UCLA
   Academic Senate Faculty Research Fund (M.T.).
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NR 88
TC 5
Z9 6
U1 1
U2 7
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD JAN
PY 2023
VL 24
IS 2
AR 1555
DI 10.3390/ijms24021555
PG 15
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA 8C3RF
UT WOS:000917529100001
PM 36675070
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Nagasawa, CK
   Kibiryeva, N
   Marshall, J
   O'Brien, JE
   Bittel, DC
AF Nagasawa, Chloe K.
   Kibiryeva, Nataliya
   Marshall, Jennifer
   O'Brien, James E., Jr.
   Bittel, Douglas C.
TI scaRNA1 Levels Alter Pseudouridylation in Spliceosomal RNA U2 Affecting
   Alternative mRNA Splicing and Embryonic Development
SO PEDIATRIC CARDIOLOGY
LA English
DT Article
DE Congenital heart defects; Spliceosomal RNAs; Pseudouridylation;
   Embryonic development; Tetralogy of fallot
ID CONGENITAL HEART-DISEASE; GENETICS
AB The heart is the first major organ to develop during embryogenesis and must receive proper spatiotemporal signaling for proper development. Failure of proper signaling between the first and second heart fields at twenty days gestation contributes to the generation of a congenital heart defect. The most common cyanotic congenital heart defect is tetralogy of Fallot (TOF) which requires surgical intervention in the first year of life. In right ventricular tissue of infants born with TOF, the levels of scaRNA1 are reduced and mRNA splicing is dysregulated. In this study, we investigate a method of quantifying pseudouridylation levels in relation to scaRNA1 levels in spliceosomal RNA U2 in three different groups of samples: right ventricular (RV) tissue of infants born with TOF versus RV tissue from normally developing infants, scaRNA1 knockdown in primary normal cardiomyocytes derived from normally developing infants, and scaRNA1 overexpression in primary cells derived from RV tissue from infants born with TOF. We hypothesize that the amount of pseudouridylation is dependent on scaRNA1 level, compromising spliceosomal function and therefore, contributing to the generation of a congenital heart defect. Our results revealed a statistically significant decrease of pseudouridylation levels in the right ventricular tissue of infants born with TOF compared to the controls. Knocking down the scaRNA1 levels in normal primary cardiomyocytes resulted in a statistically significant decrease of pseudouridylation. Finally, an overexpression of scaRNA1 in TOF primary cells resulted in an increase in pseudouridylation levels, but it did not achieve statistical significance. Our previous research provided an association between scaRNA levels, alternative splicing, and development. Here, we demonstrate that pseudouridylation levels in spliceosomal RNA U2 is dependent on the expression level of scaRNA1. Although further investigation is needed, we believe that scaRNA expression regulates biochemical modifications to spliceosomal RNAs, adjusting the fidelity of the spliceosome, allowing for controlled alternative splicing of mRNA that is important in embryonic development. If validated, this is an underappreciated mechanism that is critical for regulating proper embryonic development.
C1 [Nagasawa, Chloe K.; Bittel, Douglas C.] Kansas City Univ Med & Biosci, Kansas City, MO 64106 USA.
   [Kibiryeva, Nataliya; Marshall, Jennifer; O'Brien, James E., Jr.] Childrens Mercy Hosp, Ward Family Heart Ctr, Kansas City, MO 64108 USA.
C3 Kansas City University; Children's Mercy Hospital
RP Bittel, DC (corresponding author), Kansas City Univ Med & Biosci, Kansas City, MO 64106 USA.
EM cknagasa@utmb.edu; nkibiryeva@cmh.edu; jamarshall@cmh.edu;
   jobrien@cmh.edu; dbittel@kcumb.edu
FU Kansas City University of Medicine and Biosciences Intramural Grant
FX This research was supported by Kansas City University of Medicine and
   Biosciences Intramural Grant.
CR Adachi Hironori, 2014, World J Biol Chem, V5, P398, DOI 10.4331/wjbc.v5.i4.398
   Antonicka H, 2017, EMBO REP, V18, P28, DOI 10.15252/embr.201643391
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NR 13
TC 15
Z9 15
U1 0
U2 4
PU SPRINGER
PI NEW YORK
PA ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES
SN 0172-0643
EI 1432-1971
J9 PEDIATR CARDIOL
JI Pediatr. Cardiol.
PD FEB
PY 2020
VL 41
IS 2
BP 341
EP 349
DI 10.1007/s00246-019-02263-4
PG 9
WC Cardiac & Cardiovascular Systems; Pediatrics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Pediatrics
GA KU2ID
UT WOS:000519531100016
PM 31953571
DA 2025-04-10
ER

PT J
AU Pramfalk, C
   Pedrelli, M
   Parini, P
AF Pramfalk, Camilla
   Pedrelli, Matteo
   Parini, Paolo
TI Role of thyroid receptor β in lipid metabolism
SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
LA English
DT Review
DE Thyroid receptor; Thyroid hormone; Cholesterol; Triglyceride;
   Atherosclerosis; Reverse cholesterol transport
ID HIGH-DENSITY-LIPOPROTEIN; BILE-ACID SYNTHESIS; APOLIPOPROTEIN-A-I;
   HEPATIC CHOLESTEROL 7-ALPHA-HYDROXYLASE; CORONARY-HEART-DISEASE;
   MESSENGER-RNA LEVELS; HMG-COA REDUCTASE; HORMONE RECEPTOR; SERUM-LIPIDS;
   IODOTHYRONINE DEIODINASE
AB Thyroid hormones (THs) exert their actions by binding to thyroid hormone receptors (TRs) and thereby affect tissue differentiation, development, and metabolism in most tissues. TH-deficiency creates a less favorable lipid profile (e.g. increased plasma cholesterol levels), whereas TH-excess is associated with both positive (e.g. reduced plasma cholesterol levels) and negative (e.g. increased heart rate) effects. TRs are encoded by two genes, THRA and THRB, which, by alternative splicing, generate several isoforms (e.g. TR alpha 1, TR alpha 2, TR beta 1, and TR beta 2).TR alpha, the major TR in the heart, is crucial for heart rate and for cardiac contractility and relaxation, whereas TR beta 1, the major TR in the liver, is important for lipid metabolism. Selective modulation of TR beta 1 is thus considered as a potential therapeutic target to treat dyslipidemia without cardiac side effects. Several selective TH analogs have been tested in preclinical studies with promising results, but only a few of these compounds have so far been tested in clinical studies. This review focuses on the role of THs. TRs, and selective and non-selective TH analogs in lipid metabolism. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease. (C) 2011 Elsevier B.V. All rights reserved.
C1 [Parini, Paolo] Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Lab Med, Div Clin Chem, S-14186 Stockholm, Sweden.
   Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Biosci & Nutr, Ctr Nutr & Toxicol,Mol Nutr Unit,NOVUM, S-14186 Stockholm, Sweden.
C3 Karolinska Institutet; Karolinska University Hospital; Karolinska
   Institutet; Karolinska University Hospital
RP Parini, P (corresponding author), Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Lab Med, Div Clin Chem, C1-74, S-14186 Stockholm, Sweden.
EM paolo.parini@ki.se
OI Pedrelli, Matteo/0000-0003-0771-0569; Parini, Paolo/0000-0002-6541-8542;
   Pramfalk, Camilla/0000-0003-4928-1256
FU Swedish Research Council; Swedish Heart-Lung Foundation; Stockholm City
   Council; Karolinska Institutet; Karo Bio Research Foundation
FX This work was supported by grants from the Swedish Research Council,
   from the Swedish Heart-Lung Foundation, the Stockholm City Council, and
   the Karolinska Institutet. Paolo Parini is recipient of research grants
   from the Karo Bio Research Foundation.
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NR 126
TC 48
Z9 56
U1 1
U2 17
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0925-4439
EI 1879-260X
J9 BBA-MOL BASIS DIS
JI Biochim. Biophys. Acta-Mol. Basis Dis.
PD AUG
PY 2011
VL 1812
IS 8
SI SI
BP 929
EP 937
DI 10.1016/j.bbadis.2010.12.019
PG 9
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA 787BA
UT WOS:000292350400015
PM 21194564
OA Bronze
DA 2025-04-10
ER

PT J
AU Fardoun, M
   Dehaini, H
   Kamar, A
   Bitar, F
   Majdalani, M
   El-Rassi, I
   Nemer, G
   Arabi, M
AF Fardoun, Manal
   Dehaini, Hassan
   Kamar, Amina
   Bitar, Fadi
   Majdalani, Marianne
   El-Rassi, Issam
   Nemer, Georges
   Arabi, Mariam
TI A Novel Somatic Variant in HEY2 Unveils an Alternative Splicing Isoform
   Linked to Ventricular Septal Defect
SO PEDIATRIC CARDIOLOGY
LA English
DT Article
DE Congenital heart defects; Ventricular septal defect; Cardiac
   transcription factors; HEY2; Mutation
ID CONGENITAL HEART-DEFECTS; MUTATIONS; DISEASE; RNA; PREVALENCE;
   MORTALITY; INFANTS; GENE
AB Congenital heart defects (CHDs) are the leading cause of death in infants under 1year of age. Aberrations in the expression and function of cardiac transcription factors (TFs) are a major contributor to CHDs. Despite the numerous studies undertaken to functionally characterize these TFs, their exact role in different stages of cardiogenesis is still not fully elucidated. Here we focused on HEY2, a basic helix loop helix transcriptional repressor, and its potential role in human ventricular septal defects. Genetic analysis was performed based on sequencing of DNA and cDNA obtained from post-operational cardiac tissues and blood of 17 Lebanese patients with various CHDs. The screen covered the entire coding regions of the GATA4, NKX2.5, TBX5, TBX20 and HEY2 genes. Our results revealed two novel somatic mutations, namely p.Ala229Thr and p.161_190 del, affecting HEY2 in the diseased cardiac tissues of two patients with VSD. These results suggest a potential role of HEY2 in regulating ventricular septation in humans.
C1 [Fardoun, Manal; Nemer, Georges] Amer Univ Beirut, Dept Biochem & Mol Genet, Beirut, Lebanon.
   [Dehaini, Hassan; Kamar, Amina] Amer Univ Beirut, Dept Biol, Beirut, Lebanon.
   [Bitar, Fadi; Majdalani, Marianne; Arabi, Mariam] Amer Univ Beirut, Dept Pediat & Adolescent Med, Beirut, Lebanon.
   [El-Rassi, Issam] Amer Univ Beirut, Dept Surg, Beirut, Lebanon.
C3 American University of Beirut; American University of Beirut; American
   University of Beirut; American University of Beirut
RP Arabi, M (corresponding author), Amer Univ Beirut, Dept Pediat & Adolescent Med, Beirut, Lebanon.
EM ma81@aub.edu.lb
RI Rassi, Issam/AAE-2456-2019; Nemer, Georges/ABB-5117-2020
OI Arabi, Mariam/0000-0001-6895-1580; KAMAR, AMINA/0000-0002-9045-6452; El
   Rassi, issam/0000-0003-3850-8769
FU MPP/URB Grant from the American University of Beirut
FX We thank all patients for their participation in the study. Special
   thanks to Mrs. Inaam El-Rassy in the Molecular Core facility for Sanger
   sequencing. This work was supported by an MPP/URB Grant from the
   American University of Beirut.
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NR 23
TC 8
Z9 10
U1 1
U2 6
PU SPRINGER
PI NEW YORK
PA 233 SPRING ST, NEW YORK, NY 10013 USA
SN 0172-0643
EI 1432-1971
J9 PEDIATR CARDIOL
JI Pediatr. Cardiol.
PD JUN
PY 2019
VL 40
IS 5
BP 1084
EP 1091
DI 10.1007/s00246-019-02099-y
PG 8
WC Cardiac & Cardiovascular Systems; Pediatrics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Pediatrics
GA HZ5GB
UT WOS:000468878600027
PM 30955100
DA 2025-04-10
ER

PT J
AU Sun, ZC
   Wang, LL
   Kong, YF
   Sun, JC
   Kang, B
AF Sun, Zhicheng
   Wang, Linlong
   Kong, Yefu
   Sun, Jiachen
   Kang, Bin
TI Transcriptional regulation and alternative splicing reveal the molecular
   strategies of Bombay duck Harpadon nehereus to hypoxia
SO FISHERIES SCIENCE
LA English
DT Article
DE Transcriptome; Adaptive radiation; Dissolved oxygen; Marine fish;
   RNA-Seq
ID OXYGEN DEPLETION; EXPRESSION; RESPONSES; TOLERANCE; INSIGHTS; HAMILTON;
   PACKAGE; PATHWAY; WATERS; CHINA
AB Bombay duck Harpodon nehereus has undergone a dramatic shift from a by-catch fish species to the dominant species in the southeast coast of China. This shift has led to economic growth in the fishery and has had a significant impact on community structure, biodiversity, and resource competition in the ecosystem. Strong hypoxia tolerance may be one of the contributing factors for its population growth. This study compared the transcriptional regulation and alternative splicing in H. nehereus from the normoxic and hypoxic zone near the Yangtze Estuary. Compared with normoxia, the number of alternative splicing events increased in the gill and heart but decreased in the muscle after hypoxia, among which exon skipping was the most prevalent type in different tissues. Enrichment analysis showed that differentially expressed genes and genes with differentially alternative exons were mainly enriched in transmembrane transport and glycerophospholipid metabolic process in gill, cell cycle, and FoxO signaling pathway in heart, as well as cell cycle and reduced metabolic rate in muscle. Key candidate genes may be associated with gill remodeling, elevated heart rate, and muscle angiogenesis function. This study provides valuable genetic clues for evaluating molecular regulation strategies related to hypoxia tolerance in marine fishes.
C1 [Sun, Zhicheng; Wang, Linlong; Kang, Bin] Ocean Univ China, Key Lab Mariculture, Minist Educ, Qingdao 266003, Shandong, Peoples R China.
   [Sun, Zhicheng; Wang, Linlong; Kang, Bin] Ocean Univ China, Fisheries Coll, Qingdao 266003, Shandong, Peoples R China.
   [Kong, Yefu] Liaoning Ocean & Fisheries Sci Res Inst, Dalian 116023, Liaoning, Peoples R China.
   [Sun, Jiachen] Ocean Univ China, Coll Marine Life Sci, Qingdao 266003, Shandong, Peoples R China.
C3 Ocean University of China; Ocean University of China; Ocean University
   of China
RP Kang, B (corresponding author), Ocean Univ China, Key Lab Mariculture, Minist Educ, Qingdao 266003, Shandong, Peoples R China.; Kang, B (corresponding author), Ocean Univ China, Fisheries Coll, Qingdao 266003, Shandong, Peoples R China.
EM bkangfish@163.com
RI Sun, Jiachen/LVS-3379-2024
FU National Natural Science Foundation of China
FX The authors thank all members of the laboratory for their valuable
   discussions.
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NR 81
TC 0
Z9 0
U1 8
U2 16
PU SPRINGER JAPAN KK
PI TOKYO
PA SHIROYAMA TRUST TOWER 5F, 4-3-1 TORANOMON, MINATO-KU, TOKYO, 105-6005,
   JAPAN
SN 0919-9268
EI 1444-2906
J9 FISHERIES SCI
JI Fish. Sci.
PD MAR
PY 2024
VL 90
IS 2
BP 295
EP 305
DI 10.1007/s12562-024-01753-6
EA JAN 2024
PG 11
WC Fisheries
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Fisheries
GA JL9Q7
UT WOS:001150671900002
DA 2025-04-10
ER

PT J
AU Nagasawa, C
   Ogren, A
   Kibiryeva, N
   Marshall, J
   O'Brien, JE
   Kenmochi, N
   Bittel, DC
AF Nagasawa, Chloe
   Ogren, Allison
   Kibiryeva, Nataliya
   Marshall, Jennifer
   O'Brien, James E., Jr.
   Kenmochi, Naoya
   Bittel, Douglas C.
TI The Role of scaRNAs in Adjusting Alternative mRNA Splicing in Heart
   Development
SO JOURNAL OF CARDIOVASCULAR DEVELOPMENT AND DISEASE
LA English
DT Review
DE alternative mRNA splicing; congenital heart defects; scaRNAs; small
   cajal body-associated RNAs; tetralogy of Fallot
ID SMALL NUCLEOLAR RNAS; SMALL NUCLEAR; MICRORNAS; DEFECTS
AB Congenital heart disease (CHD) is a leading cause of death in children <1 year of age. Despite intense effort in the last 10 years, most CHDs (similar to 70%) still have an unknown etiology. Conotruncal based defects, such as Tetralogy of Fallot (TOF), a common complex of devastating heart defects, typically requires surgical intervention in the first year of life. We reported that the noncoding transcriptome in myocardial tissue from children with TOF is characterized by significant variation in levels of expression of noncoding RNAs, and more specifically, a significant reduction in 12 small cajal body-associated RNAs (scaRNAs) in the right ventricle. scaRNAs are essential for the biochemical modification and maturation of small nuclear RNAs (spliceosomal RNAs), which in turn are critical components of the spliceosome. This is particularly important because we also documented that splicing of mRNAs that are critical for heart development was dysregulated in the heart tissue of infants with TOF. Furthermore, we went on to show, using the zebrafish model, that altering the expression of these same scaRNAs led to faulty mRNA processing and heart defects in the developing embryo. This review will examine how scaRNAs may influence spliceosome fidelity in exon retention during heart development and thus contribute to regulation of heart development.
C1 [Nagasawa, Chloe; Ogren, Allison; Bittel, Douglas C.] Kansas City Univ, Coll Biosci, Kansas City, MO 64106 USA.
   [Kibiryeva, Nataliya; Marshall, Jennifer; O'Brien, James E., Jr.] Univ Missouri Kansas City, Childrens Mercy Hosp, Ward Family Heart Ctr, Sch Med, Kansas City, MO 64108 USA.
   [Kenmochi, Naoya] Univ Miyazaki, Frontier Sci Res Ctr, Miyazaki 8891692, Japan.
C3 Kansas City University; Children's Mercy Hospital; University of
   Missouri System; University of Missouri Kansas City; University of
   Miyazaki
RP Bittel, DC (corresponding author), Kansas City Univ, Coll Biosci, Kansas City, MO 64106 USA.
EM cnagasawa94@kcumb.edu; allison.ogren@kcumb.edu; nkibiryeva@cmh.edu;
   jamarshall@cmh.edu; jobrien@cmh.edu; kenmochi@med.miyazaki-u.ac.jp;
   dbittel@kcumb.edu
RI Kenmochi, Naoya/ABF-3564-2021
OI Ogren, Allison/0000-0001-8933-3968
FU Kansas City Area Life Sciences Institution; CMH Clinical Scholar
   Katherine Barry Richards Foundation; JSPSKAKENHI [2591003, 24591556];
   Takeda Science Foundation; Fraternal Order of Eagles, Kansas;
   Grants-in-Aid for Scientific Research [24591556] Funding Source: KAKEN
FX Kansas City Area Life Sciences Institution; Fraternal Order of Eagles,
   Kansas; CMH Clinical Scholar Katherine Barry Richards Foundation;
   JSPSKAKENHI Grants 2591003 and 24591556, and a grant from the Takeda
   Science Foundation.
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NR 35
TC 21
Z9 22
U1 0
U2 2
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2308-3425
J9 J CARDIOVASC DEV DIS
JI J. Cardiovasc. Dev. Dis.
PD JUN
PY 2018
VL 5
IS 2
AR 26
DI 10.3390/jcdd5020026
PG 12
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA HG7HK
UT WOS:000455161100008
PM 29738469
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Liu, XM
   Du, SL
   Miao, R
   Wang, LF
   Zhong, JC
AF Liu, Xin-Ming
   Du, Sheng-Li
   Miao, Ran
   Wang, Le-Feng
   Zhong, Jiu-Chang
TI Targeting the forkhead box protein P1 pathway as a novel therapeutic
   approach for cardiovascular diseases
SO HEART FAILURE REVIEWS
LA English
DT Review
DE Forkhead box protein P1; Heart failure; Congenital heart defects;
   Atherosclerosis; Cardiac remodeling
ID CARDIOMYOCYTE PROLIFERATION; TRANSCRIPTION FACTORS; CARDIAC-HYPERTROPHY;
   MONOCYTE DIFFERENTIATION; FOXP1; GROWTH; CANCER; FAMILY; CELLS;
   ATHEROSCLEROSIS
AB Cardiovascular disease (CVD) is the leading cause of death worldwide and encompasses diverse diseases of the vasculature, myocardium, cardiac electrical circuit, and cardiac development. Forkhead box protein P1 (Foxp1) is a large multi-domain transcriptional regulator belonging to the Fox family with winged helix DNA-binding protein, which plays critical roles in cardiovascular homeostasis and disorders. The broad distribution of Foxp1 and alternative splicing isoforms implicate its distinct functions in diverse cardiac and vascular cells and tissue types. Foxp1 is essential for diverse biological processes and has been shown to regulate cellular proliferation, apoptosis, oxidative stress, fibrosis, angiogenesis, cardiovascular remodeling, and dysfunction. Notably, both loss-of-function and gain-of-function approaches have defined critical roles of Foxp1 in CVD. Genetic deletion of Foxp1 results in pathological cardiac remodeling, exacerbation of atherosclerotic lesion formation, prolonged occlusive thrombus formation, severe cardiac defects, and embryo death. In contrast, activation of Foxp1 performs a wide range of physiological effects, including cell growth, hypertrophy, differentiation, angiogenesis, and cardiac development. More importantly, Foxp1 exerts anti-inflammatory and anti-atherosclerotic effects in controlling coronary thrombus formation and myocardial infarction (MI). Thus, targeting for Foxp1 signaling has emerged as a pre-warning biomarker and a novel therapeutic approach against progression of CVD, and an increased understanding of cardiovascular actions of the Foxp1 signaling will help to develop effective interventions. In this review, we focus on the diverse actions and underlying mechanisms of Foxp1 highlighting its roles in CVD, including heart failure, MI, atherosclerosis, congenital heart defects, and atrial fibrillation.
C1 [Liu, Xin-Ming; Du, Sheng-Li; Wang, Le-Feng; Zhong, Jiu-Chang] Capital Med Univ, Ctr Heart, Beijing Chaoyang Hosp, Beijing 100020, Peoples R China.
   [Liu, Xin-Ming; Du, Sheng-Li; Wang, Le-Feng; Zhong, Jiu-Chang] Capital Med Univ, Beijing Key Lab Hypertens, Beijing Chaoyang Hosp, Beijing 100020, Peoples R China.
   [Miao, Ran; Zhong, Jiu-Chang] Capital Med Univ, Med Res Ctr, Beijing Chaoyang Hosp, Beijing 100020, Peoples R China.
C3 Capital Medical University; Capital Medical University; Capital Medical
   University
RP Wang, LF; Zhong, JC (corresponding author), Capital Med Univ, Ctr Heart, Beijing Chaoyang Hosp, Beijing 100020, Peoples R China.; Wang, LF; Zhong, JC (corresponding author), Capital Med Univ, Beijing Key Lab Hypertens, Beijing Chaoyang Hosp, Beijing 100020, Peoples R China.; Zhong, JC (corresponding author), Capital Med Univ, Med Res Ctr, Beijing Chaoyang Hosp, Beijing 100020, Peoples R China.
EM wlf20182021@163.com; jczhong@sina.com
RI Du, Sheng-Li/LXB-3096-2024
OI Zhong, Jiuchang/0000-0002-2315-3515
FU National Natural Science Foundation of China [81770253, 81370362];
   National Major Research Plan Training Program [91849111]; talent project
   of Beijing Chaoyang Hospital Affiliated to Capital Medical University
FX This work was supported by the National Natural Science Foundation of
   China (81770253, 81370362), the National Major Research Plan Training
   Program (91849111), and talent project of Beijing Chaoyang Hospital
   Affiliated to Capital Medical University.
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NR 86
TC 11
Z9 12
U1 1
U2 25
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 1382-4147
EI 1573-7322
J9 HEART FAIL REV
JI Heart Fail. Rev.
PD JAN
PY 2022
VL 27
IS 1
BP 345
EP 355
DI 10.1007/s10741-020-09992-2
EA JUL 2020
PG 11
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA YC8WS
UT WOS:000546822000001
PM 32648149
DA 2025-04-10
ER

PT J
AU Saba, Z
   Nassar, R
   Ungerleider, RM
   Oakeley, AE
   Anderson, PAW
AF Saba, Z
   Nassar, R
   Ungerleider, RM
   Oakeley, AE
   Anderson, PAW
TI Cardiac troponin T isoform expression correlates with pathophysiological
   descriptors in patients who underwent corrective surgery for congenital
   heart disease
SO CIRCULATION
LA English
DT Article
DE atrium; inotropic agents; heart failure; molecular biology; proteins
ID SKELETAL-MUSCLE; MOLECULAR-BASIS; RABBIT HEART; ADULT; SHIFTS; FORCE;
   RAT
AB Background This study examined cardiac troponin T(cTnT) isoform expression in patients who has undergone surgery at Duke University Medical Center (Durham, NC) between December 1, 1993, and January 31, 1995, to correct congenital heart defects. The human heart expresses four cTnT isoforms (cTnT(1) through cTnT(4)) whose sequence differences result from combinatorial alternative splicing of two exons. We have previously shown that cTnT(4) is expressed at higher levels in severely failing hearts from transplant patients. In this study, we tested the hypothesis that congenital heart defects that have a more negative effect on myocardial function increase cTnT(4) expression. We used the presence or absence of drug treatment for heart failure or congested circulation before surgery and the duration of inotropic support after corrective surgery as indicators of the pathophysiological state of the heart just before surgery.
   Methods and Results Rights atrial appendage tissue was collected from 34 patients, 6 days to 35 years old (median age, 34 months). The amounts of the cTnT(1) through cTnT(4) isoforms, measured as a percentage of total cTnT, were determined from Western blots probed with Mab13-11, a cTnT-specific monoclonal antibody. We found that cTnT(4) expression correlated positively with the duration of inotropic support and was higher in patients who received drug treatment before surgery than in those who did not. Furthermore, we found that the percent of cTnT(4) was significantly higher in hearts with congenital defects that caused congestive failure than in hearts with tetralogy of Fallot.
   Conclusion These findings suggest that in patients wit congenital cardiac defects, cTnT(4) expression is modulated by heart failure and is increased in hearts that are more hemodynamically stressed.
C1 DUKE UNIV,MED CTR,DEPT PEDIAT,DIV PEDIAT CARDIOL,DURHAM,NC 27710.
   DUKE UNIV,MED CTR,DEPT SURG,DURHAM,NC 27710.
C3 Duke University; Duke University
FU NHLBI NIH HHS [HL-42250, HL-20749] Funding Source: Medline
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TC 40
Z9 49
U1 0
U2 0
PU AMER HEART ASSOC
PI DALLAS
PA 7272 GREENVILLE AVENUE, DALLAS, TX 75231-4596
SN 0009-7322
J9 CIRCULATION
JI Circulation
PD AUG 1
PY 1996
VL 94
IS 3
BP 472
EP 476
DI 10.1161/01.CIR.94.3.472
PG 5
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA UZ051
UT WOS:A1996UZ05100036
PM 8759091
DA 2025-04-10
ER

PT J
AU Gallagher, TL
   Arribere, JA
   Geurts, PA
   Exner, CRT
   McDonald, KL
   Dill, KK
   Marr, HL
   Adkar, SS
   Garnett, AT
   Amacher, SL
   Conboy, JG
AF Gallagher, Thomas L.
   Arribere, Joshua A.
   Geurts, Paul A.
   Exner, Cameron R. T.
   McDonald, Kent L.
   Dill, Kariena K.
   Marr, Henry L.
   Adkar, Shaunak S.
   Garnett, Aaron T.
   Amacher, Sharon L.
   Conboy, John G.
TI Rbfox-regulated alternative splicing is critical for zebrafish cardiac
   and skeletal muscle functions
SO DEVELOPMENTAL BIOLOGY
LA English
DT Article
DE Alternative splicing; Zebrafish; Muscle; rbfox; a2bp1l; rbm9
ID MUSCULAR-DYSTROPHY; GENE-EXPRESSION; CELL MIGRATION; PROTEIN; SLOW;
   FOX-1; RNA; IDENTIFICATION; TRANSCRIPTOME; SUPERVILLIN
AB Rbfox RNA binding proteins are implicated as regulators of phylogenetically-conserved alternative splicing events important for muscle function. To investigate the function of rbfox genes, we used morpholino-mediated knockdown of muscle-expressed rbfox1l and rbfox2 in zebrafish embryos. Single and double morphant embryos exhibited changes in splicing of overlapping sets of bioinformatically-predicted rbfox target exons, many of which exhibit a muscle-enriched splicing pattern that is conserved in vertebrates. Thus, conservation of intronic Rbfox binding motifs is a good predictor of Rbfox-regulated alternative splicing. Morphology and development of single morphant embryos were strikingly normal; however, muscle development in double morphants was severely disrupted. Defects in cardiac muscle were marked by reduced heart rate and in skeletal muscle by complete paralysis. The predominance of wavy myofibers and abnormal thick and thin filaments in skeletal muscle revealed that myofibril assembly is defective and disorganized in double morphants. Ultra-structural analysis revealed that although sarcomeres with electron dense M- and Z-bands are present in muscle fibers of rbfox1l/rbox2 morphants, they are substantially reduced in number and alignment. Importantly, splicing changes and morphological defects were rescued by expression of morpholino-resistant rbfox cDNA. Additionally, a target-blocking MO complementary to a single UGCAUG motif adjacent to an rbfox target exon of fxr1 inhibited inclusion in a similar manner to rbfox knockdown, providing evidence that Rbfox regulates the splicing of target exons via direct binding to intronic regulatory motifs. We conclude that Rbfox proteins regulate an alternative splicing program essential for vertebrate heart and skeletal muscle functions. Published by Elsevier Inc.
C1 [Gallagher, Thomas L.; Arribere, Joshua A.; Geurts, Paul A.; Exner, Cameron R. T.; Dill, Kariena K.; Marr, Henry L.; Adkar, Shaunak S.; Garnett, Aaron T.; Amacher, Sharon L.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
   [Gallagher, Thomas L.; Arribere, Joshua A.; Marr, Henry L.; Adkar, Shaunak S.; Conboy, John G.] Univ Calif Berkeley, Lawrence Berkeley Lab, Berkeley, CA 94720 USA.
   [McDonald, Kent L.] Univ Calif Berkeley, Electron Microscopy Lab, Berkeley, CA 94720 USA.
C3 University of California System; University of California Berkeley;
   United States Department of Energy (DOE); Lawrence Berkeley National
   Laboratory; University of California System; University of California
   Berkeley; University of California System; University of California
   Berkeley
RP Amacher, SL (corresponding author), Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
EM amacher@berkeley.edu; jgconboy@lbl.gov
FU National Institutes of Health (NIH) [HL45182, GM061952, GM07232];
   American Heart Association [0825194F]; UCB; UC Berkeley Center for
   Integrative Genomics; Lawrence Berkeley National Laboratory
   [DE-AC02-05CH11231]; National Institute of General Medical Sciences
   [T32GM007232] Funding Source: NIH RePORTER; American Heart Association
   (AHA) [0825194F] Funding Source: American Heart Association (AHA)
FX We thank Michael Zhang (CSHL) for sharing data prior to publication as
   well as Clarissa Henry (UMaine), Christine Beattie (OSU), Jiandong Liu
   and Didier Stainier (UCSF) for advice. We also thank Holly Aaron (UCB
   Molecular Imaging Center), the UCB Flow Cytometry Facility, and Jen St.
   Hilaire, Deborah Weinman, and Keely McDaniel (UCB Fish Facility). This
   work was supported by National Institutes of Health (NIH) grants HL45182
   (JGC) and GM061952 (SEA), an American Heart Association grant 0825194F
   (TLG), the UCB Haas Scholars Program (JAA), NIH Training Grant GM07232
   (PAG and CRTE), and the UC Berkeley Center for Integrative Genomics
   (SEA, ATG), and carried out in part at Lawrence Berkeley National
   Laboratory under Contract No. DE-AC02-05CH11231.
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NR 65
TC 75
Z9 86
U1 0
U2 12
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0012-1606
EI 1095-564X
J9 DEV BIOL
JI Dev. Biol.
PD NOV 15
PY 2011
VL 359
IS 2
BP 251
EP 261
DI 10.1016/j.ydbio.2011.08.025
PG 11
WC Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Developmental Biology
GA 843GH
UT WOS:000296659800009
PM 21925157
OA Green Accepted, Bronze
DA 2025-04-10
ER

PT J
AU Burns, TA
   Dours-Zimmermann, MT
   Zimmermann, DR
   Krug, EL
   Comte-Walters, S
   Reyes, L
   Davis, MA
   Schey, KL
   Schwacke, JH
   Kern, CB
   Mjaatvedt, CH
AF Burns, Tara A.
   Dours-Zimmermann, Maria T.
   Zimmermann, Dieter R.
   Krug, Edward L.
   Comte-Walters, Susana
   Reyes, Leticia
   Davis, Monica A.
   Schey, Kevin L.
   Schwacke, John H.
   Kern, Christine B.
   Mjaatvedt, Corey H.
TI Imbalanced Expression of Vcan mRNA Splice Form Proteins Alters
   Heart Morphology and Cellular Protein Profiles
SO PLOS ONE
LA English
DT Article
ID CHONDROITIN SULFATE PROTEOGLYCAN; MOUSE PG-M; EXTRACELLULAR-MATRIX;
   DILATED CARDIOMYOPATHY; PROTEOLYTIC CLEAVAGE; VERSICAN CLEAVAGE;
   EMBRYONIC HEART; PERIOSTIN; GENE; CELLS
AB The fundamental importance of the proteoglycan versican to early heart formation was clearly demonstrated by the Vcan null mouse called heart defect (hdf). Total absence of the Vcan gene halts heart development at a stage prior to the heart's pulmonary/aortic outlet segment growth. This creates a problem for determining the significance of versican's expression in the forming valve precursors and vascular wall of the pulmonary and aortic roots. This study presents data from a mouse model, Vcan((tm1Zim)), of heart defects that results from deletion of exon 7 in the Vcan gene. Loss of exon 7 prevents expression of two of the four alternative splice forms of the Vcan gene. Mice homozygous for the exon 7 deletion survive into adulthood, however, the inability to express the V2 or V0 forms of versican results in ventricular septal defects, smaller cushions/valve leaflets with diminished myocardialization and altered pulmonary and aortic outflow tracts. We correlate these phenotypic findings with a large-scale differential protein expression profiling to identify compensatory alterations in cardiac protein expression at E13.5 post coitus that result from the absence of Vcan exon 7. The Vcan (tm1Zim) hearts show significant changes in the relative abundance of several cytoskeletal and muscle contraction proteins including some previously associated with heart disease. These alterations define a protein fingerprint that provides insight to the observed deficiencies in pre-valvular/septal cushion mesenchyme and the stability of the myocardial phenotype required for alignment of the outflow tract with the heart ventricles.
C1 [Burns, Tara A.; Krug, Edward L.; Reyes, Leticia; Davis, Monica A.; Schwacke, John H.; Kern, Christine B.; Mjaatvedt, Corey H.] Med Univ S Carolina, Dept Regenerat Med, Charleston, SC 29425 USA.
   [Burns, Tara A.; Krug, Edward L.; Reyes, Leticia; Davis, Monica A.; Schwacke, John H.; Kern, Christine B.; Mjaatvedt, Corey H.] Med Univ S Carolina, Dept Cell Biol, Charleston, SC 29425 USA.
   [Comte-Walters, Susana] Med Univ S Carolina, Dept Cell & Mol Pharmacol, Charleston, SC 29425 USA.
   [Dours-Zimmermann, Maria T.; Zimmermann, Dieter R.] Univ Zurich Hosp, Inst Surg Pathol, CH-8091 Zurich, Switzerland.
   [Schey, Kevin L.] Vanderbilt Univ, Dept Biochem, Sch Med, Nashville, TN 37232 USA.
C3 Medical University of South Carolina; Medical University of South
   Carolina; Medical University of South Carolina; University of Zurich;
   University Zurich Hospital; Vanderbilt University
RP Mjaatvedt, CH (corresponding author), Med Univ S Carolina, Dept Regenerat Med, Charleston, SC 29425 USA.
EM mjaatvch@musc.edu
OI Krug, Edward/0000-0002-4345-6580
FU NIH NHLBI [66231]; American Heart Association; NIH NHLBI Cardiovascular
   Proteomics Center [N01-HV-28282]; NIH NCRR [C06 RR018823]; Swiss
   National Science Foundation; Velux Foundation
FX This work was supported by NIH NHLBI 66231 and American Heart
   Association Grant-in Aid to CHM; NIH NHLBI Cardiovascular Proteomics
   Center (contract N01-HV-28282; to ELK and KLS); NIH NCRR C06 RR018823
   (to ELK); and grants from the Swiss National Science Foundation and
   Velux Foundation (to MTD-Z and DRZ). The funders had no role in study
   design, data collection and analysis, decision to publish, or
   preparation of the manuscript.
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NR 86
TC 19
Z9 22
U1 0
U2 4
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD FEB 20
PY 2014
VL 9
IS 2
AR e89133
DI 10.1371/journal.pone.0089133
PG 16
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA AB3UC
UT WOS:000331714700065
PM 24586547
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Azim, S
   Banday, AR
   Tabish, M
AF Azim, Shafquat
   Banday, Abdul Rouf
   Tabish, Mohammad
TI Identification of alternatively spliced multiple transcripts of
   5-hydroxytryptamine receptor in mouse
SO BRAIN RESEARCH BULLETIN
LA English
DT Article
DE 5-Hydroxytryptamine receptors (HTR4); Alternative splicing; Variants; 5
   ' Untranslated region (5 ' UTR); Exons; Introns; Transcripts
ID SEROTONIN 5-HT4 RECEPTORS; CONSTITUTIVE ACTIVITY; GENOMIC ORGANIZATION;
   SIGNAL SEQUENCES; NERVOUS-SYSTEM; HUMAN ATRIUM; VARIANTS; CLONING;
   PHARMACOLOGY; BRAIN
AB 5-Hydroxytryptamine receptors (HTRs) are coded by seventeen different genes in mouse. One of them is htr4 that codes for the HTR4 receptor, a G-protein coupled receptor containing seven transmembrane domains. In mouse, the gene is reported to contain 6 exons and 5 introns. Our present study reports the presence of four transcript variants of this gene encoding different N-termini. These transcripts are expressed in neuronal as well as non-neuronal tissues of mouse. We have identified five novel coding exons present at the 5' end of the gene which splice with the published internal exon in an alternative manner making a total of five transcripts, four new transcript variants (T1, T2l, T2s and 13) and one published earlier. All five transcripts encoding different N-termini were expressed in mouse brain. It was interesting to note the expression of only 13 transcript that was also detected in heart muscle and is the only htr4 transcript expressed in heart. For the first time a transcript of htr4 gene was detected in the heart of the mouse which might help us to make use of small laboratory animals to study HTR4 in heart. As this transcript is unique to the heart it can serve as potential therapeutic target for various cardiovascular disorders and dysregulation of heart rate, atrial contraction and atrial relaxation. These variants display heterogeneous properties in terms of the presence of signal peptide, acetylation, phosphorylation and glycosylation. Thus alternative splicing of htr4 producing heterogeneous N-termini increases the diversity of the receptor. (C) 2011 Elsevier Inc. All rights reserved.
C1 [Azim, Shafquat; Banday, Abdul Rouf; Tabish, Mohammad] Aligarh Muslim Univ, Fac Life Sci, Dept Biochem, Aligarh 202002, Uttar Pradesh, India.
C3 Aligarh Muslim University
RP Tabish, M (corresponding author), Aligarh Muslim Univ, Fac Life Sci, Dept Biochem, Aligarh 202002, Uttar Pradesh, India.
EM tabish.bcmlab@gmail.com
RI BANDAY, ABDUL/A-9555-2014; Taheri, Majid/V-4415-2019
OI BANDAY, ABDUL ROUF/0000-0002-1521-340X
FU CSIR, New Delhi, India; Department of Biotechnology (DBT), Ministry of
   Science and Technology, New Delhi
FX The authors are thankful to CSIR, New Delhi, India for providing senior
   research fellowship to SA. Partial funding from the Department of
   Biotechnology (DBT), Ministry of Science and Technology, New Delhi and
   necessary facilities provided by AMU, Aligarh, India is thankfully
   acknowledged.
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NR 44
TC 9
Z9 9
U1 0
U2 6
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 0361-9230
J9 BRAIN RES BULL
JI Brain Res. Bull.
PD FEB 10
PY 2012
VL 87
IS 2-3
BP 250
EP 258
DI 10.1016/j.brainresbull.2011.10.016
PG 9
WC Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 909FP
UT WOS:000301548300016
PM 22079627
DA 2025-04-10
ER

PT J
AU Patil, P
   Kibiryeva, N
   Uechi, T
   Marshall, J
   O'Brien, JE
   Artman, M
   Kenmochi, N
   Bittel, DC
AF Patil, Prakash
   Kibiryeva, Nataliya
   Uechi, Tamayo
   Marshall, Jennifer
   O'Brien, James E., Jr.
   Artman, Michael
   Kenmochi, Naoya
   Bittel, Douglas C.
TI scaRNAs regulate splicing and vertebrate heart development
SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
LA English
DT Article
DE Congenital heart defect; Tetralogy of Fallot; Splicing; Spliceosome;
   scaRNA; Zebrafish
ID SPINAL MUSCULAR-ATROPHY; CARDIOVASCULAR DEVELOPMENT; GENE-EXPRESSION;
   RNA; ZEBRAFISH; DISEASE; DEFECTS; CELLS; SPLICEOSOME; MECHANISMS
AB Alternative splicing (AS) plays an important role in regulating mammalian heart development, but a link between misregulated splicing and congenital heart defects (CHDs) has not been shown. We reported that more than 50% of genes associated with heart development were alternatively spliced in the right ventricle (RV) of infants with tetralogy of Fallot (TOF). Moreover, there was a significant decrease in the level of 12 small cajal body-specific RNAs (scaRNAs) that direct the biochemical modification of specific nucleotides in spliceosomal RNAs. We sought to determine if scaRNA levels influence patterns of AS and heart development. We used primary cells derived from the RV of infants with TOF to show a direct link between scaRNA levels and splice isoforms of several genes that regulate heart development (e.g., GATA4, NOTCH2, DAAM1, DICER1, MBNL1 and MBNL2). In addition, we used antisense morpholinos to knock down the expression of two scaRNAs (scarna1 and snord94) in zebrafish and saw a corresponding disruption of heart development with an accompanying alteration in splice isoforms of cardiac regulatory genes. Based on these combined results, we hypothesize that scaRNA modification of spliceosomal RNAs assists in fine tuning the spliceosome for dynamic selection of mRNA splice isoforms. Our results are consistent with disruption of splicing patterns during early embryonic development leading to insufficient communication between the first and second heart fields, resulting in conotruncal misalignment and TOF. Our findings represent a new paradigm for determining the mechanisms underlying congenital cardiac malformations. (C) 2015 The Authors. Published by Elsevier B.V.
C1 [Patil, Prakash; Uechi, Tamayo; Kenmochi, Naoya] Miyazaki Univ, Frontier Sci Res Ctr, Miyazaki, Japan.
   [Kibiryeva, Nataliya; Marshall, Jennifer; O'Brien, James E., Jr.; Bittel, Douglas C.] Univ Missouri, Sch Med, Childrens Mercy Hosp, Ward Family Heart Ctr, Kansas City, MO 64108 USA.
   [Artman, Michael] Univ Missouri, Sch Med, Childrens Mercy Hosp, Dept Pediat, Kansas City, MO 64108 USA.
C3 University of Miyazaki; Children's Mercy Hospital; University of
   Missouri System; University of Missouri Kansas City; University of
   Missouri System; University of Missouri Kansas City; Children's Mercy
   Hospital
RP Kenmochi, N (corresponding author), Miyazaki Univ, Frontier Sci Res Ctr, Miyazaki, Japan.
RI PATIL, PRAKASH/HHS-3504-2022; Kenmochi, Naoya/ABF-3564-2021
OI Patil, Prakash/0000-0002-1263-8517
FU Kansas City Area Life Sciences Institution; Fraternal Order of Eagles,
   Kansas; Katherine Barry Richards Foundation; JSPSKAKENHI [2591003,
   24591556]; Takeda Science Foundation; CMH; Grants-in-Aid for Scientific
   Research [24591556] Funding Source: KAKEN
FX Kansas City Area Life Sciences Institution, Fraternal Order of Eagles,
   Kansas, CMH Clinical Scholar, Katherine Barry Richards Foundation,
   JSPSKAKENHI Grants 2591003 (N.K.) and 24591556 (T.U.), and a grant from
   the Takeda Science Foundation (T.U.).
CR Andelfinger G, 2011, EXPERT REV CARDIOVAS, V9, P655, DOI [10.1586/ERC.11.79, 10.1586/erc.11.79]
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NR 37
TC 23
Z9 25
U1 0
U2 10
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0925-4439
EI 0006-3002
J9 BBA-MOL BASIS DIS
JI Biochim. Biophys. Acta-Mol. Basis Dis.
PD AUG
PY 2015
VL 1852
IS 8
BP 1619
EP 1629
DI 10.1016/j.bbadis.2015.04.016
PG 11
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA CK9HB
UT WOS:000356550100006
PM 25916634
OA hybrid
DA 2025-04-10
ER

PT J
AU Liu, TY
   Chen, YC
   Jong, YJ
   Tsai, HJ
   Lee, CC
   Chang, YS
   Chang, JG
   Chang, YF
AF Liu, Ting-Yuan
   Chen, Yu-Chia
   Jong, Yuh-Jyh
   Tsai, Huai-Jen
   Lee, Chien-Chin
   Chang, Ya-Sian
   Chang, Jan-Gowth
   Chang, Yung-Fu
TI Muscle developmental defects in heterogeneous nuclear Ribonucleoprotein
   A1 knockout mice
SO OPEN BIOLOGY
LA English
DT Article
DE alternative splicing; embryonic development; hnRNP A1; knockout mice;
   musde development
ID HNRNP A1; SKELETAL-MUSCLE; HEART DEVELOPMENT; GENE-EXPRESSION;
   SMOOTH-MUSCLE; MYOSIN-VI; DIFFERENTIATION; CARDIOMYOPATHY; REPRESSION;
   PROTEINS
AB Heterogeneous ribonucleoprotein A1 (hnRNP A1) is crucial for regulating alternative splicing. Its integrated function within an organism has not, however, been identified. We generated hnRNP A1 knockout mice to study the role of hnRNPA1 in vivo. The knockout mice, hnRNP A1(-/-), showed embryonic lethality because of muscle developmental defects. The blood pressure and heart rate of the heterozygous mice were higher than those of the wild-type mice, indicating heart function defects. We performed mouse exon arrays to study the muscle development mechanism. The processes regulated by hnRNP A1 included cell adhesion and muscle contraction. The expression levels of muscle development-related genes in hnRNPA1(+/-) mice were significantly different from those in wild-type mice, as detected using qRT-PCR. We further confirmed the alternative splicing patterns of muscle development-related genes including mef2c, lrrfip1, usp28 and abcc9. Alternative mRNA isoforms of these genes were increased in hnRNP A1(+/-) mice compared with wild-type mice. Furthermore, we revealed that the functionally similar hnRNP A2/B1 did not compensate for the expression of hnRNP A1 in organisms. In summary, our study demonstrated that hnRNP A1 plays a critical and irreplaceable role in embryonic muscle development by regulating the expression and alternative splicing of muscle-related genes.
C1 [Liu, Ting-Yuan; Chen, Yu-Chia; Jong, Yuh-Jyh] Kaohsiung Med Univ, Coll Med, Grad Inst Med, Kaohsiung, Taiwan.
   [Jong, Yuh-Jyh] Kaohsiung Med Univ, Coll Med, Grad Inst Clin Med, Kaohsiung, Taiwan.
   [Chang, Yung-Fu] Kaohsiung Med Univ, Coll Life Sci, Dept Biomed Sci & Environm Biol, Kaohsiung, Taiwan.
   [Jong, Yuh-Jyh] Kaohsiung Med Univ Hosp, Dept Pediat, Kaohsiung, Taiwan.
   [Jong, Yuh-Jyh] Kaohsiung Med Univ Hosp, Dept Clin Lab, Kaohsiung, Taiwan.
   [Jong, Yuh-Jyh] Natl Chiao Tung Univ, Inst Mol Med & Bioengn, Dept Biol Sci & Technol, Coll Biol Sci & Technol, Hsinchu, Taiwan.
   [Tsai, Huai-Jen] Mackay Med Coll, Inst Biomed Sci, New Taipei, Taiwan.
   [Lee, Chien-Chin; Chang, Ya-Sian; Chang, Jan-Gowth] China Med Univ, Epigenome Res Ctr, Taichung, Taiwan.
   [Chang, Ya-Sian; Chang, Jan-Gowth] China Med Univ, Dept Lab Med, Taichung, Taiwan.
   [Chang, Jan-Gowth] China Med Univ, Sch Med, Taichung, Taiwan.
   [Chang, Ya-Sian] China Med Univ, Dept Med Lab Sci & Biotechnol, Taichung, Taiwan.
C3 Kaohsiung Medical University; Kaohsiung Medical University; Kaohsiung
   Medical University; Kaohsiung Medical University; Kaohsiung Medical
   University Hospital; Kaohsiung Medical University; Kaohsiung Medical
   University Hospital; National Yang Ming Chiao Tung University; Mackay
   Medical College; China Medical University Taiwan; China Medical
   University Taiwan; China Medical University Taiwan; China Medical
   University Taiwan
RP Chang, YF (corresponding author), Kaohsiung Med Univ, Coll Life Sci, Dept Biomed Sci & Environm Biol, Kaohsiung, Taiwan.; Chang, JG (corresponding author), China Med Univ, Epigenome Res Ctr, Taichung, Taiwan.; Chang, JG (corresponding author), China Med Univ, Dept Lab Med, Taichung, Taiwan.; Chang, JG (corresponding author), China Med Univ, Sch Med, Taichung, Taiwan.
EM d6781@mail.cmuh.org.tw; m795003@kmu.edu.tw
OI Jong, Yuh-Jyh/0000-0002-1735-1101
FU National Science Council, Taiwan [NSC 96-2314-B-037-035-MY3, NSC
   96-2314-B-037-034-MY3, NSC 102-2320-B-039-039]
FX This study was supported, in part, by grants from the National Science
   Council, Taiwan to Y.-F.C. (NSC 96-2314-B-037-035-MY3), Y.-J.J. (NSC
   96-2314-B-037-034-MY3) and J.-G.C. (NSC 102-2320-B-039-039).
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NR 38
TC 37
Z9 44
U1 2
U2 12
PU ROYAL SOC
PI LONDON
PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND
SN 2046-2441
J9 OPEN BIOL
JI Open Biol
PD JAN
PY 2017
VL 7
IS 1
AR 160303
DI 10.1098/rsob.160303
PG 12
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA EJ7DR
UT WOS:000393382200014
PM 28077597
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Semplicini, A
   Siffert, W
   Sartori, M
   Monari, A
   Naber, C
   Frigo, G
   Santonastaso, M
   Cozzutti, E
   Winnicki, M
   Palatini, P
AF Semplicini, A
   Siffert, W
   Sartori, M
   Monari, A
   Naber, C
   Frigo, G
   Santonastaso, M
   Cozzutti, E
   Winnicki, M
   Palatini, P
TI G protein β3 subunit gene 825T allele is associated with
   increased left ventricular mass in young subjects with mild hypertension
SO AMERICAN JOURNAL OF HYPERTENSION
LA English
DT Article
DE G protein; GNB3 signal transduction; genetics; hypertrophy; left
   ventricular function; hypertension
ID AMBULATORY BLOOD-PRESSURE; ECHOCARDIOGRAPHIC MEASUREMENTS; IMMORTALIZED
   LYMPHOBLASTS; HYPERTROPHY; VARIANT; INDIVIDUALS; ACTIVATION; OBESITY;
   RISK
AB Background: A nucleotide substitution (C -->T) at position 825 of the gene GNB3 encoding the beta (3) subunit of heterotrimeric G proteins is associated with alternative splicing and enhanced signal transduction. There is accumulating evidence from different populations that the 825T allele is associated with increased prevalence of hypertension, obesity, and left ventricular hypertrophy. However, it is unclear to what extent the 825T allele has a direct influence on left ventricular structure, independently of the effects of pressure and body mass index. Therefore we explored whether the GNB3 825T allele is associated with increased left ventricular mass index in a selected and homogeneous group of young, never treated, mild hypertensives.
   Procedures: Young subjects (n = 207, aged 18 to 45 years) were genotyped at the GNB3 825 locus. In each patient, 24-h ambulatory blood pressure (BP) measurement and two-dimensional guided M-mode echocardiography combined with Doppler sonography were performed.
   Results: The genotype distribution among patients was in Hardy-Weinberg equilibrium. Patients carrying the 825T allele had an increased left ventricular mass index (95.1 +/- 1.5 nu 89.7 +/- 1.5 g/m(2); p = .01) in comparison to those with CC genotype. The association between left ventricular mass index and 825T allele was independent of,gender, age, BP, heart rate, alcohol intake, and physical activity.
   Conclusions: In young patients with mild hypertension without heart disease the 825T allele is associated with an increased left ventricular mass index. These hypothesis-generating data suggest that GNB3 825T allele may be considered as one genetic marker predisposing to an increase in left ventricular mass in hypertensives, and justifies larger studies. (C) 2001 American Journal of Hypertension, Ltd.
C1 Univ Padua, Dept Clin & Expt Med, Padua, Italy.
   Univ Essen Gesamthsch Klinikum, Inst Pharmakol, D-4300 Essen, Germany.
   Univ Essen Gesamthsch Klinikum, Abt Kardiol, D-4300 Essen, Germany.
   Vittorio Veneto Town Hosp, Vittorio Veneto, Italy.
   Mayo Clin, Rochester, MN USA.
C3 University of Padua; University of Duisburg Essen; University of
   Duisburg Essen; ULSS 2 Marca TV; Ospedale Vittorio Veneto; Mayo Clinic
RP Semplicini, A (corresponding author), Univ Padua Polyclin, Clin Med 4, Via Guistiniani 2, I-35126 Padua, Italy.
RI Sartori, Michelangelo/JAC-7959-2023; Winnicki, Mikolaj/J-2477-2018;
   Semplicini, Andrea/B-5959-2013
OI Semplicini, Andrea/0000-0003-0652-0739; Sartori,
   Michelangelo/0000-0003-3466-4676
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NR 26
TC 31
Z9 31
U1 0
U2 1
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 0895-7061
J9 AM J HYPERTENS
JI Am. J. Hypertens.
PD DEC
PY 2001
VL 14
IS 12
BP 1191
EP 1195
DI 10.1016/S0895-7061(01)02227-0
PG 5
WC Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 503KT
UT WOS:000172798200004
PM 11775125
OA Bronze
DA 2025-04-10
ER

PT J
AU Magomedova, L
   Tiefenbach, J
   Zilberman, E
   Le Billan, F
   Voisin, V
   Saikali, M
   Boivin, V
   Robitaille, M
   Gueroussov, S
   Irimia, M
   Ray, D
   Patel, R
   Xu, C
   Jeyasuria, P
   Bader, GD
   Hughes, TR
   Morris, QD
   Scott, MS
   Krause, H
   Angers, S
   Blencowe, BJ
   Cummins, CL
AF Magomedova, Lilia
   Tiefenbach, Jens
   Zilberman, Emma
   Le Billan, Florian
   Voisin, Veronique
   Saikali, Michael
   Boivin, Vincent
   Robitaille, Melanie
   Gueroussov, Serge
   Irimia, Manuel
   Ray, Debashish
   Patel, Rucha
   Xu, ChangJiang
   Jeyasuria, Pancharatnam
   Bader, Gary D.
   Hughes, Timothy R.
   Morris, Quaid D.
   Scott, Michelle S.
   Krause, Henry
   Angers, Stephane
   Blencowe, Benjamin J.
   Cummins, Carolyn L.
TI ARGLU1 is a transcriptional coactivator and splicing regulator important
   for stress hormone signaling and development
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID NUCLEAR RECEPTOR COACTIVATORS; VITAMIN-D-RECEPTOR; PRE-MESSENGER-RNA;
   INTERACTING PROTEIN; COREGULATORS; ACETYLTRANSFERASE; ACTIVATION;
   VERTEBRATE; DIVERSITY; ARGININE
AB Stress hormones bind and activate the glucocorticoid receptor (GR) in many tissues including the brain. We identified arginine and glutamate rich 1 (ARGLU1) in a screen for new modulators of glucocorticoid signaling in the CNS. Biochemical studies show that the glutamate rich C-terminus of ARGLU1 coactivates multiple nuclear receptors including the glucocorticoid receptor (GR) and the arginine rich N-terminus interacts with splicing factors and binds to RNA. RNA-seq of neural cells depleted of ARGLU1 revealed significant changes in the expression and alternative splicing of distinct genes involved in neurogenesis. Loss of ARGLU1 is embryonic lethal in mice, and knockdown in zebrafish causes neurodevelopmental and heart defects. Treatment with dexamethasone, a GR activator, also induces changes in the pattern of alternatively spliced genes, many of which were lost when ARGLU1 was absent. Importantly, the genes found to be alternatively spliced in response to glucocorticoid treatment were distinct from those under transcriptional control by GR, suggesting an additional mechanism of glucocorticoid action is present in neural cells. Our results thus show that ARGLU1 is a novel factor for embryonic development that modulates basal transcription and alternative splicing in neural cells with consequences for glucocorticoid signaling.
C1 [Magomedova, Lilia; Zilberman, Emma; Le Billan, Florian; Saikali, Michael; Robitaille, Melanie; Patel, Rucha; Angers, Stephane; Cummins, Carolyn L.] Univ Toronto, Dept Pharmaceut Sci, Toronto, ON M5S 3M2, Canada.
   [Tiefenbach, Jens; Voisin, Veronique; Gueroussov, Serge; Irimia, Manuel; Ray, Debashish; Xu, ChangJiang; Bader, Gary D.; Hughes, Timothy R.; Morris, Quaid D.; Krause, Henry; Blencowe, Benjamin J.] Univ Toronto, Donnelly Ctr Cellular & Biomol Res, Toronto, ON M5S 3E1, Canada.
   [Boivin, Vincent; Scott, Michelle S.] Univ Sherbrooke, Dept Biochim, Fac Med & Sci Sante, Sherbrooke, PQ J1E 4K8, Canada.
   [Gueroussov, Serge; Bader, Gary D.; Hughes, Timothy R.; Morris, Quaid D.; Blencowe, Benjamin J.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.
   [Jeyasuria, Pancharatnam] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Perinatal Initiat, Detroit, MI 48201 USA.
   [Angers, Stephane] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada.
C3 University of Toronto; University of Toronto; University of Sherbrooke;
   University of Toronto; Wayne State University; University of Toronto
RP Cummins, CL (corresponding author), Univ Toronto, Dept Pharmaceut Sci, Toronto, ON M5S 3M2, Canada.
EM carolyn.cumminsr@utoronto.ca
RI Irimia, Manuel/E-3040-2010; Morris, Quaid/ABE-8343-2020; Le Billan,
   Florian/KHD-0188-2024; Robitaille, Melanie/ABA-5861-2020; Krause,
   Henry/LZF-2069-2025; Pancharatnam, Jeyasuria/B-4710-2008; Angers,
   Stephane/E-1432-2014
OI Ray, Debashish/0000-0003-2021-1115; Robitaille,
   Melanie/0000-0001-9354-5162; Saikali, Michael Fadi/0009-0000-2202-911X;
   Pancharatnam, Jeyasuria/0000-0002-1388-906X; Le Billan,
   Florian/0000-0002-3400-9295; Irimia, Manuel/0000-0002-2179-2567; voisin,
   veronique/0000-0002-3405-9532; Cummins, Carolyn/0000-0001-7603-6577;
   Magomedova, Lilia/0000-0001-8151-1424; Angers,
   Stephane/0000-0001-7241-9044; Morris, Quaid/0000-0002-2760-6999; Krause,
   Henry/0000-0002-6182-7074
FU Natural Sciences and Engineering Research Council of Canada (NSERC)
   [RGPIN 03666-14]; Connaught New Investigator Award; J. P. Bickell
   Foundation; OntarioGraduate Scholarship; CIHR Foundation grant; NSERC;
   Natural Sciences and Engineering Research Council of Canada (NSERC)
   [CGS-D]
FX Natural Sciences and Engineering Research Council of Canada (NSERC)
   [RGPIN 03666-14 to C. L. C., CGS-D to L. M.], a Connaught New
   Investigator Award (to C. L. C.); J. P. Bickell Foundation (to C. L.
   C.); L. M. was funded by an OntarioGraduate Scholarship; B. J. B. holds
   the Banbury Chair in Medical Research at the University of Toronto and
   work in his lab is funded from a CIHR Foundation grant. Funding for open
   access charge: NSERC grant.
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NR 63
TC 17
Z9 18
U1 0
U2 10
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0305-1048
EI 1362-4962
J9 NUCLEIC ACIDS RES
JI Nucleic Acids Res.
PD APR 8
PY 2019
VL 47
IS 6
BP 2856
EP 2870
DI 10.1093/nar/gkz010
PG 15
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA HY2PJ
UT WOS:000467964800018
PM 30698747
OA Green Published, Green Submitted, gold
DA 2025-04-10
ER

PT J
AU Lu, S
   Yin, XM
AF Lu, Shu
   Yin, Xiaomin
TI Overexpression of Dyrk1A regulates cardiac troponin T splicing in cells
   and mice
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE Cardiac troponin T; Exon 5; Alternative splicing; Dyrk1A
ID CONGENITAL HEART-DEFECTS; DOWN-SYNDROME; MOUSE MODEL; GENE; ISOFORMS;
   EXPRESSION; MUTATION; DOSAGE; ADULT; EXON
AB The human heart expresses four isoforms of cardiac troponin T (cTnT) through alternative splicing of exons 4 and 5 of the cTnT gene. Alternative splicing of cTnT exon 5 is developmentally regulated. cTnT isoforms containing exon 5 are expressed in the fetal and neonatal heart but not in the mature heart. SRp55 is an essential splicing factor involved in cTnT exon 5 splicing and it is phosphorylated by Dyrk1A (dual specificity tyrosine phosphorylation regulated kinase 1A). In the present study, we found Dyrk1A interacted with SRp55 and enhanced its promotion of cTnT exon 5 inclusion. The shift from cTnT exon 5 inclusion to exclusion during development was delayed in the heart of Ts65Dn mice due to Dyrk1A overexpression. These results provide new insight into the role of Dyrk1A in the neonatal cardiac development. (C) 2016 Elsevier Inc. All rights reserved.
C1 [Lu, Shu] Nantong Univ, Affiliated Hosp, Dept Intens Care Unit, Nantong 226001, Jiangsu, Peoples R China.
   [Yin, Xiaomin] Nantong Univ, Sch Med, Dept Biochem, Nantong 226001, Jiangsu, Peoples R China.
   [Yin, Xiaomin] Capital Med Univ, Xuanwu Hosp, Dept Pharmacol, Beijing 100053, Peoples R China.
C3 Nantong University; Nantong University; Capital Medical University
RP Yin, XM (corresponding author), Nantong Univ, Sch Med, Dept Biochem, Nantong 226001, Jiangsu, Peoples R China.
EM yinxiaomin@126.com
FU Natural Science Foundation of Nantong University [14ZY020]; National
   Natural Science Foundation of China [81503077]; Basic Research Program
   of Jiangsu Education Department Grant [13KJB320015]; Priority Academic
   Program Development of Jiangsu Higher Education Institution (PAPD); Open
   Program of Key Laboratory Foundation of Capital Medical University
   [1300-1140170555]
FX This work was supported in part by funds from Natural Science Foundation
   of Nantong University (14ZY020); National Natural Science Foundation of
   China Grant (grant 81503077); Basic Research Program of Jiangsu
   Education Department Grant (grant 13KJB320015); and a project funded by
   the Priority Academic Program Development of Jiangsu Higher Education
   Institution (PAPD); The Open Program of Key Laboratory Foundation of
   Capital Medical University (1300-1140170555).
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U2 4
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD MAY 13
PY 2016
VL 473
IS 4
BP 993
EP 998
DI 10.1016/j.bbrc.2016.04.004
PG 6
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA DL7MB
UT WOS:000375823700034
PM 27049307
DA 2025-04-10
ER

PT J
AU Huang, HG
   Zhang, B
   Hartenstein, PA
   Chen, JN
   Lin, S
AF Huang, HG
   Zhang, B
   Hartenstein, PA
   Chen, JN
   Lin, S
TI NXT2 is required for embryonic heart development in zebrafish
SO BMC DEVELOPMENTAL BIOLOGY
LA English
DT Article
ID NUCLEAR-PORE COMPLEX; CARDIAC-VALVE FORMATION; MESSENGER-RNA EXPORT;
   NUCLEOCYTOPLASMIC TRANSPORT; MENTAL-RETARDATION; GENE-EXPRESSION;
   PROTEIN; TAP; PATHWAY; MUTATION
AB Background: NXT2 is a member of NXT family proteins that are generally involved in exporting nuclear RNA in eukaryotic cells. It is not known if NXT2 has any function in specific biological processes.
   Results: A zebrafish mutant exhibiting specific heart defects during embryogenesis was generated by animal cloning- mediated retroviral insertions. Molecular analysis indicated that the mutant phenotype was caused by a disruption of NXT2. Whole- mount RNA in situ hybridization showed that NXT2 transcripts were clearly detectable in embryonic heart as well as other tissues. Further analysis revealed that expression level of one form of alternative splicing NXT2 mRNA transcripts was significantly reduced, resulting in deficient myocardial cell differentiation and the malformation of cardiac valve at the atrioventricular boundary. The defects could be reproduced by morpholino anti- sense oligo knockdown of NXT2.
   Conclusion: NXT2 has a critical role in maintaining morphogenetic integrity of embryonic heart in vertebrate species.
C1 Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA.
   Peking Univ, Coll Life Sci, Ctr Dev Biol & Genet, Beijing 100871, Peoples R China.
C3 University of California System; University of California Los Angeles;
   Peking University
RP Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA.
EM haigenh@ucla.edu; zhangbo@pku.org.cn; pez2001us@yahoo.com;
   chenjn@mcdb.ucla.edu; shuolin@ucla.edu
RI Zhang, Bo/K-7162-2012; Chen, Jau-Nian/AAM-7808-2020
OI Chen, Jau-Nian/0000-0001-8807-3607
FU NICHD NIH HHS [R01HD41367, R01 HD041367] Funding Source: Medline; NIDDK
   NIH HHS [R01 DK065638, R01 DK65638] Funding Source: Medline
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NR 50
TC 44
Z9 51
U1 0
U2 7
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1471-213X
J9 BMC DEV BIOL
JI BMC Dev. Biol.
PD MAR 24
PY 2005
VL 5
AR 7
DI 10.1186/1471-213X-5-7
PG 12
WC Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Developmental Biology
GA 997VP
UT WOS:000234277200001
PM 15790397
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Li, XY
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   Yu, YW
   Jin, J
AF Li, Xiaoyong
   Shi, Lei
   Xu, Ming
   Zheng, Xun
   Yu, Yiwen
   Jin, Jing
TI RCAN1 Mutation and Functional Characterization in Children with
   Sporadic Congenital Heart Disease
SO PEDIATRIC CARDIOLOGY
LA English
DT Article
DE Congenital heart defect; DSCR1; Mutation; Down syndrome
ID DOWN-SYNDROME; TRANSCRIPTION FACTOR; NF-ATC; DSCR1; ASSOCIATION;
   INHIBITOR; DEFECTS; NEURONS; REGION; ROLES
AB Congenital heart disease (CHD) is the most frequent birth defect. RCAN1 (regulator of calcineurin 1) contributes to CHD in Down syndrome. However, whether RCAN1 is also associated with nonsyndromic CHD remains unclear. This study sequenced the exons and flanking region of RCAN1 in 128 sporadic CHD patients and 150 normal controls. We identified six novel heterozygous mutations in CHD patients. Functional assay showed that the g.482G > T could obviously raise the promoter activity of RCAN1.4 in vitro; However, we failed to detect the expression of RCAN1 in the right auricle, which made it confused to evaluate the pathogenicity of this mutation. In addition, we demonstrated that c.290T > C and g.1056+58C > A had no effect on the alternative splicing of RCAN1. The *196C > T, *790G > A, and *1278C > G did not influence the translation of RCAN1 post transcription. In conclusion, a novel mutation of g.482G > T in RCAN1 may be related to CHD by causing overexpression of RCAN1.4.
C1 [Li, Xiaoyong; Shi, Lei; Xu, Ming; Zheng, Xun; Yu, Yiwen; Jin, Jing] Wuhan Asia Heart Hosp, Cardiac Dynam Lab, Dept Cardiac Surg, Wuhan 430022, Hubei, Peoples R China.
RP Jin, J (corresponding author), Wuhan Asia Heart Hosp, Cardiac Dynam Lab, Dept Cardiac Surg, Wuhan 430022, Hubei, Peoples R China.
EM jjgf801206@sina.com
OI li, xiaoyong/0009-0008-3199-6441
FU Wuhan Municipal Planning Commission of Science and Research Fund
   [WX15A11]
FX The authors feel grateful to the children and parents involved in the
   study. This research was funded by Grant WX15A11 from Wuhan Municipal
   Planning Commission of Science and Research Fund. We would like to thank
   the great assistance from Dr. Chun Wu (Children's Hospital of Chongqing
   Medical University).
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NR 25
TC 7
Z9 8
U1 0
U2 2
PU SPRINGER
PI NEW YORK
PA 233 SPRING ST, NEW YORK, NY 10013 USA
SN 0172-0643
EI 1432-1971
J9 PEDIATR CARDIOL
JI Pediatr. Cardiol.
PD FEB
PY 2018
VL 39
IS 2
BP 226
EP 235
DI 10.1007/s00246-017-1746-y
PG 10
WC Cardiac & Cardiovascular Systems; Pediatrics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Pediatrics
GA FV0UQ
UT WOS:000424275400002
PM 28993896
DA 2025-04-10
ER

PT J
AU Bélanger, C
   Bérubé-Simard, FA
   Leduc, E
   Bernas, G
   Campeau, PM
   Lalani, SR
   Martin, DM
   Bielas, S
   Moccia, A
   Srivastava, A
   Silversides, DW
   Pilon, N
AF Belanger, Catherine
   Berube-Simard, Felix-Antoine
   Leduc, Elizabeth
   Bernas, Guillaume
   Campeau, Philippe M.
   Lalani, Seema R.
   Martin, Donna M.
   Bielas, Stephanie
   Moccia, Amanda
   Srivastava, Anshika
   Silversides, David W.
   Pilon, Nicolas
TI Dysregulation of cotranscriptional alternative splicing underlies CHARGE
   syndrome
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
   AMERICA
LA English
DT Article
DE alternative splicing; CHARGE syndrome; neural crest cells; sex reversal;
   Fam172a
ID CHD7 MUTATION; ARGONAUTE COMPLEXES; GENE-EXPRESSION; MOUSE MODEL;
   PROTEIN; TRANSCRIPTION; HAPLOINSUFFICIENCY; PHENOTYPE; DEFECTS; MICE
AB CHARGE syndrome-which stands for coloboma of the eye, heart defects, atresia of choanae, retardation of growth/development, genital abnormalities, and ear anomalies-is a severe developmental disorder with wide phenotypic variability, caused mainly by mutations in CHD7 (chromodomain helicase DNA-binding protein 7), known to encode a chromatin remodeler. The genetic lesions responsible for CHD7 mutation-negative cases are unknown, at least in part because the pathogenic mechanisms underlying CHARGE syndrome remain poorly defined. Here, we report the characterization of a mouse model for CHD7 mutation-negative cases of CHARGE syndrome generated by insertional mutagenesis of Fam172a (family with sequence similarity 172, member A). We show that Fam172a plays a key role in the regulation of cotranscriptional alternative splicing, notably by interacting with Ago2 (Argonaute-2) and Chd7. Validation studies in a human cohort allow us to propose that dysregulation of cotranscriptional alternative splicing is a unifying pathogenic mechanism for both CHD7 mutation-positive and CHD7 mutation-negative cases. We also present evidence that such splicing defects can be corrected in vitro by acute rapamycin treatment.
C1 [Belanger, Catherine; Berube-Simard, Felix-Antoine; Leduc, Elizabeth; Bernas, Guillaume; Pilon, Nicolas] Univ Quebec Montreal, Dept Biol Sci, Mol Genet Dev Lab, Montreal, PQ H2X 3Y7, Canada.
   [Belanger, Catherine; Berube-Simard, Felix-Antoine; Leduc, Elizabeth; Bernas, Guillaume; Pilon, Nicolas] Univ Quebec Montreal, BioMed Res Ctr, Montreal, PQ H2X 3Y7, Canada.
   [Campeau, Philippe M.] Univ Montreal, Dept Pediat, Montreal, PQ H3T 1C5, Canada.
   [Campeau, Philippe M.] Univ Montreal, Ctr Hosp Univ St Justine, Res Ctr, Montreal, PQ H3T 1C5, Canada.
   [Martin, Donna M.] Univ Michigan, Dept Pediat, Sch Med, Ann Arbor, MI 48109 USA.
   [Martin, Donna M.; Bielas, Stephanie; Moccia, Amanda; Srivastava, Anshika] Univ Michigan, Dept Human Genet, Sch Med, Ann Arbor, MI 48109 USA.
   [Bielas, Stephanie; Moccia, Amanda; Srivastava, Anshika] Univ Michigan, Sch Med, Dept Neurosci, Ann Arbor, MI 48109 USA.
   [Silversides, David W.] Univ Montreal, Dept Vet Biomed, Fac Vet Med, Montreal, PQ J2S 2M2, Canada.
C3 University of Quebec; University of Quebec Montreal; University of
   Quebec; University of Quebec Montreal; Universite de Montreal;
   Universite de Montreal; Centre Hospitalier Universitaire Sainte-Justine;
   University of Michigan System; University of Michigan; University of
   Michigan System; University of Michigan; University of Michigan System;
   University of Michigan; Universite de Montreal
RP Pilon, N (corresponding author), Univ Quebec Montreal, Dept Biol Sci, Mol Genet Dev Lab, Montreal, PQ H2X 3Y7, Canada.; Pilon, N (corresponding author), Univ Quebec Montreal, BioMed Res Ctr, Montreal, PQ H2X 3Y7, Canada.
EM pilon.nicolas@uqam.ca
RI ; Campeau, Philippe/J-8614-2015
OI Pilon, Nicolas/0000-0003-3641-0776; Campeau,
   Philippe/0000-0001-9713-7107; Srivastava, Anshika/0000-0003-0699-3704
FU CHARGE Syndrome Foundation; Canadian Institutes of Health Research Grant
   [376482]; Fondation du Grand Defi Pierre Lavoie; NIH [R01NS097862, R01
   DC009410, R01 DC014456]; Donita B. Sullivan, MD Research Professorship
   in Pediatrics and Communicable Diseases; NIH Training Grant Michigan
   Predoctoral Training in Genetics [T32GM007544]; National Institute of
   General Medical Sciences [T32GM007544] Funding Source: NIH RePORTER
FX We thank D. Raiwet (University of Montreal) for the phenotypic screening
   of the Toupee line; O. Souchkova [University of Quebec at Montreal
   (UQAM)] for help with mouse husbandry and breeding; D. Flipo (UQAM) for
   assistance with confocal imaging and FACS analyses; R. Moreau's
   laboratory (UQAM) for help with microcomputed tomography; Dr. M. Simard
   for kindly providing the psi-CHECK2-let-7x8 vector; Dr. J. W. Belmont
   and P. Hernandez (Baylor College of Medicine) for generously providing
   the lymphoblastoid cell lines; the Proteomics Discovery Platform of the
   Institut de Recherches Cliniques de Montreal for the mass spectrometry
   analyses; and the Massively Parallel Sequencing Platform and the
   Bioinformatics Platform of McGill University and Genome Quebec
   Innovation Center for the deep sequencing and the analyses of sequencing
   results, respectively. This work was funded by grants from the CHARGE
   Syndrome Foundation and the Canadian Institutes of Health Research Grant
   376482 (to N.P.). C.B. is also supported by a doctoral scholarship from
   the Fondation du Grand Defi Pierre Lavoie. N.P. is a Senior Research
   Scholar of the Fonds de la Recherche du Quebec-Sante as well as the
   recipient of the UQAM Research Chair on Rare Genetic Diseases. This work
   was also funded by NIH Grants R01NS097862 (to S.B.), R01 DC009410 (to
   D.M.M.), and R01 DC014456 (to D.M.M.); Donita B. Sullivan, MD Research
   Professorship in Pediatrics and Communicable Diseases (to D.M.M.); and
   NIH Training Grant Michigan Predoctoral Training in Genetics
   (T32GM007544 to A.M.).
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NR 85
TC 22
Z9 24
U1 0
U2 8
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
EI 1091-6490
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD JAN 23
PY 2018
VL 115
IS 4
BP E620
EP E629
DI 10.1073/pnas.1715378115
PG 10
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA FT4BW
UT WOS:000423097800011
PM 29311329
OA hybrid, Green Published, Green Accepted
DA 2025-04-10
ER

PT J
AU Astrof, S
   Crowley, D
   Hynes, RO
AF Astrof, Sophie
   Crowley, Denise
   Hynes, Richard O.
TI Multiple cardiovascular defects caused by the absence of alternatively
   spliced segments of fibronectin
SO DEVELOPMENTAL BIOLOGY
LA English
DT Article
DE cardiovascular development; fibronectin; alternative splicing
ID EXTRA DOMAIN-A; ED-B DOMAIN; MESSENGER-RNA; CELL-ADHESION;
   SMOOTH-MUSCLE; ISOFORM DISTRIBUTION; SIGNAL-TRANSDUCTION; BINDING
   DOMAINS; RAT FIBRONECTIN; III REPEATS
AB Alternatively spliced variants of fibronectin (FN) containing exons EIIIA and EIIIB are expressed around newly forming vessels in development and disease but are downregulated in mature vasculature. The sequences and patterns of expression of these splice variants are highly conserved among vertebrates, suggestive of their biological importance; however the functions of EIIIA and EIIIB-containing FNs are unknown. To understand the role(s) of these splice variants, we deleted both EIIIA and EIIIB exons from the FN gene and observed embryonic lethality with incomplete penetrance by embryonic day 10.5. Deletion of both EIIIA and EIIIB exons did not affect synthesis or cell surface deposition of FN, indicating that embryonic lethality was due specifically to the absence of EIIIA and EIIIB exons from FN. EIIIA/EIIIB double-null embryos displayed multiple embryonic cardiovascular defects, including vascular hemorrhage, failure of remodeling embryonic and yolk sac vasculature, defective placental angiogenesis and heart defects. In addition, we observed defects in coverage and association with dorsal aortae of alpha-smooth-muscle-actin-positive cells. Our studies indicate that the presence or absence of EIIIA and EIIIB exons alters the function of FN and demonstrate the requirement for these alternatively spliced exons in cardiovascular development. (C) 2007 Elsevier Inc. All rights reserved.
C1 MIT, Howard Hughes Med Inst, Ctr Canc Res, Dept Biol, Cambridge, MA 02139 USA.
C3 Howard Hughes Medical Institute; Massachusetts Institute of Technology
   (MIT)
RP Hynes, RO (corresponding author), MIT, Howard Hughes Med Inst, Ctr Canc Res, Dept Biol, Cambridge, MA 02139 USA.
EM rohynes@mit.edu
RI Astrof, Sophie/I-4071-2019
OI Astrof, Sophie/0000-0001-9338-9083
FU NHLBI NIH HHS [P01 HL066105, P01-HL066105, P01 HL066105-06A1] Funding
   Source: Medline
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NR 58
TC 108
Z9 142
U1 0
U2 6
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0012-1606
EI 1095-564X
J9 DEV BIOL
JI Dev. Biol.
PD NOV 1
PY 2007
VL 311
IS 1
BP 11
EP 24
DI 10.1016/j.ydbio.2007.07.005
PG 14
WC Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Developmental Biology
GA 228CC
UT WOS:000250703700002
PM 17706958
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Ogren, A
   Kibiryeva, N
   Marshall, J
   O'Brien, JE
   Bittel, DC
AF Ogren, Allison
   Kibiryeva, Nataliya
   Marshall, Jennifer
   O'Brien, James E., Jr.
   Bittel, Douglas C.
TI Snord94 expression level alters methylation at C<SUP>62</SUP> in snRNA
   U6
SO PLOS ONE
LA English
DT Article
AB Understanding the regulation of development can help elucidate the pathogenesis behind many developmental defects found in humans and other vertebrates. Evidence has shown that alternative splicing of messenger RNA (mRNA) plays a role in developmental regulation, but our knowledge of the underlying mechanisms that regulate alternative splicing are incomplete. Notably, a subset of small noncoding RNAs known as scaRNAs (small cajal body associated RNAs) contribute to spliceosome maturation and function through guiding covalent modification of spliceosomal RNAs with either methylation or pseudouridylation on specific nucleotides, but the developmental significance of these modifications is not well understood. Our focus is on one such scaRNA, known as SNORD94 or U94, that guides methylation on one specific cytosine (C-62) on spliceosomal RNA U6, thus potentially altering spliceosome function during embryogenesis. We previously showed that in the myocardium of infants with heart defects, mRNA is alternatively spliced as compared to control tissues. We also demonstrated that alternatively spliced genes were concentrated in the pathways that control heart development. Furthermore, we showed that modifying expression of scaRNAs alters mRNA splicing in human cells, and zebrafish embryos. Here we present evidence that SNORD94 levels directly influence levels of methylation at its target region in U6, suggesting a potential mechanism for modifying alternative splicing of mRNA. The potential importance of scaRNAs as a developmentally important regulatory mechanism controlling alternative splicing of mRNA is unappreciated and needs more research.
C1 [Ogren, Allison; Bittel, Douglas C.] Kansas City Univ Med & Biosci KCU, Coll Biosci, Kansas City, MO 64106 USA.
   [Kibiryeva, Nataliya; Marshall, Jennifer; O'Brien, James E., Jr.; Bittel, Douglas C.] Childrens Mercy Hosp, Ward Family Heart Ctr, Kansas City, MO 64108 USA.
C3 Kansas City University; Children's Mercy Hospital
RP Bittel, DC (corresponding author), Kansas City Univ Med & Biosci KCU, Coll Biosci, Kansas City, MO 64106 USA.; Bittel, DC (corresponding author), Childrens Mercy Hosp, Ward Family Heart Ctr, Kansas City, MO 64108 USA.
EM dbittel@kcumb.edu
OI Ogren, Allison/0000-0001-8933-3968
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NR 22
TC 2
Z9 3
U1 0
U2 2
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD DEC 5
PY 2019
VL 14
IS 12
AR e0226035
DI 10.1371/journal.pone.0226035
PG 11
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA LP0JY
UT WOS:000534009700092
PM 31805133
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Fan, C
   Chen, QY
   Wang, QK
AF Fan, Chun
   Chen, Qiuyun
   Wang, Qing Kenneth
TI Functional Role of Transcriptional Factor TBX5 in Pre-mRNA Splicing and
   Holt-Oram Syndrome via Association with SC35
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID GENE FAMILY; MUTATIONS; PROTEIN; HEART; COACTIVATOR; BINDING; LIMB;
   SPECIFICITY; MECHANISMS; INTERACTS
AB TBX5 is a T-box transcriptional factor required for cardio-genesis and limb development. TBX5 mutations cause Holt-Oram syndrome characterized by congenital heart defects and upper limb deformations. Here we establish a novel function for TBX5 in pre-mRNA splicing, and we show that this function is relevant to the pathogenesis of Holt-Oram syndrome, providing a novel pathogenic mechanism for the disease. Proteomics in combination with affinity purification identifies splicing factor SC35 as a candidate TBX5-associating protein. Co-immunoprecipitation and glutathione S-transferase pulldown assays confirm the complex formation between TBX5 and SC35. TBX5 can bind to RNA homopolymers (polyribonucleotides) and to the 5'-splice site, which overrides the binding of SC35 to the same RNA. Overexpression of TBX5 increases the efficiency of pre-mRNA splicing and regulates alternative splice site selection. However, co-expression of TBX5 and SC35 antagonizes each other's positive effect on splicing. The most severe TBX5 mutation, G80R, with complete penetrance of the cardiac phenotype, strongly affects pre-mRNA splicing, whereas other mutations with incomplete penetrance of the cardiac phenotype, including R237Q, do not alter the splicing activity of TBX5. This study establishes TBX5 as the first cardiac gene and the first human disease gene with dual roles in both transcriptional activation and pre-mRNA splicing.
C1 Cleveland Clin, Ctr Cardiovasc Genet, Dept Mol Cardiol, Lerner Res Inst, Cleveland, OH 44195 USA.
   Huazhong Univ Sci & Technol, Key Lab Mol Biophys, Minist Educ, Wuhan 430074, Peoples R China.
   Huazhong Univ Sci & Technol, Ctr Human Genome Res, Wuhan 430074, Peoples R China.
C3 Cleveland Clinic Foundation; Huazhong University of Science &
   Technology; Huazhong University of Science & Technology
RP Wang, QK (corresponding author), Cleveland Clin, Ctr Cardiovasc Genet NE40, Cleveland, OH 44195 USA.
EM wangq2@ccf.org
RI chen, qy/JXM-3217-2024
FU China Natural Science Foundation [30670857]
FX This work was supported in part by China Natural Science Foundation
   Grant 30670857 ( to Q. W.).
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NR 33
TC 42
Z9 47
U1 0
U2 7
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD SEP 18
PY 2009
VL 284
IS 38
BP 25653
EP 25663
DI 10.1074/jbc.M109.041368
PG 11
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 493LK
UT WOS:000269738000023
PM 19648116
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Tooley, M
   Lynch, D
   Bernier, F
   Parboosingh, J
   Bhoj, E
   Zackai, E
   Calder, A
   Itasaki, N
   Wakeling, E
   Scott, R
   Lees, M
   Clayton-Smith, J
   Blyth, M
   Morton, J
   Shears, D
   Kini, U
   Homfray, T
   Clarke, A
   Barnicoat, A
   Wallis, C
   Hewitson, R
   Offiah, A
   Saunders, M
   Langton-Hewer, S
   Hilliard, T
   Davis, P
   Smithson, S
AF Tooley, Madeleine
   Lynch, Danielle
   Bernier, Francois
   Parboosingh, Jillian
   Bhoj, Elizabeth
   Zackai, Elaine
   Calder, Alistair
   Itasaki, Nobue
   Wakeling, Emma
   Scott, Richard
   Lees, Melissa
   Clayton-Smith, Jill
   Blyth, Moira
   Morton, Jenny
   Shears, Debbie
   Kini, Usha
   Homfray, Tessa
   Clarke, Angus
   Barnicoat, Angela
   Wallis, Colin
   Hewitson, Rebecca
   Offiah, Amaka
   Saunders, Michael
   Langton-Hewer, Simon
   Hilliard, Tom
   Davis, Peter
   Smithson, Sarah
TI Cerebro-Costo-Mandibular Syndrome: Clinical, Radiological, and Genetic
   Findings
SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A
LA English
DT Article
DE Cerebro-costo-mandibular syndrome; CCM syndrome; rib gaps; micrognathia;
   Pierre Robin syndrome
ID PRENATAL ULTRASONOGRAPHIC DIAGNOSIS; OF-THE-LITERATURE; MICROGNATHIA;
   DEFECTS; RIBS; MACHINERY; ANOMALIES; ORIGIN
AB Cerebro-Costo-Mandibular syndrome (CCMS) is a rare autosomal dominant condition comprising branchial archderivative malformations with striking rib-gaps. Affected patients often have respiratory difficulties, associated with upper airway obstruction, reduced thoracic capacity, and scoliosis. We describe a series of 12 sporadic and 4 familial patients including 13 infants/children and 3 adults. Severe micrognathia and reduced numbers of ribs with gaps are consistent findings. Cleft palate, feeding difficulties, respiratory distress, tracheostomy requirement, and scoliosis are common. Additional malformations such as horseshoe kidney, hypospadias, and septal heart defect may occur. Microcephaly and significant developmental delay are present in a small minority of patients. Key radiological findings are of a narrow thorax, multiple posterior rib gaps and abnormal costo-transverse articulation. A novel finding in 2 patients is bilateral accessory ossicles arising from the hyoid bone. Recently, specific mutations in SNRPB, which encodes components of the major spliceosome, have been found to cause CCMS. These mutations cluster in an alternatively spliced regulatory exon and result in altered SNRPB expression. DNA was available from 14 patients and SNRPB mutations were identified in 12 (4 previously reported). Eleven had recurrent mutations previously described in patients with CCMS and one had a novel mutation in the alternative exon. These results confirm the specificity of SNRPB mutations in CCMS and provide further evidence for the role of spliceosomal proteins in craniofacial and thoracic development. (C) 2016 Wiley Periodicals, Inc.
C1 [Tooley, Madeleine; Smithson, Sarah] St Michaels Hosp, Dept Clin Genet, Southwell St, Bristol BS2 8EG, Avon, England.
   [Lynch, Danielle; Bernier, Francois; Parboosingh, Jillian] Univ Calgary, Dept Med Genet, Calgary, AB, Canada.
   [Bhoj, Elizabeth; Zackai, Elaine] Childrens Hosp Philadelphia, Dept Clin Genet, Philadelphia, PA 19104 USA.
   [Calder, Alistair] Great Ormond St Childrens Hosp, Dept Radiol, London, England.
   [Itasaki, Nobue] Univ Bristol, Ctr Comparat & Clin Anat, Bristol, Avon, England.
   [Wakeling, Emma] North West London Hosp NHS Trust, North West Thames Reg Genet Serv, London, England.
   [Scott, Richard; Lees, Melissa; Barnicoat, Angela] Great Ormond St Childrens Hosp, Dept Clin Genet, London, England.
   [Clayton-Smith, Jill] St Marys Hosp, Dept Clin Genet, Manchester, Lancs, England.
   [Blyth, Moira] Chapel Allerton Hosp, Dept Clin Genet, Leeds, W Yorkshire, England.
   [Morton, Jenny] Birmingham Womens Hosp, Dept Clin Genet, Birmingham, W Midlands, England.
   [Shears, Debbie; Kini, Usha] Churchill Hosp, Dept Clin Genet, Oxford, England.
   [Homfray, Tessa] St George Hosp, Dept Clin Genet, London, England.
   [Clarke, Angus] Univ Wales Hosp, Dept Clin Genet, Cardiff, S Glam, Wales.
   [Wallis, Colin; Hewitson, Rebecca] Great Ormond St Childrens Hosp, Dept Paediat Resp Med, London, England.
   [Offiah, Amaka] Sheffield Childrens NHS Fdn Trust, Acad Unit Child Hlth, Sheffield, S Yorkshire, England.
   [Saunders, Michael] St Michaels Hosp, Dept Otolaryngol, Bristol, Avon, England.
   [Langton-Hewer, Simon; Hilliard, Tom] Bristol Royal Hosp Children, Dept Paediat Resp Med, London, England.
   [Davis, Peter] Bristol Royal Hosp Children, Dept Paediat Intens Care, Bristol, Avon, England.
C3 University of Calgary; University of Pennsylvania; Pennsylvania
   Medicine; Childrens Hospital of Philadelphia; University of London;
   University College London; Great Ormond Street Hospital for Children NHS
   Foundation Trust; University of Bristol; University of London;
   University College London; Great Ormond Street Hospital for Children NHS
   Foundation Trust; University of Manchester; Chapel Allerton Hospital;
   Birmingham Women's Hospital; University of Oxford; City St Georges,
   University of London; Cardiff University; University of London;
   University College London; Great Ormond Street Hospital for Children NHS
   Foundation Trust; Sheffield Children's NHS Foundation Trust; Bristol
   Royal Hospital For Children; Bristol Royal Hospital For Children
RP Smithson, S (corresponding author), St Michaels Hosp, Dept Clin Genet, Southwell St, Bristol BS2 8EG, Avon, England.
EM Sarah.Smithson@UHBristol.nhs.uk
RI Clarke, Anthony/KIH-6024-2024; Bernier, Dr. Francois/AAP-2174-2020;
   Offiah, Amaka/G-2911-2010
OI Wakeling, Emma/0000-0001-5712-0044; Offiah, Amaka/0000-0001-8991-5036;
   Blyth, Moira/0000-0002-4312-413X; Itasaki, Nobue/0000-0003-0587-9141;
   Hewitson, Rebecca/0000-0002-0024-1723; Kini, Usha/0000-0001-9111-5433;
   Bernier, Francois/0000-0001-7063-4269
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NR 38
TC 20
Z9 24
U1 0
U2 15
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1552-4825
EI 1552-4833
J9 AM J MED GENET A
JI Am. J. Med. Genet. A
PD MAY
PY 2016
VL 170
IS 5
BP 1115
EP 1126
DI 10.1002/ajmg.a.37587
PG 12
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA DR5LH
UT WOS:000379944000003
PM 26971886
DA 2025-04-10
ER

PT J
AU Geisler, SB
   Robinson, D
   Hauringa, M
   Raeker, MO
   Borisov, AB
   Westfall, MV
   Russell, MW
AF Geisler, Sarah B.
   Robinson, Dustin
   Hauringa, Maria
   Raeker, Maide O.
   Borisov, Andrei B.
   Westfall, Margaret V.
   Russell, Mark W.
TI Obscurin-like 1, OBSL1, is a novel cytoskeletal protein related to
   obscurin
SO GENOMICS
LA English
DT Article
DE obscurin; obscurin-like 1; SPEG; intercalated disc; Z line; M band;
   cytoskeleton
ID LIGHT-CHAIN KINASES; CARDIAC MYOCYTES; CAENORHABDITIS-ELEGANS;
   SARCOPLASMIC-RETICULUM; EPIDERMOLYSIS-BULLOSA; NUCLEAR-ENVELOPE;
   SKELETAL-MUSCLE; GENE; PLECTIN; ORGANIZATION
AB Cytoskeletal adaptor proteins serve vital functions in linking the internal cytoskeleton of cells to the cell membrane, particularly at sites of cell-cell and cell-matrix interactions. The importance of these adaptors to the structural integrity of the cell is evident from the number of clinical disease states attributable to defects in these networks. In the heart, defects in the cytoskeletal support system that surrounds and supports the myofibril result in dilated cardiomyopathy and congestive heart failure. In this study, we report the cloning and characterization of a novel cytoskeletal adaptor, obscurin-like 1 (OBSL1), which is closely related to obscurin, a giant structural protein required for sarcomere assembly. Multiple isoforms arise from alternative splicing, ranging in predicted molecular mass from 130 to 230 kDa. OBSL1 is located on human chromosome 2q35 within 100 kb of SPEG, another gene related to obscurin. It is expressed in a broad range of tissues and localizes to the intercalated discs, to the perinuclear region, and overlying the Z lines and M bands of adult rat cardiac myocytes. Further characterization of this novel cytoskeletal linker will have important implications for understanding the physical interactions that stabilize and support cell-matrix, cell-cell, and intracellular cytoskeletal connections. (c) 2007 Elsevier Inc. All rights reserved.
C1 Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA.
   Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA.
C3 University of Michigan System; University of Michigan; University of
   Michigan System; University of Michigan
RP Russell, MW (corresponding author), Univ Michigan, Dept Pediat & Communicable Dis, L1242 Womens Hosp Box 0204,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA.
EM mruss@umich.edu
OI Westfall, Margaret/0000-0001-9491-0125
FU NHLBI NIH HHS [HL075093, R01 HL075093] Funding Source: Medline
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NR 39
TC 63
Z9 80
U1 2
U2 8
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0888-7543
EI 1089-8646
J9 GENOMICS
JI Genomics
PD APR
PY 2007
VL 89
IS 4
BP 521
EP 531
DI 10.1016/j.ygeno.2006.12.004
PG 11
WC Biotechnology & Applied Microbiology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Genetics & Heredity
GA 155EF
UT WOS:000245560000009
PM 17289344
OA Green Accepted, Bronze
DA 2025-04-10
ER

PT J
AU Chen, YY
   Yang, BX
   Zhang, XM
   Chen, SC
   Wang, MH
   Hu, LY
   Pan, NN
   Li, SY
   Shi, WH
   Yang, ZH
   Wang, L
   Tan, YJ
   Wang, J
   Wang, YL
   Xing, QH
   Ma, ZH
   Li, JS
   Huang, HF
   Zhang, JL
   Xu, CM
AF Chen, Yiyao
   Yang, Bingxin
   Zhang, Xiaoyu Merlin
   Chen, Songchang
   Wang, Minhui
   Hu, Liya
   Pan, Nina
   Li, Shuyuan
   Shi, Weihui
   Yang, Zhenhua
   Wang, Li
   Tan, Yajing
   Wang, Jian
   Wang, Yanlin
   Xing, Qinghe
   Ma, Zhonghua
   Li, Jinsong
   Huang, He-feng
   Zhang, Jinglan
   Xu, Chenming
TI Biallelic variants in RBM42 cause a multisystem disorder with
   neurological, facial, cardiac, and musculoskeletal involvement
SO PROTEIN & CELL
LA English
DT Article
DE RBM42 gene; RNA-binding protein; neurodevelopmental disorder; Au-Kline
   syndrome; alternative splicing
ID HNRNP K; PROTEINS; DISRUPTION; FRAMEWORK; GENOME
AB Here, we report a previously unrecognized syndromic neurodevelopmental disorder associated with biallelic loss-of-function variants in the RBM42 gene. The patient is a 2-year-old female with severe central nervous system (CNS) abnormalities, hypotonia, hearing loss, congenital heart defects, and dysmorphic facial features. Familial whole-exome sequencing (WES) reveals that the patient has two compound heterozygous variants, c.304C>T (p.R102*) and c.1312G>A (p.A438T), in the RBM42 gene which encodes an integral component of splicing complex in the RNA-binding motif protein family. The p.A438T variant is in the RRM domain which impairs RBM42 protein stability in vivo. Additionally, p.A438T disrupts the interaction of RBM42 with hnRNP K, which is the causative gene for Au-Kline syndrome with overlapping disease characteristics seen in the index patient. The human R102* or A438T mutant protein failed to fully rescue the growth defects of RBM42 ortholog knockout & UDelta;FgRbp1 in Fusarium while it was rescued by the wild-type (WT) human RBM42. A mouse model carrying Rbm42 compound heterozygous variants, c.280C>T (p.Q94*) and c.1306_1308delinsACA (p.A436T), demonstrated gross fetal developmental defects and most of the double mutant animals died by E13.5. RNA-seq data confirmed that Rbm42 was involved in neurological and myocardial functions with an essential role in alternative splicing (AS). Overall, we present clinical, genetic, and functional data to demonstrate that defects in RBM42 constitute the underlying etiology of a new neurodevelopmental disease which links the dysregulation of global AS to abnormal embryonic development.
C1 [Chen, Yiyao; Xing, Qinghe] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China.
   [Chen, Songchang; Shi, Weihui; Huang, He-feng; Zhang, Jinglan; Xu, Chenming] Fudan Univ, Obstet & Gynecol Hosp, Inst Reprod & Dev, Shanghai 200011, Peoples R China.
   [Chen, Yiyao; Yang, Bingxin; Chen, Songchang; Pan, Nina; Li, Shuyuan; Wang, Li; Tan, Yajing; Wang, Jian; Zhang, Jinglan; Xu, Chenming] Shanghai Jiao Tong Univ, Int Peace Matern & Child Hlth Hosp, Sch Med, Shanghai 200030, Peoples R China.
   [Chen, Yiyao; Yang, Bingxin; Li, Shuyuan; Huang, He-feng; Zhang, Jinglan] Shanghai Key Lab Embryo Original Dis, Shanghai 200030, Peoples R China.
   [Zhang, Xiaoyu Merlin; Li, Jinsong] Univ Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Chinese Acad Sci, Ctr Excellence Mol Cell Sci,State Key Lab Cell Bio, Shanghai 200031, Peoples R China.
   [Ma, Zhonghua] Zhejiang Univ, Inst Biotechnol, State Key Lab Rice Biol, Key Lab Mol Biol Crop Pathogens & Insects, Hangzhou 310058, Peoples R China.
   [Hu, Liya] Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA.
   [Xing, Qinghe] Fudan Univ, Childrens Hosp, Shanghai 201102, Peoples R China.
   [Li, Jinsong] Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China.
   [Li, Jinsong] Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Life Sci, Hangzhou 310024, Zhejiang, Peoples R China.
   [Huang, He-feng] Chinese Acad Med Sci 2019RU056, Res Units Embryo Original Dis, Shanghai 20030, Peoples R China.
C3 Fudan University; Fudan University; Shanghai Jiao Tong University;
   Chinese Academy of Sciences; University of Chinese Academy of Sciences,
   CAS; Center for Excellence in Molecular Cell Science, CAS; Zhejiang
   University; Baylor College of Medicine; Fudan University; ShanghaiTech
   University; Chinese Academy of Sciences; University of Chinese Academy
   of Sciences, CAS
RP Huang, HF; Zhang, JL; Xu, CM (corresponding author), Fudan Univ, Obstet & Gynecol Hosp, Inst Reprod & Dev, Shanghai 200011, Peoples R China.; Zhang, JL; Xu, CM (corresponding author), Shanghai Jiao Tong Univ, Int Peace Matern & Child Hlth Hosp, Sch Med, Shanghai 200030, Peoples R China.; Huang, HF; Zhang, JL (corresponding author), Shanghai Key Lab Embryo Original Dis, Shanghai 200030, Peoples R China.
EM huanghefg@hotmail.com; jinglanzhang@foxmail.com; chenming_xu2006@163.com
RI Liu, Yuxuan/JVO-7759-2024; li, xianfeng/GYD-5825-2022; Liu,
   Zhe/KEJ-5299-2024; Chenming, XU/AAI-2607-2020; ZHU,
   XIAOYU/HJY-7240-2023; Zhao, Jinghan/LBI-2002-2024; Li,
   yuancheng/IUO-3866-2023; Zhang, Jinglan/AAI-1793-2020
OI Zhang, Jinglan/0000-0002-4600-7123; Zhang, Xiaoyu/0000-0001-6088-9807
FU National Key Research and Development Program of China [2020YFA0804000,
   2021YFC2701002, 2022YFC2703702]; National Natural Science Foundation of
   China [81971344, 81901495, 82071661, 82171677, 82088102, 82192864,
   82271898]; Science and Technology Commission of Shanghai Municipality
   [17411972900, 23ZR1408000, 21Y21901002, 22S31901500]; CAMS Innovation
   Fund for Medical Sciences [2019-I2M-5-064]; Shanghai Municipal
   Commission of Health and family planning [202140110, 20215Y0216];
   Collaborative Innovation Program of Shanghai Municipal Health Commission
   [2020CXJQ01]; Clinical Research Plan of SHDC [SHDC2020CR1008A]; Shanghai
   Clinical Research Center for Gynecological Diseases [22MC1940200];
   Shanghai Frontiers Science Research Center of Reproduction and
   Development; Shanghai Urogenital System Diseases Research Center; 
   [2022ZZ01012]
FX This study was supported by the National Key Research and Development
   Program of China (Nos. 2020YFA0804000, 2021YFC2701002 and
   2022YFC2703702), the National Natural Science Foundation of China (Nos.
   81971344, 81901495, 82071661, 82171677, 82088102, 82192864 and
   82271898), the Science and Technology Commission of Shanghai
   Municipality (Nos. 17411972900, 23ZR1408000, 21Y21901002 and
   22S31901500), CAMS Innovation Fund for Medical Sciences
   (2019-I2M-5-064), Shanghai Municipal Commission of Health and family
   planning (202140110 and 20215Y0216), Collaborative Innovation Program of
   Shanghai Municipal Health Commission (2020CXJQ01), Clinical Research
   Plan of SHDC (SHDC2020CR1008A), Shanghai Clinical Research Center for
   Gynecological Diseases (22MC1940200), Shanghai Urogenital System
   Diseases Research Center (2022ZZ01012) and Shanghai Frontiers Science
   Research Center of Reproduction and Development.
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NR 59
TC 3
Z9 3
U1 5
U2 28
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 1674-800X
EI 1674-8018
J9 PROTEIN CELL
JI Protein Cell
PD JAN 3
PY 2024
VL 15
IS 1
BP 52
EP 68
DI 10.1093/procel/pwad034
EA JUL 2023
PG 17
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA FG0U3
UT WOS:001033371300001
PM 37294900
OA gold
DA 2025-04-10
ER

PT J
AU Fuentes, JJ
   Pritchard, MA
   Estivill, X
AF Fuentes, JJ
   Pritchard, MA
   Estivill, X
TI Genomic organization, alternative splicing, and expression patterns of
   the DSCR1 (Down syndrome candidate region 1) gene
SO GENOMICS
LA English
DT Article
AB Down syndrome is a major cause of mental retardation and congenital heart defects and is due to the presence of three copies of human chromosome 21 in the affected individual. We have identified a gene, DSCR1 (HGMW-approved symbol), from the region 21q22.1-q22.2, which is highly expressed in human fetal brain and adult heart. Structural features of the conceptual protein encourage us to propose involvement of DSCR1 in the regulation of transcription and/or signal transduction. Higher expression of RNA in the brains of young rats compared to adults suggests a possible role for the gene in the development of the central nervous system. We have determined the genomic organization of DSCR1 and identified three additional alternative first exons by RACE and cDNA library screening. DSCR1 spans nearly 45 kb of genomic DNA and comprises seven exons, four of which (exons 1-4) are alternative first exons. All the exons are flanked by splice junctions that conform to the consensus AG-GT motif. We have studied the expression patterns of the alternative first exons. Exon 2 was detected in fetal brain and liver by RT-PCR. Both exons 1 and 4 were differentially expressed in fetal brain, lung, liver, and kidney and in all adult tissues tested by Northern analysis with two not-able exceptions: exon 1 was not detected in adult kidney and exon 4 was not found in adult brain, The high level of expression of exon 1 in fetal brain suggests that this alternative form of DSCR1 has an important role in brain development. This information should help us to understand the possible relationship of DSCR1 with Down syndrome and aid in the development of animal models. (C) 1997 Academic Press.
C1 IRO,MED & MOL GENET CTR,DEPT MOL GENET,LHOSPITALET LLOBR 08907,BARCELONA,SPAIN.
RI Estivill, Xavier/A-3125-2013
OI Estivill, Xavier/0000-0002-0723-2256
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NR 6
TC 165
Z9 177
U1 0
U2 4
PU ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495
SN 0888-7543
J9 GENOMICS
JI Genomics
PD SEP 15
PY 1997
VL 44
IS 3
BP 358
EP 361
DI 10.1006/geno.1997.4866
PG 4
WC Biotechnology & Applied Microbiology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Genetics & Heredity
GA XY274
UT WOS:A1997XY27400015
PM 9325060
DA 2025-04-10
ER

PT J
AU Maslen, CL
   Babcock, D
   Redig, JK
   Kapeli, K
   Akkari, YM
   Olson, SB
AF Maslen, Cheryl L.
   Babcock, Darcie
   Redig, Jennifer K.
   Kapeli, Katannya
   Akkari, Yassmine M.
   Olson, Susan B.
TI CRELD2: Gene mapping, alternate splicing, and comparative genomic
   identification of the promoter region
SO GENE
LA English
DT Article
DE AVSD2; congenital heart defects; CRELD1; endocrine system; nicotinic
   acetylcholine receptor
AB CRELD2 is the second member of the CRELD family of proteins. The only other CRELD family member, encoded by CRELD1, is also known as the AVSD2 gene as mutations in CPELD1 are associated with cardiac atrioventricular septal defects (AVSD). Like CRELD1, CRELD2 is ubiquitously expressed during development and by mature tissues. Recently, a specific CRELD2 isoform (CRELD2 beta) was implicated as a regulator of a4 beta 2 nicotinic acetylcholine receptor expression, suggesting that the CRELD family has widely diverse biological roles in both developmental events and subsequent cell function. Here we report additional characterization of CRELD2, which was undertaken to further our understanding of this important family. Mapping of CRELD2 by FISH shows that it maps to 22q13 rather than the GenBank reported locus of 22p13. Comparative genomic analysis of upstream sequences shows a discrete region that is highly conserved among diverse species with hallmark features indicative of a promoter region. Functional analysis demonstrates that this region has promoter activity. Consistent with widespread expression of CRELD2, this region is GC-rich and lacks a TATA box. Overall, the highest levels of CRELD2 expression occur in adult endocrine tissues. However, alternative splicing of CRELD2 is extensive with positive identification of several splice variants expressed by most normal fetal and adult tissues. Confirmed splice variants encode 5 different CRELD2 isoforms that differ significantly in composition indicating that CRELD2 function is varied and as yet poorly understood. (c) 2006 Elsevier B.V. All rights reserved.
C1 Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97239 USA.
   Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA.
   Oregon Hlth & Sci Univ, Heart Res Ctr, Portland, OR 97239 USA.
C3 Oregon Health & Science University; Oregon Health & Science University;
   Oregon Health & Science University
RP Maslen, CL (corresponding author), Oregon Hlth & Sci Univ, Dept Med, L-465,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA.
EM maslenc@ohsu.edu
FU NCRR NIH HHS [5 M01 RR00334] Funding Source: Medline
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NR 9
TC 15
Z9 19
U1 0
U2 7
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0378-1119
EI 1879-0038
J9 GENE
JI Gene
PD NOV 1
PY 2006
VL 382
BP 111
EP 120
DI 10.1016/j.gene.2006.06.016
PG 10
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 105RQ
UT WOS:000242050400013
PM 16919896
DA 2025-04-10
ER

PT J
AU Zhu, LL
   Choudhary, K
   Gonzalez-Teran, B
   Ang, YS
   Thomas, R
   Stone, NR
   Liu, L
   Zhou, P
   Zhu, CC
   Ruan, HM
   Huang, Y
   Jin, SB
   Pelonero, A
   Koback, F
   Padmanabhan, A
   Sadagopan, N
   Hsu, A
   Costa, MW
   Gifford, CA
   van Bemmel, J
   Hüttenhain, R
   Vedantham, V
   Conklin, BR
   Black, BL
   Bruneau, BG
   Steinmetz, L
   Krogan, NJ
   Pollard, KS
   Srivastava, D
AF Zhu, Lili
   Choudhary, Krishna
   Gonzalez-Teran, Barbara
   Ang, Yen-Sin
   Thomas, Reuben
   Stone, Nicole R.
   Liu, Lei
   Zhou, Ping
   Zhu, Chenchen
   Ruan, Hongmei
   Huang, Yu
   Jin, Shibo
   Pelonero, Angelo
   Koback, Frances
   Padmanabhan, Arun
   Sadagopan, Nandhini
   Hsu, Austin
   Costa, Mauro W.
   Gifford, Casey A.
   van Bemmel, Joke
   Huttenhain, Ruth
   Vedantham, Vasanth
   Conklin, Bruce R.
   Black, Brian L.
   Bruneau, Benoit G.
   Steinmetz, Lars
   Krogan, Nevan J.
   Pollard, Katherine S.
   Srivastava, Deepak
TI Transcription Factor GATA4 Regulates Cell Type-Specific Splicing Through
   Direct Interaction With RNA in Human Induced Pluripotent Stem
   Cell-Derived Cardiac Progenitors
SO CIRCULATION
LA English
DT Article
DE GATA4 transcription factor; induced pluripotent stem cells; myocytes;
   cardiac; RNA-binding motifs; RNA splicing
ID GENOME-WIDE ANALYSIS; GENE; CARDIOMYOPATHY; MUTATIONS; DISCOVERY;
   ENDODERM; DISEASE; ROBUST; READS; RBM20
AB Background: GATA4 (GATA-binding protein 4), a zinc finger-containing, DNA-binding transcription factor, is essential for normal cardiac development and homeostasis in mice and humans, and mutations in this gene have been reported in human heart defects. Defects in alternative splicing are associated with many heart diseases, yet relatively little is known about how cell type- or cell state-specific alternative splicing is achieved in the heart. Here, we show that GATA4 regulates cell type-specific splicing through direct interaction with RNA and the spliceosome in human induced pluripotent stem cell-derived cardiac progenitors. Methods: We leveraged a combination of unbiased approaches including affinity purification of GATA4 and mass spectrometry, enhanced cross-linking with immunoprecipitation, electrophoretic mobility shift assays, in vitro splicing assays, and unbiased transcriptomic analysis to uncover GATA4's novel function as a splicing regulator in human induced pluripotent stem cell-derived cardiac progenitors. Results: We found that GATA4 interacts with many members of the spliceosome complex in human induced pluripotent stem cell-derived cardiac progenitors. Enhanced cross-linking with immunoprecipitation demonstrated that GATA4 also directly binds to a large number of mRNAs through defined RNA motifs in a sequence-specific manner. In vitro splicing assays indicated that GATA4 regulates alternative splicing through direct RNA binding, resulting in functionally distinct protein products. Correspondingly, knockdown of GATA4 in human induced pluripotent stem cell-derived cardiac progenitors resulted in differential alternative splicing of genes involved in cytoskeleton organization and calcium ion import, with functional consequences associated with the protein isoforms. Conclusions: This study shows that in addition to its well described transcriptional function, GATA4 interacts with members of the spliceosome complex and regulates cell type-specific alternative splicing via sequence-specific interactions with RNA. Several genes that have splicing regulated by GATA4 have functional consequences and many are associated with dilated cardiomyopathy, suggesting a novel role for GATA4 in achieving the necessary cardiac proteome in normal and stress-responsive conditions.
C1 [Zhu, Lili; Choudhary, Krishna; Gonzalez-Teran, Barbara; Ang, Yen-Sin; Thomas, Reuben; Stone, Nicole R.; Liu, Lei; Zhou, Ping; Huang, Yu; Pelonero, Angelo; Koback, Frances; Padmanabhan, Arun; Sadagopan, Nandhini; Hsu, Austin; Costa, Mauro W.; Gifford, Casey A.; van Bemmel, Joke; Huttenhain, Ruth; Conklin, Bruce R.; Bruneau, Benoit G.; Krogan, Nevan J.; Pollard, Katherine S.; Srivastava, Deepak] Gladstone Inst, San Francisco, CA USA.
   [Zhu, Lili; Gonzalez-Teran, Barbara; Ang, Yen-Sin; Stone, Nicole R.; Liu, Lei; Zhou, Ping; Huang, Yu; Pelonero, Angelo; Koback, Frances; Padmanabhan, Arun; Sadagopan, Nandhini; Costa, Mauro W.; Gifford, Casey A.; van Bemmel, Joke; Conklin, Bruce R.; Bruneau, Benoit G.; Srivastava, Deepak] Roddenberry Ctr Stem Cell Biol & Med Gladstone, San Francisco, CA USA.
   [Zhu, Chenchen; Steinmetz, Lars] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
   [Zhu, Chenchen; Steinmetz, Lars] Stanford Genome Technol Ctr, Palo Alto, CA USA.
   [Ruan, Hongmei; Vedantham, Vasanth; Conklin, Bruce R.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.
   [Ruan, Hongmei; Vedantham, Vasanth; Black, Brian L.; Bruneau, Benoit G.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA.
   [Huttenhain, Ruth; Conklin, Bruce R.; Krogan, Nevan J.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA.
   [Huttenhain, Ruth; Krogan, Nevan J.] Univ Calif San Francisco, Quantitat Biosci Inst, San Francisco, CA 94143 USA.
   [Bruneau, Benoit G.; Srivastava, Deepak] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA.
   [Pollard, Katherine S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, Inst Computat Hlth Sci, San Francisco, CA 94143 USA.
   [Pollard, Katherine S.] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA.
   [Srivastava, Deepak] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA USA.
   [Jin, Shibo] Univ Calif Berkeley, Mol & Cell Biol Dept, Div Cellular & Dev Biol, Berkeley, CA USA.
   [Steinmetz, Lars] European Mol Biol Lab, Genome Biol Unit, Heidelberg, Germany.
   [Pollard, Katherine S.] Chan Zuckerberg Biohub, San Francisco, CA USA.
C3 University of California System; University of California San Francisco;
   The J David Gladstone Institutes; Stanford University; Stanford
   University; University of California System; University of California
   San Francisco; University of California System; University of California
   San Francisco; University of California System; University of California
   San Francisco; University of California System; University of California
   San Francisco; University of California System; University of California
   San Francisco; University of California System; University of California
   San Francisco; University of California System; University of California
   San Francisco; University of California System; University of California
   San Francisco; University of California System; University of California
   Berkeley; European Molecular Biology Laboratory (EMBL)
RP Srivastava, D (corresponding author), Gladstone Inst Cardiovasc Dis, 1650 Owens St, San Francisco, CA 94158 USA.
EM deepak.srivastava@gladstone.ucsf.edu
RI Hsu, Austin/GZK-8164-2022; Choudhary, Krishna/P-3626-2019; Conklin,
   Bruce/E-4738-2019; Huttenhain, Ruth/KAL-8227-2024; Costa,
   Mauro/S-9219-2018
OI Gifford, Casey/0000-0002-7757-573X; Srivastava,
   Deepak/0000-0002-3480-5953; Costa, Mauro/0000-0003-3579-8625;
   Huttenhain, Ruth/0000-0002-0896-5910; Steinmetz,
   Lars/0000-0002-3962-2865; zhu, lili/0009-0003-4119-5270
FU National Institutes of Health [DP2HL152425, P01 HL146366, R01 HL057181,
   R01 HL015100, R01 HL127240]; Roddenberry Foundation; L.K. Whittier
   Foundation; Dario and Irina Sattui, Younger Family Fund; National Heart
   Lung and Blood Institute [R01HL127240, P01HL146366, K08HL157700] Funding
   Source: NIH RePORTER
FX Funding provided by the National Institutes of Health (grant DP2HL152425
   to V.V.; grant P01 HL146366 to D.S., B.G.B., K.S.P., B.R.C., B.L.B., and
   N.J.K.; and grants R01 HL057181, R01 HL015100, and R01 HL127240 to
   D.S.), the Roddenberry Foundation, L.K. Whittier Foundation, Dario and
   Irina Sattui, Younger Family Fund, and Additional Ventures.
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U2 14
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7322
EI 1524-4539
J9 CIRCULATION
JI Circulation
PD SEP 6
PY 2022
VL 146
IS 10
BP 770
EP 787
DI 10.1161/CIRCULATIONAHA.121.057620
PG 18
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 4G9FF
UT WOS:000849492000009
PM 35938400
OA Green Submitted, Bronze, Green Accepted
DA 2025-04-10
ER

PT J
AU Nitschke, L
   Hu, RC
   Miller, AN
   Cooper, TA
AF Nitschke, Larissa
   Hu, Rong-Chi
   Miller, Andrew N.
   Cooper, Thomas A.
TI Rescue of Scn5a mis-splicing does not improve the structural and
   functional heart defects of a DM1 heart mouse model
SO HUMAN MOLECULAR GENETICS
LA English
DT Article
DE myotonic dystrophy; alternative splicing; repeat expansion disorders;
   SCN5A; cardiac conduction
ID MYOTONIC-DYSTROPHY TYPE-1; CARDIAC CONDUCTION DEFECT; PRE-MESSENGER-RNA;
   LONG QT SYNDROME; BRUGADA-SYNDROME; MUSCLEBLIND PROTEINS; CHLORIDE
   CHANNEL; NUCLEAR FOCI; CTG REPEAT; MUTATION
AB Myotonic Dystrophy Type 1 (DM1) is an autosomal dominant multisystemic disorder for which cardiac features, including conduction delays and arrhythmias, are the second leading cause of disease mortality. DM1 is caused by expanded CTG repeats in the 3 ' untranslated region of the DMPK gene. Transcription of the expanded DMPK allele produces mRNAs containing long tracts of CUG repeats, which sequester the Muscleblind-Like family of RNA binding proteins, leading to their loss-of-function and the dysregulation of alternative splicing. A well-characterized mis-regulated splicing event in the DM1 heart is the increased inclusion of SCN5A exon 6A rather than the mutually exclusive exon 6B that normally predominates in adult heart. As previous work showed that forced inclusion of Scn5a exon 6A in mice recapitulates cardiac DM1 phenotypes, we tested whether rescue of Scn5a mis-splicing would improve the cardiac phenotypes in a DM1 heart mouse model. We generated mice lacking Scn5a exon 6A to force the expression of the adult SCN5A isoform including exon 6B and crossed these mice to our previously established CUG960 DM1 heart mouse model. We showed that correction Scn5a mis-splicing does not improve the DM1 heart conduction delays and structural changes induced by CUG repeat RNA expression. Interestingly, we found that in addition to Scn5a mis-splicing, Scn5a expression is reduced in heart tissues of CUG960 mice and DM1-affected individuals. These data indicate that Scn5a mis-splicing is not the sole driver of DM1 heart deficits and suggest a potential role for reduced Scn5a expression in DM1 cardiac disease.
C1 [Nitschke, Larissa; Hu, Rong-Chi; Miller, Andrew N.; Cooper, Thomas A.] Baylor Coll Med, Dept Pathol & Immunol, 1 Baylor Plaza, Houston, TX 77030 USA.
   [Hu, Rong-Chi; Cooper, Thomas A.] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA.
   [Cooper, Thomas A.] Baylor Coll Med, Dept Mol & Cellular Biol, 1 Baylor Plaza, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Baylor College of Medicine; Baylor College
   of Medicine
RP Cooper, TA (corresponding author), Baylor Coll Med, Room 268B Mail Stop BCM315,1 Baylor Plaza, Houston, TX 77030 USA.
EM nitschke@bcm.edu; Rong-Chi.Hu@bcm.edu; andrewmiller1884@gmail.com;
   tcooper@bcm.edu
OI Cooper, Thomas/0000-0002-9238-0578; Nitschke,
   Larissa/0000-0002-8040-2100
FU National Institutes of Health [R01HL147020, R01AR082852, F32AR083267,
   P30CA125123, S10OD032380, UM1HG006348, R01DK114356]; Myotonic Dystrophy
   Foundation
FX This work was supported by the National Institutes of Health
   [R01HL147020 and R01AR082852 to T.A.C.; F32AR083267 to L.N.] and a
   postdoctoral fellowship from the Myotonic Dystrophy Foundation [L.N.].
   The Genetically Engineered Rodent Models Core at Baylor College of
   Medicine is partially supported by the National Institutes of Health
   [P30CA125123]. The Mouse Phenotyping Core at Baylor College of Medicine
   is partially supported by the National Institutes of Health
   [S10OD032380; UM1HG006348; R01DK114356].
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NR 38
TC 1
Z9 1
U1 0
U2 0
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0964-6906
EI 1460-2083
J9 HUM MOL GENET
JI Hum. Mol. Genet.
PD AUG 11
PY 2024
VL 33
IS 20
BP 1789
EP 1799
DI 10.1093/hmg/ddae117
EA AUG 2024
PG 11
WC Biochemistry & Molecular Biology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Genetics & Heredity
GA I0J8P
UT WOS:001287928600001
PM 39126705
DA 2025-04-10
ER

PT J
AU Ihara, K
   Sasano, T
   Hiraoka, Y
   Togo-Ohno, M
   Soejima, Y
   Sawabe, M
   Tsuchiya, M
   Ogawa, H
   Furukawa, T
   Kuroyanagi, H
AF Ihara, Kensuke
   Sasano, Tetsuo
   Hiraoka, Yuichi
   Togo-Ohno, Marina
   Soejima, Yurie
   Sawabe, Motoji
   Tsuchiya, Megumi
   Ogawa, Hidesato
   Furukawa, Tetsushi
   Kuroyanagi, Hidehito
TI A missense mutation in the RSRSP stretch of Rbm20 causes dilated
   cardiomyopathy and atrial fibrillation in mice
SO SCIENTIFIC REPORTS
LA English
DT Article
ID SPLICING REGULATOR RBM20; CARDIAC-HYPERTROPHY; DIFFERENTIAL EXPRESSION;
   TITIN ISOFORMS; GENE; ARRHYTHMIA; STIFFNESS; ALIGNMENT; KNOCKOUT;
   CLONING
AB Dilated cardiomyopathy (DCM) is a fatal heart disease characterized by left ventricular dilatation and cardiac dysfunction. Recent genetic studies on DCM have identified causative mutations in over 60 genes, including RBM20, which encodes a regulator of heart-specific splicing. DCM patients with RBM20 mutations have been reported to present with more severe cardiac phenotypes, including impaired cardiac function, atrial fibrillation (AF), and ventricular arrhythmias leading to sudden cardiac death, compared to those with mutations in the other genes. An RSRSP stretch of RBM20, a hotspot of missense mutations found in patients with idiopathic DCM, functions as a crucial part of its nuclear localization signals. However, the relationship between mutations in the RSRSP stretch and cardiac phenotypes has never been assessed in an animal model. Here, we show that Rbm20 mutant mice harboring a missense mutation S637A in the RSRSP stretch, mimicking that in a DCM patient, demonstrated severe cardiac dysfunction and spontaneous AF and ventricular arrhythmias mimicking the clinical state in patients. In contrast, Rbm20 mutant mice with frame-shifting deletion demonstrated less severe phenotypes, although loss of RBM20-dependent alternative splicing was indistinguishable. -RBM20S637A protein cannot be localized to the nuclear speckles, but accumulated in cytoplasmic, perinuclear granule-like structures in cardiomyocytes, which might contribute to the more severe cardiac phenotypes.
C1 [Ihara, Kensuke; Furukawa, Tetsushi] Tokyo Med & Dent Univ TMDU, Med Res Inst, Dept Bioinformat Pharmacol, Tokyo 1138510, Japan.
   [Ihara, Kensuke; Sasano, Tetsuo] Tokyo Med & Dent Univ TMDU, Dept Cardiovasc Med, Tokyo 1138510, Japan.
   [Hiraoka, Yuichi] Tokyo Med & Dent Univ TMDU, Med Res Inst, Lab Mol Neurosci, Tokyo 1138510, Japan.
   [Togo-Ohno, Marina; Kuroyanagi, Hidehito] Tokyo Med & Dent Univ TMDU, Med Res Inst, Gene Express Lab, Tokyo 1138510, Japan.
   [Soejima, Yurie; Sawabe, Motoji] Tokyo Med & Dent Univ TMDU, Grad Sch Med & Dent Sci, Dept Mol Pathol, Tokyo 1138510, Japan.
   [Tsuchiya, Megumi; Ogawa, Hidesato] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 5650871, Japan.
C3 Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU);
   Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU);
   Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU);
   Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU);
   Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU);
   The University of Osaka
RP Ihara, K (corresponding author), Tokyo Med & Dent Univ TMDU, Med Res Inst, Dept Bioinformat Pharmacol, Tokyo 1138510, Japan.; Ihara, K (corresponding author), Tokyo Med & Dent Univ TMDU, Dept Cardiovasc Med, Tokyo 1138510, Japan.; Kuroyanagi, H (corresponding author), Tokyo Med & Dent Univ TMDU, Med Res Inst, Gene Express Lab, Tokyo 1138510, Japan.
EM iharcvm@tmd.ac.jp; kuroyana.end@tmd.ac.jp
RI Ogawa, Hidesato/M-3778-2019
OI Ihara, Kensuke/0000-0002-2436-9588; Ogawa, Hidesato/0000-0001-9740-9010
FU Nanken-Kyoten, TMDU; Japan Heart Foundation;  [JP20K08467]; 
   [JP20K21385]; Grants-in-Aid for Scientific Research [20K08467, 20K07029,
   20K21385, 20H05322] Funding Source: KAKEN
FX We thank Dr. Jun K. Takeuchi and Dr. Yasuhiro Maejima for their helpful
   discussions and Eichi Watabe for technical assistance. We thank Wei Guo
   of University of Wyoming for anti-RBM20 antibody used in our preliminary
   experiment. This study was supported by Japan Heart Foundation Dr.
   Hiroshi Irisawa & Dr. Aya Irisawa Memorial Research Grant (to K.I.),
   Grant-in-Aid for Scientific Research (JP20K08467 to K.I. and JP20K21385
   to H.K.), and Nanken-Kyoten, TMDU (to H.K., K.I. and Y.H.). We would
   like to thank Editage (www.editage.com) for English language editing.
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NR 69
TC 32
Z9 36
U1 0
U2 4
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD OCT 27
PY 2020
VL 10
IS 1
AR 17894
DI 10.1038/s41598-020-74800-8
PG 14
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA QD3FK
UT WOS:000615408400001
PM 33110103
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Vad, OB
   Angeli, E
   Liss, M
   Ahlberg, G
   Andreasen, L
   Christophersen, IE
   Hansen, CC
   Moller, S
   Hellsten, Y
   Haunsoe, S
   Tveit, A
   Svendsen, JH
   Gotthardt, M
   Lundegaard, PR
   Olesen, MS
AF Vad, Oliver B.
   Angeli, Elisavet
   Liss, Martin
   Ahlberg, Gustav
   Andreasen, Laura
   Christophersen, Ingrid E.
   Hansen, Camilla C.
   Moller, Sophie
   Hellsten, Ylva
   Haunsoe, Stig
   Tveit, Arnljot
   Svendsen, Jesper H.
   Gotthardt, Michael
   Lundegaard, Pia R.
   Olesen, Morten S.
TI Loss of Cardiac Splicing Regulator RBM20 Is Associated With
   Early-Onset Atrial Fibrillation
SO JACC-BASIC TO TRANSLATIONAL SCIENCE
LA English
DT Article
DE alternative splicing; atrial cardiomyopathy; atrial fibrillation;
   genetics; RBM20
ID DILATED CARDIOMYOPATHY; GENE; EXPRESSION; VARIANTS; RESOURCE; MUTATION;
   HEART
AB We showed an association between atrial fibrillation and rare loss -of -function (LOF) variants in the cardiac splicing regulator RBM20 in 2 independent cohorts. In a rat model with loss of RBM20, we demonstrated altered splicing of sarcomere genes (NEXN, TTN, TPM1, MYOM1, and LDB3), and differential expression in key cardiac genes. We identified altered sarcomere and mitochondrial structure on electron microscopy imaging and found compromised mitochondrial function. Finally, we demonstrated that 3 novel LOF variants in RBM20, identified in patients with atrial fibrillation, lead to significantly reduced splicing activity. Our results implicate alternative splicing as a novel proarrhythmic mechanism in the atria. (J Am Coll Cardiol Basic Trans Science 2024;9:163-180) (c) 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).
C1 [Vad, Oliver B.; Ahlberg, Gustav; Andreasen, Laura; Haunsoe, Stig; Svendsen, Jesper H.; Lundegaard, Pia R.; Olesen, Morten S.] Copenhagen Univ Hosp Rigshosp, Dept Cardiol, Copenhagen, Denmark.
   [Vad, Oliver B.; Angeli, Elisavet; Ahlberg, Gustav; Lundegaard, Pia R.; Olesen, Morten S.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Biomed Sci, Copenhagen, Denmark.
   [Liss, Martin; Gotthardt, Michael] Helmholtz Assoc, Max Delbruck Ctr Mol Med, Neuromuscular & Cardiovasc Cell Biol, Berlin, Germany.
   [Christophersen, Ingrid E.; Tveit, Arnljot] Vestre Viken Hosp Trust, Dept Med Res, Baerum Hosp, Gjettum, Norway.
   [Christophersen, Ingrid E.] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway.
   [Hansen, Camilla C.; Moller, Sophie; Hellsten, Ylva] Univ Copenhagen, Dept Nutr Exercise & Sports, August Krogh Sect Human Physiol, Copenhagen, Denmark.
   [Tveit, Arnljot] Univ Oslo, Inst Clin Med, Dept Cardiol, Oslo, Norway.
   [Svendsen, Jesper H.] Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
   [Gotthardt, Michael] Charite Univ Med Berlin, Dept Cardiol, Berlin, Germany.
   [Gotthardt, Michael] German Ctr Cardiovasc Res, Partner site Berlin, Berlin, Germany.
   [Olesen, Morten S.] Univ Copenhagen, Dept Biomed Sci, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
C3 University of Copenhagen; Copenhagen University Hospital;
   Rigshospitalet; University of Copenhagen; Helmholtz Association; Max
   Delbruck Center for Molecular Medicine; University of Oslo; University
   of Copenhagen; University of Oslo; University of Copenhagen; Berlin
   Institute of Health; Free University of Berlin; Humboldt University of
   Berlin; Charite Universitatsmedizin Berlin; German Centre for
   Cardiovascular Research; University of Copenhagen
RP Olesen, MS (corresponding author), Univ Copenhagen, Dept Biomed Sci, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark.
EM mortensol@sund.ku.dk
RI Møller, Sophie/HGD-0641-2022; Hansen, Camilla/AAX-6215-2021; Gotthardt,
   Michael/ABE-8274-2021; Lundegaard, Pia/E-5804-2018; olesen,
   morten/AAC-5752-2021; Vad, Oliver/JPL-1547-2023; Svendsen, Jesper
   Hastrup/G-8573-2017; Hellsten, Ylva/B-3420-2015
OI Hansen, Camilla/0000-0003-2839-6150; Moller, Sophie/0000-0002-3714-2227;
   Angeli, Elisavet/0000-0003-4104-909X; Lundegaard,
   Pia/0000-0002-8284-1844; Svendsen, Jesper Hastrup/0000-0001-8466-8515;
   Hellsten, Ylva/0000-0002-2435-9558; Gotthardt,
   Michael/0000-0003-1788-3172
FU Novo Nordisk Foundation; John and Birthe Meyer Foundation; Research
   Foundation of the Heart Centre Rigshospitalet; Villadsen Family
   Foundation; Arvid Nilsson Foundation; Danish Council for Independent
   Research; Research Foundation at Rigshospitalet; Skibsreder Per
   Henriksens R., og hustrus fond; Department of Clinical Medicine
   (University of Copenhagen); Dr Gotthardt was supported by the Deuts;
   Deutsche Forschungsgemeinschaft; Leducq Foundation
FX This work was supported by the Novo Nordisk Foundation, John and Birthe
   Meyer Foundation, Research Foundation of the Heart Centre
   Rigshospitalet, Villadsen Family Foundation, Arvid Nilsson Foundation,
   Danish Council for Independent Research, Research Foundation at
   Rigshospitalet, Skibsreder Per Henriksens R., og hustrus fond, and
   Department of Clinical Medicine (University of Copenhagen) . Dr Ahlberg
   has received a grant from the Novo Nordisk Foundation,
   BRIDGE-Translational Excellence Programme. Dr Gotthardt was supported by
   the Deutsche Forschungsgemeinschaft and the Leducq Foundation. Dr
   Svendsen has received a fee for participating in the Advisory Board
   (Medtronic) ; and speaker fees from Medtronic not related to this work.
   Dr Gotthardt has a consultancy agreement with River BioMedics; and has
   received speaker honoraria from Bayer not related to this work. Dr
   Olesen has received speaker fees from Biosense Webster not related to
   this work. All other authors have re-ported that they have no
   relationships relevant to the contents of this paper to disclose.
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NR 63
TC 9
Z9 9
U1 0
U2 2
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA STE 800, 230 PARK AVE, NEW YORK, NY 10169 USA
SN 2452-302X
J9 JACC-BASIC TRANSL SC
JI JACC-Basic Transl. Sci.
PD FEB
PY 2024
VL 9
IS 2
BP 163
EP 180
DI 10.1016/j.jacbts.2023.08.008
EA FEB 2024
PG 18
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA MU0A9
UT WOS:001196019600001
PM 38510713
OA gold, Green Accepted, Green Published
DA 2025-04-10
ER

PT J
AU You, YY
   Wang, W
   Zhu, WS
   Xu, J
AF You, Yangyang
   Wang, Wei
   Zhu, Wenshu
   Xu, Jian
TI Identification of functional lncRNAs in atrial fibrillation based on RNA
   sequencing
SO BMC CARDIOVASCULAR DISORDERS
LA English
DT Article
DE Long noncoding RNA; Atrial fibrillation; RNA sequencing; AC009509.2;
   Biomarker; Prediction
ID EXPRESSION; INFLAMMATION; HYPERTROPHY; BIOMARKERS; GENES
AB Background Atrial fibrillation (AF) is one of the most common arrhythmia contributing to serious conditions such as stroke and heart failure. Recent studies demonstrated that long noncoding RNAs (lncRNAs) were related to cardiovascular disease. However, the molecular mechanisms of AF are not fully clear. This study intended to discover lncRNAs that are differentially expressed in AF compared with controls and evaluate the potential functions of these lncRNAs.Methods Ninety-seven patients (49 patients with AF and 48 patients without AF) were included in this study. Among these patients, leucocyte suspensions of 3 AF patients and 3 controls were sent for RNA-seq analysis to select differentially expressed lncRNA and mRNA. Different lncRNA expressions were validated in another samples (46 AF patients and 45 controls). Gene ontology (GO) enrichment analysis was conducted to annotate the function of selected mRNAs. Alternative splicing (AS) analysis was performed and a lncRNA-mRNA network was also constructed. The receiver operating characteristics (ROC) curve was used to evaluate diagnostic values. Logistic regression analysis was utilized to assess the risk or protective factor of AF.Results A total of 223 mRNAs and 105 lncRNAs were detected in AF patients compared with controls. Total 4 lncRNAs (LINC01781, AC009509.2, AL662844.3, AL662844.4) associated with AF were picked out for validation in another samples by quantitative real-time PCR (qRT-PCR), detecting that upregulated AC009509.2 and downregulated LINC01781 in AF patients. Multivariate logistic regression analysis illustrated that left atrial diameter (OR 1.201; 95% CI 1.093-1.320; P=0.000) and AC009509.2 (OR 1.732; 95% CI 1.092-2.747; P=0.020) were related to AF respectively. ROC curve showed that AC009509.2, LINC01781 and left atrial diameter (LAD) were predictors of AF. For LINC01781, the area under the curve (AUC) was 0.654 (95% CI 0.541-0.767, P=0.0113). For AC009509.2, the AUC was 0.710 (95% CI 0.599-0.822, P=0.0005). Bioinformatic methods (GO enrichment, AS analysis and lncRNA-mRNA network construction) were performed to reveal the role of lncRNAs.Conclusions This study discussed differentially expressed lncRNA and their potential interaction with mRNA in AF. LncRNA AC009509.2 could be a new potential biomarker for AF prediction.
C1 [You, Yangyang; Wang, Wei; Xu, Jian] Univ Sci & Technol China, Affiliated Hosp USTC 1, Dept Cardiol, Div Life Sci & Med, Hefei 230001, Anhui, Peoples R China.
   [Zhu, Wenshu] Bengbu First Peoples Hosp, Dept Cardiol, Bengbu 233000, Anhui, Peoples R China.
C3 Chinese Academy of Sciences; University of Science & Technology of
   China, CAS
RP Xu, J (corresponding author), Univ Sci & Technol China, Affiliated Hosp USTC 1, Dept Cardiol, Div Life Sci & Med, Hefei 230001, Anhui, Peoples R China.
EM ahslyyxujian@163.com
OI wang, haoyu/0009-0001-2467-5331
FU Central Government Guidance for Local Science and Technology Development
   [2017070802D145]
FX This research was supported by Central Government Guidance for Local
   Science and Technology Development (2017070802D145). The funding
   institution was not involved in the collection of data and writing this
   article.
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NR 34
TC 1
Z9 1
U1 0
U2 4
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1471-2261
J9 BMC CARDIOVASC DISOR
JI BMC Cardiovasc. Disord.
PD NOV 6
PY 2023
VL 23
IS 1
AR 539
DI 10.1186/s12872-023-03573-5
PG 11
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA X7AE8
UT WOS:001099927400002
PM 37932671
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Shang, LJL
   Dudley, SC
AF Shang, LJL
   Dudley, SC
TI Tandem promoters and developmentally regulated 5′- and 3′-mRNA
   untranslated regions of the mouse Scn5a cardiac sodium channel
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID RAT SKELETAL-MUSCLE; BRUGADA-SYNDROME; GENE-EXPRESSION; MESSENGER-RNA;
   HUMAN BRAIN; TRANSLATIONAL REGULATION; FUNCTIONAL EXPRESSION;
   ATRIAL-FIBRILLATION; DOG-MODEL; MUTATION
AB The SCN5A gene encodes a voltage-sensitive sodium channel expressed in cardiac and skeletal muscle. Coding region mutations cause cardiac sudden death syndromes and conduction system failure. Polymorphisms in the 5'-sequence adjacent to the SCN5A gene have been linked to cardiac arrhythmias. We identified three alternative 5'-splice variants (1A, 1B, and 1C) of the untranslated exon 1 and two 3'-variants in the murine Scn5a mRNA. Two of the exon 1 isoforms ( 1B and 1C) were novel when compared with the published human and rat SCN5A sequences. Quantitative real time PCR results showed that the abundance of the isoforms varied during cardiac development. The 1A, 1B, and 1C mRNA splice variants increased 7.8 +/- 1.7-fold (E1A), 6.0 +/- 1.0-fold (E1B), and 20.6 +/- 3.7-fold (E1C) from fetal to adult heart, respectively. Promoter deletion and luciferase reporter gene analysis using cardiac and skeletal muscle cell lines demonstrated a pattern of distinct cardiac-specific enhancer elements associated with exons 1A and 1C. In the case of exon 1C, the enhancer element appeared to be within the exon. A 5'-repressor preceded each cardiac enhancer element. We concluded that the murine Na+ channel has both 5'- and 3'-untranslated region mRNA variants that are developmentally regulated and that the promoter region contains two distinct cardiac-specific enhancer regions. The presence of homologous human splicing suggests that that these regions may be fruitful new areas of study in understanding cardiac sodium channel regulation and the genetic susceptibility to sudden death.
C1 Emory Univ, Sch Med, Dept Med, Div Cardiol, Atlanta, GA 30322 USA.
   Atlanta Vet Affairs Med Ctr, Decatur, GA 30322 USA.
C3 Emory University; US Department of Veterans Affairs; Veterans Health
   Administration (VHA); Atlanta VA Health Care System
RP Emory Univ, VAMC, Div Cardiol, 1670 Clairmont Rd 111B, Decatur, GA 30033 USA.
EM sdudley@emory.edu
RI Dudley, Samuel/A-7085-2009
OI Dudley, Samuel/0000-0001-5843-5961
FU NHLBI NIH HHS [HL64828] Funding Source: Medline
CR Antzelevitch C, 2002, CIRC RES, V91, P1114, DOI 10.1161/01.RES.0000046046.53721.90
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NR 33
TC 55
Z9 62
U1 0
U2 3
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
SN 0021-9258
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD JAN 14
PY 2005
VL 280
IS 2
BP 933
EP 940
DI 10.1074/jbc.M409977200
PG 8
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 885ZF
UT WOS:000226195200012
PM 15485820
OA hybrid
DA 2025-04-10
ER

PT J
AU Josephs, K
   Patel, K
   Janson, CM
   Montagna, C
   McDonald, TV
AF Josephs, Katherine
   Patel, Kunjan
   Janson, Christopher M.
   Montagna, Cristina
   McDonald, Thomas V.
TI Compound heterozygous CASQ2 mutations and long-term course of
   catecholaminergic polymorphic ventricular tachycardia
SO MOLECULAR GENETICS & GENOMIC MEDICINE
LA English
DT Article
DE Atrial fibrillation; autosomal recessive; calsequestrin-2;
   catecholaminergic polymorphic ventricular tachycardia; alternative
   splicing
ID CALSEQUESTRIN; HEARTS; CA2+
AB BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited cardiac disorder characterized by episodic ventricular tachycardia during adrenergic stimulation. It is associated with significant morbidity and mortality. Knowledge of the underlying genetic cause, pathogenesis, and the natural history of the disease remains incomplete. Approximately 50% of CPVT cases are caused by dominant mutations in the cardiac ryanodine receptor (RYR2) gene, <5% of cases are accounted for by recessive mutations in cardiac calsequestrin (CASQ2) or Triadin (TRDN).
   MethodsWe report a family with two CASQ2 gene mutations. A research-based next-generation sequencing (NGS) initiative was used in a patient with a severe CPVT phenotype and her clinically unaffected son. Reverse transcription polymerase chain reaction (RT-PCR) from platelet RNA was used to assess the consequences of predicted splice variants.
   ResultsNGS revealed that the proband carried a novel c.199C>T (p.Gln67*) mutation and a previously reported splice site mutation c.532+1G>A in CASQ2. Her son is a heterozygous carrier of the c.199C>T (p.Gln67*) mutation alone and the proband was compound heterozygous at CASQ2. RNA analysis demonstrated that the splice site mutation results in the retention of intron 3 with no full-length CASQ2 mRNA.
   ConclusionThis study describes a novel CPVT genotype and further characterizes the effect of a previously reported CASQ2 splice site mutation. The long-term follow-up of 23years since first symptom provides additional insight into the natural history of CASQ2-associated CPVT.
C1 [Josephs, Katherine; Patel, Kunjan; Montagna, Cristina] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10461 USA.
   [Janson, Christopher M.] Albert Einstein Coll Med, Dept Pediat Cardiol, Bronx, NY 10461 USA.
   [Janson, Christopher M.; McDonald, Thomas V.] Montefiore Med Ctr, 111 E 210th St, Bronx, NY 10467 USA.
   [McDonald, Thomas V.] Albert Einstein Coll Med, Dept Med Cardiol, Bronx, NY 10461 USA.
   [McDonald, Thomas V.] Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA.
C3 Yeshiva University; Montefiore Medical Center; Albert Einstein College
   of Medicine; Montefiore Medical Center; Albert Einstein College of
   Medicine; Yeshiva University; Montefiore Medical Center; Albert Einstein
   College of Medicine; Montefiore Medical Center; Albert Einstein College
   of Medicine; Yeshiva University; Montefiore Medical Center; Albert
   Einstein College of Medicine; Yeshiva University
RP McDonald, TV (corresponding author), Albert Einstein Coll Med, Dept Cardiol, Forchheimer G35B,1300 Morris Pk Ave, Bronx, NY 10461 USA.
EM tom.mcdonald@einstein.yu.edu
OI McDonald, Thomas/0000-0002-6075-0888; Josephs,
   Katherine/0000-0001-7688-615X
FU National Heart, Lung, and Blood Institute [HL120782]
FX National Heart, Lung, and Blood Institute (Grant/Award Number:
   'HL120782').
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NR 15
TC 10
Z9 12
U1 0
U2 2
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 2324-9269
J9 MOL GENET GENOM MED
JI Mol. Genet. Genom. Med.
PD NOV
PY 2017
VL 5
IS 6
BP 788
EP 794
DI 10.1002/mgg3.323
PG 7
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA FQ7ZC
UT WOS:000418581200018
PM 29178653
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Kracklauer, MP
   Feng, HZ
   Jiang, WR
   Lin, JLC
   Lin, JJC
   Jin, JP
AF Kracklauer, Martin P.
   Feng, Han-Zhong
   Jiang, Wenrui
   Lin, Jenny L-C
   Lin, Jim J. -C.
   Jin, Jian-Ping
TI Discontinuous thoracic venous cardiomyocytes and heart exhibit
   synchronized developmental switch of troponin isoforms
SO FEBS JOURNAL
LA English
DT Article
DE cardiac muscle; development; myofilament protein; pulmonary vein;
   troponin isoform switch
ID MYOSIN HEAVY-CHAIN; PULMONARY VEINS; ATRIAL-FIBRILLATION;
   CARDIAC-MUSCLE; RADIOFREQUENCY ABLATION; STRIATED-MUSCLE; TRANSGENIC
   MICE; RAT; EXPRESSION; PATHWAYS
AB Cardiomyocyte-like cells have been reported in thoracic veins of rodents and other mammals, but their differentiation state and relationship to the muscle mass in the heart remain to be characterized. Here we investigated the distribution, ultrastructure, expression and developmental regulation of myofilament proteins of mouse and rat pulmonary and azygos venous cardiomyocytes. Tracing cardiomyocytes in transgenic mouse tissues using a lacZ reporter gene driven by a cloned rat cardiac troponin T promoter demonstrated scattered distribution of cardiomyocytes discontinuous from the atrial sleeves. The longitudinal axis of venous cardiomyocytes is perpendicular to that of the vessel. These cells contain typical sarcomere structures and intercalated discs as shown in electron microscopic images, and express cardiac isoforms of troponin T, troponin I and myosin. The expression of troponin I isoform genes and the alternative splicing of cardiac troponin T in thoracic venous cardiomyocytes are regulated during postnatal development in precise synchrony with that in the heart. However, the patterns of cardiac troponin T splicing in adult rat thoracic venous cardiomyocytes are slightly but clearly distinct from those in the atrial and ventricular muscles. The data indicate that mouse and rat thoracic venous cardiomyocytes residing in extra-cardiac tissue possess a physiologically differentiated state and an intrinsically pre-set developmental clock, which are apparently independent of the very different hemodynamic environments and functional features of the vessels and heart.
C1 [Kracklauer, Martin P.; Feng, Han-Zhong; Jiang, Wenrui; Lin, Jenny L-C; Jin, Jian-Ping] Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA.
   [Lin, Jenny L-C; Lin, Jim J. -C.] Univ Iowa, Dept Biol, Iowa City, IA 52242 USA.
C3 Wayne State University; University of Iowa
RP Jin, JP (corresponding author), Wayne State Univ, Sch Med, Dept Physiol, 540 E Canfield, Detroit, MI 48201 USA.
EM jjin@med.wayne.edu
RI Jin, Jian-Ping/AAD-1149-2020
OI Montanari, Martti/0000-0002-3988-7804; Jin, JP/0000-0001-9932-1063
FU National Institutes of Health [AR048816, HL086720, HL098945]
FX We thank Hui Wang and Geoff Cady for technical assistance. This work was
   supported by National Institutes of Health grants AR048816, HL086720 and
   HL098945 to J.-P.J.
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NR 46
TC 18
Z9 23
U1 0
U2 4
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1742-464X
J9 FEBS J
JI FEBS J.
PD FEB
PY 2013
VL 280
IS 3
BP 880
EP 891
DI 10.1111/febs.12076
PG 12
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 079JT
UT WOS:000314167100008
PM 23176202
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Tang, SC
   Yang, KC
   Hu, CJ
   Chiou, HY
   Wu, CC
   Jeng, JS
AF Tang, Sung-Chun
   Yang, Kai-Chien
   Hu, Chaur-Jong
   Chiou, Hung-Yi
   Wu, Chau Chung
   Jeng, Jiann-Shing
TI Elevated Plasma Level of Soluble Form of RAGE in Ischemic Stroke
   Patients with Dementia
SO NEUROMOLECULAR MEDICINE
LA English
DT Article
DE Ischemic stroke; Vascular dementia; sRAGE; esRAGE
ID GLYCATION END-PRODUCTS; VASCULAR DEMENTIA; ALZHEIMERS-DISEASE; RECEPTOR;
   DIAGNOSIS
AB The receptor for advanced glycation end products (RAGE) and its downstream pathways are involved in various inflammatory and immune responses. Importantly, there is soluble RAGE (sRAGE) that forms either by alternative splicing of RAGE messenger ribonucleic acid as the endogenous soluble form of RAGE (esRAGE) or by proteolytic cleavage of full-length RAGE protein. This study aimed to investigate the associations of the plasma levels of sRAGE and esRAGE in ischemic stroke (IS) patients with and without dementia. This cross-sectional study recruited patients with IS at a university medical center. Vascular dementia was defined as the scale of Clinical Dementia Ranking (CDR) ae 1. Standard enzyme-linked immunosorbent assay was used to measure the plasma concentration of sRAGE and esRAGE. From November 2014 to October 2015, a total of 172 IS patients (mean age: 72.1 +/- 7.5 years, 64.5% male) were recruited, including 73 with CDR = 0, 63 with CDR = 0.5, and 36 with CDR ae 1. In univariate analysis, IS patients with dementia were older and had more diabetes mellitus, less atrial fibrillation, and higher post-stroke modified Rankin Scale scores than those without dementia. Plasma levels of sRAGE and esRAGE were significantly higher in IS patients with than those without dementia (1.44 +/- 1.29 vs. 1.03 +/- 0.48 and 0.39 +/- 0.40 vs. 0.24 +/- 0.13 ng/mL, both p < 0.01). Importantly, both parameters remained independent after adjustment for clinical variables (OR 2.683, p = 0.013 and OR 39.192, p = 0.006, respectively). In summary, plasma sRAGE and esRAGE were elevated in those with dementia compared with those without dementia among IS patients.
C1 [Tang, Sung-Chun; Jeng, Jiann-Shing] Natl Taiwan Univ Hosp, Dept Neurol, Taipei, Taiwan.
   [Yang, Kai-Chien; Wu, Chau Chung] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan.
   [Hu, Chaur-Jong] Taipei Med Univ Hosp, Dept Neurol, Taipei, Taiwan.
   [Hu, Chaur-Jong] Shuang Ho Hosp, Taipei, Taiwan.
   [Chiou, Hung-Yi] Taipei Med Univ, Sch Publ Hlth, Taipei, Taiwan.
C3 National Taiwan University; National Taiwan University Hospital;
   National Taiwan University; National Taiwan University Hospital; Taipei
   Medical University Hospital; Taipei Medical University; Taipei Medical
   University; Shuang Ho Hospital; Taipei Medical University
RP Jeng, JS (corresponding author), Natl Taiwan Univ Hosp, Dept Neurol, Taipei, Taiwan.
EM jsjeng@ntu.edu.tw
RI Chen, Chien-Chin/A-9977-2016; Chen, Li-Tzong/D-2071-2010; Chuang,
   Hung-Yi/C-9143-2009; Yang, Kai-Chien/AAO-6991-2021; Chaou,
   Chung-Hsien/AAZ-7344-2020
OI JENG, JIANN-SHING/0000-0002-1456-3686; Tang,
   Sung-Chun/0000-0003-3731-5973; Chiou, Hung Yi/0000-0002-4545-9697; Yang,
   Kai-Chien/0000-0002-9128-9166
FU Taiwan Ministry of Science and Technology [105-2314-B-002-001]
FX No other funding sources, except Taiwan Ministry of Science and
   Technology Grant (105-2314-B-002-001), involved in the study design,
   data collection, analysis and interpretation, or writing of this report.
CR Alexiou P, 2010, CURR MED CHEM, V17, P2232, DOI 10.2174/092986710791331086
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NR 17
TC 20
Z9 20
U1 0
U2 2
PU HUMANA PRESS INC
PI TOTOWA
PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA
SN 1535-1084
EI 1559-1174
J9 NEUROMOL MED
JI Neuromol. Med.
PD DEC
PY 2017
VL 19
IS 4
BP 579
EP 583
DI 10.1007/s12017-017-8471-9
PG 5
WC Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA FM4RO
UT WOS:000415009400011
PM 29098526
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Chiang, HL
   Wang, NHH
   Song, IW
   Chang, CP
   Wen, MS
   Chien, YH
   Hwu, WL
   Tsai, FJ
   Chen, YT
   Wu, JY
AF Chiang, Hung-Lun
   Wang, Nana Hsiang-Hua
   Song, I-Wen
   Chang, Chun-Ping
   Wen, Ming-Shien
   Chien, Yin-Hsiu
   Hwu, Wuh-Liang
   Tsai, Fuu-Jen
   Chen, Yuan-Tsong
   Wu, Jer-Yuarn
TI Genetic epidemiological study doesn't support GLA IVS4+919G&gt;A
   variant is a significant mutation in Fabry disease
SO MOLECULAR GENETICS AND METABOLISM
LA English
DT Article
ID REPLACEMENT THERAPY; ALPHA-GALACTOSIDASE; CERAMIDETRIHEXOSIDASE; TAIWAN
AB Background: The GIA IVS4 + 919G>A which is linked to late-onset Fabry disease shows high frequency in Taiwan.
   Methods: To determine whether IVS4+ 919G>A is a frequent cause of heart disease, we genotyped it in normal controls and other disease cohorts (type 2 diabetes, heart failure, ventricular tachycardia, atrial fibrillation and coronary artery disease). Normal controls and diabetes patients carrying the variant were evaluated for their cardiac condition. Minigene constructs were used to study GIA splicing patterns in different cell lines.
   Results: GIA IVS4 + 919A was found in 4/1634 males (0.245%) and 2/1634 females (0.123%) in normal controls and in 4/2133 males (0.188%) and 7/1816 females (0.385%) in the type 2 diabetes cohort. Of all the 17 IVS4 + 919A carriers in these two groups, only two males reported heart-related disease (myocardial infarction and hypertensive heart disease). Furthermore, in the heart disease cohort (n = 649), only one male carried the variant. Minigene constructs showed that the AGS (stomach) cell line showed a distinct CIA splicing pattern.
   Conclusion: Most subjects carrying GIA IVS4 + 919A did not show abnormal cardiac phenotypes. The near-absence of GIA IVS4 +919A in heart disease cohort suggested that this variant is not a frequent cause of overt heart diseases in Taiwan and that the genotype-phenotype correlation and natural course of the disease need further investigation. We also showed that the GIA IVS4 + 919G>A nucleotide change did influence alternative splicing in a tissue-specific manner.
   Synopsis: The GIA IVS4 + 919G>A variant is not a frequent cause of overt heart disease in Taiwan. (C) 2017 Published by Elsevier Inc.
C1 [Chiang, Hung-Lun; Chen, Yuan-Tsong] Natl Yang Ming Univ, Inst Clin Med, Taipei, Taiwan.
   [Chiang, Hung-Lun; Wang, Nana Hsiang-Hua; Song, I-Wen; Chang, Chun-Ping; Chen, Yuan-Tsong; Wu, Jer-Yuarn] Acad Sinica, Inst Biomed Sci, 128,Sect 2,Acad Rd, Taipei 11529, Taiwan.
   [Wen, Ming-Shien] Chang Gung Univ, Sch Med, Taoyuan, Taiwan.
   [Chien, Yin-Hsiu; Hwu, Wuh-Liang] Natl Taiwan Univ Hosp, Dept Med Genet, Taipei, Taiwan.
   [Tsai, Fuu-Jen] China Med Univ Hosp, Dept Med Genet, Taichung, Taiwan.
   [Chen, Yuan-Tsong] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27706 USA.
   [Tsai, Fuu-Jen] China Med Univ, Sch Chinese Med, Taichung, Taiwan.
   [Wu, Jer-Yuarn] China Med Univ, Grad Inst Chinese Med Sci, Taichung, Taiwan.
C3 National Yang Ming Chiao Tung University; Academia Sinica - Taiwan;
   Chang Gung University; National Taiwan University; National Taiwan
   University Hospital; China Medical University Taiwan; China Medical
   University Hospital - Taiwan; Duke University; China Medical University
   Taiwan; China Medical University Taiwan
RP Chen, YT; Wu, JY (corresponding author), Acad Sinica, Inst Biomed Sci, 128,Sect 2,Acad Rd, Taipei 11529, Taiwan.
EM chen0010@ibms.sinica.edu.tw; jywu@ibms.sinica.edu.tw
RI Tsai, Fuu-Jen/J-4140-2015; Song, I-Wen/AAW-9307-2020; Wu,
   Jer-Yuarn/S-7010-2018; Chien, Yin-Hsiu/I-2348-2019
OI HWU, WUH-LIANG/0000-0001-6690-4879; Chiang,
   Hung-Lun/0000-0001-5464-2189; CHIEN, YIN-HSIU/0000-0001-8802-5728
FU Academia Sinica Genomic Medicine Multicenter Study, Taiwan [40-05-GMM]
FX This study was partially supported by Academia Sinica Genomic Medicine
   Multicenter Study, Taiwan (40-05-GMM). The funding organization had no
   role in the design or conduct of this research. The authors alone are
   responsible for the content and writing of the paper.
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NR 19
TC 8
Z9 10
U1 0
U2 2
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 1096-7192
EI 1096-7206
J9 MOL GENET METAB
JI Mol. Genet. Metab.
PD MAY
PY 2017
VL 121
IS 1
BP 22
EP 27
DI 10.1016/j.ymgme.2017.03.005
PG 6
WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research &
   Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental
   Medicine
GA EV8IO
UT WOS:000402024100004
PM 28377241
DA 2025-04-10
ER

PT J
AU Refaat, MM
   Lubitz, SA
   Makino, S
   Islam, Z
   Frangiskakis, JM
   Mehdi, H
   Gutmann, R
   Zhang, ML
   Bloom, HL
   MacRae, CA
   Dudley, SC
   Shalaby, AA
   Weiss, R
   McNamara, DM
   London, B
   Ellinor, PT
AF Refaat, Marwan M.
   Lubitz, Steven A.
   Makino, Seiko
   Islam, Zahid
   Frangiskakis, J. Michael
   Mehdi, Haider
   Gutmann, Rebecca
   Zhang, Michael L.
   Bloom, Heather L.
   MacRae, Calum A.
   Dudley, Samuel C.
   Shalaby, Alaa A.
   Weiss, Raul
   McNamara, Dennis M.
   London, Barry
   Ellinor, Patrick T.
TI Genetic variation in the alternative splicing regulator RBM20 is
   associated with dilated cardiomyopathy
SO HEART RHYTHM
LA English
DT Article
DE Dilated cardiomyopathy; Genetics; Mutation; Single nucleotide
   polymorphism; RBM20
ID HEART-FAILURE; MUTATIONS; FREQUENCY; DISEASE; RELATIVES
AB BACKGROUND Dilated cardiomyopathy (DCM) is a leading cause of heart failure and death. The etiology of DCM is genetically heterogeneous.
   OBJECTIVES We sought to define the prevalence of mutations in the RNA splicing protein RBM20 in a large cohort with DCM and to determine whether genetic variation in RBM20 is associated with clinical outcomes.
   METHODS Subjects included in the Genetic Risk Assessment of Defibrillator Events (GRADE) study were aged at least 18 years, had an ejection fraction of <= 30%, and an implantable cardioverter-defibrillator (ICD). The coding region and splice junctions of RBM20 were screened in subjects with DCM; 2 common polymorphisms in RBM20, rs942077 and rs35141404, were genotyped in all GRADE subjects.
   RESULTS A total of 1465 subjects were enrolled in the GRADE study, and 283 with DCM were screened for RBM20 mutations. The mean age of subjects with DCM was 58 +/- 13 years, 64% were males, and the mean follow-up time was 24.2 +/- 17.1 months after ICD placement. RBM20 mutations were identified in 8 subjects with DCM (2.8%). Mutation carriers had a similar survival, transplantation rate, and frequency of ICD therapy compared with nonmutation carriers. Three of 8 subjects with RBM20 mutations (37.5%) had atrial fibrillation (AF), whereas 19 subjects without mutations (7.4%) had AF (P = .02). Among all GRADE subjects, rs35141404 was associated with AF (minor allele odds ratio = 0.62; 95% confidence interval = 0.44-0.86; P = .006). In the subset of GRADE subjects with DCM, rs35141404 was associated with AF (minor allele odds ratio = 0.58; P = .047).
   CONCLUSIONS: Mutations in RBM20 were observed in approximately 3% of subjects with DCM. There were no differences in survival, transplantation rate, and frequency of ICD therapy in mutation carriers.
C1 [Lubitz, Steven A.; Makino, Seiko; Zhang, Michael L.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA.
   [Refaat, Marwan M.; Islam, Zahid; Frangiskakis, J. Michael; Mehdi, Haider; Gutmann, Rebecca; Shalaby, Alaa A.; McNamara, Dennis M.; London, Barry] Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA 15213 USA.
   [Lubitz, Steven A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA.
   [Bloom, Heather L.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA.
   [MacRae, Calum A.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02115 USA.
   [Dudley, Samuel C.] Univ Illinois, Cardiol Sect, Chicago, IL USA.
   [Weiss, Raul] Ohio State Univ, Med Ctr, Div Cardiovasc Med, Columbus, OH 43210 USA.
C3 Harvard University; Harvard University Medical Affiliates; Massachusetts
   General Hospital; Pennsylvania Commonwealth System of Higher Education
   (PCSHE); University of Pittsburgh; Harvard University; Harvard
   University Medical Affiliates; Massachusetts General Hospital; Emory
   University; Harvard University; Harvard University Medical Affiliates;
   Brigham & Women's Hospital; University of Illinois System; University of
   Illinois Chicago; University of Illinois Chicago Hospital; University
   System of Ohio; Ohio State University
RP Ellinor, PT (corresponding author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA.
EM londonb@upmc.edu; pellinor@partners.org
RI Islam, Zahidul/AAP-1951-2020; Refaat, Marwan/AAI-2179-2021; Bloom,
   Heather/AFW-0982-2022; Dudley, Samuel/A-7085-2009
OI London, Barry/0000-0003-1506-3947; Ellinor, Patrick/0000-0002-2067-0533;
   Dudley, Samuel/0000-0001-5843-5961
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NR 35
TC 126
Z9 143
U1 0
U2 13
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 1547-5271
EI 1556-3871
J9 HEART RHYTHM
JI Heart Rhythm
PD MAR
PY 2012
VL 9
IS 3
BP 390
EP 396
DI 10.1016/j.hrthm.2011.10.016
PG 7
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 898CJ
UT WOS:000300712700019
PM 22004663
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Zhu, CQ
   Chen, ZL
   Guo, W
AF Zhu, Chaoqun
   Chen, Zhilong
   Guo, Wei
TI Pre-mRNA mis-splicing of sarcomeric genes in heart failure
SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
LA English
DT Review
DE Alternative splicing; Sarcomeric genes; Splicing factor; Heart failure
ID TROPONIN-T ISOFORMS; DILATED CARDIOMYOPATHY; TITIN ISOFORM;
   ALPHA-TROPOMYOSIN; SKELETAL-MUSCLE; CA2+ SENSITIVITY; OLIGONUCLEOTIDE
   COMPLEMENTARY; MYOCARDIAL STIFFNESS; REGULATORY ELEMENTS; SPLICING
   REGULATION
AB Pre-mRNA splicing is an important biological process that allows production of multiple proteins from a single gene in the genome, and mainly contributes to protein diversity in eulcaryotic organisms. Alternative splicing is commonly governed by RNA binding proteins to meet the ever-changing demands of the cell. However, the mis-splicing may lead to human diseases. In the heart of human, mis-regulation of alternative splicing has been associated with heart failure. In this short review, we focus on alternative splicing of sarcomeric genes and review mis-splicing related heart failure with relatively well studied Sarcomeric genes and splicing mechanisms with identified regulatory factors. The perspective of alternative splicing based therapeutic strategies in heart failure has also been discussed. (C) 2016 Elsevier B.V. All rights reserved.
C1 [Zhu, Chaoqun; Chen, Zhilong; Guo, Wei] Univ Wyoming, Coll Agr & Nat Resources, Anim Sci, Laramie, WY 82071 USA.
   [Chen, Zhilong] Northwest A&F Univ, Coll Anim Sci & Technol, Yangling 712100, Shaanxi, Peoples R China.
C3 University of Wyoming; Northwest A&F University - China
RP Guo, W (corresponding author), Univ Wyoming, Coll Agr & Nat Resources, Anim Sci, Laramie, WY 82071 USA.
RI Guo, Wei/KJM-4941-2024
OI guo, wei/0000-0002-9158-8107
FU National Institute of General Medical Sciences [1003088F]; American
   Heart Association (AHA) [1003018]; Agricultural Experiment Station's
   competitive Grant from USDA/NIFA [1003093K]
FX This work was supported by National Institute of General Medical
   Sciences (1003088F), American Heart Association (AHA) (1003018) and
   Agricultural Experiment Station's competitive Grant from USDA/NIFA
   (1003093K).
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NR 106
TC 25
Z9 28
U1 0
U2 19
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0925-4439
EI 0006-3002
J9 BBA-MOL BASIS DIS
JI Biochim. Biophys. Acta-Mol. Basis Dis.
PD AUG
PY 2017
VL 1863
IS 8
SI SI
BP 2056
EP 2063
DI 10.1016/j.bbadis.2016.11.008
PG 8
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA EZ9KB
UT WOS:000405048200020
PM 27825848
OA Green Accepted, Green Published
DA 2025-04-10
ER

PT J
AU Draper, I
   Huang, WT
   Pande, S
   Zou, AR
   Calamaras, TD
   Choe, RH
   Correia-Branco, A
   Mei, AL
   Chen, HH
   Littel, HR
   Gunasekaran, M
   Wells, NM
   Bruels, CC
   Daugherty, AL
   Wolf, MJ
   Kang, PB
   Yang, VK
   Slonim, DK
   Wallingford, MC
   Blanton, RM
AF Draper, Isabelle
   Huang, Wanting
   Pande, Suchita
   Zou, Aaron
   Calamaras, Timothy D.
   Choe, Richard H.
   Correia-Branco, Ana
   Mei, Ariel L.
   Chen, Howard H.
   Littel, Hannah R.
   Gunasekaran, Mekala
   Wells, Natalya M.
   Bruels, Christine C.
   Daugherty, Audrey L.
   Wolf, Matthew J.
   Kang, Peter B.
   Yang, Vicky K.
   Slonim, Donna K.
   Wallingford, Mary C.
   Blanton, Robert M.
TI The splicing factor hnRNPL demonstrates conserved myocardial regulation
   across species and is altered in heart failure
SO FEBS LETTERS
LA English
DT Article
DE cardiomyopathy; heart failure; hnRNPL; mRNA splicing; splicing factors
ID MITRAL-VALVE; RNA; STABILITY; GENE; HYPERTROPHY; EXPRESSION; MODEL;
   TITIN
AB Heart failure (HF) is highly prevalent. Mechanisms underlying HF remain incompletely understood. Splicing factors (SF), which control pre-mRNA alternative splicing, regulate cardiac structure and function. This study investigated regulation of the splicing factor heterogeneous nuclear ribonucleoprotein-L (hnRNPL) in the failing heart. hnRNPL protein increased in left ventricular tissue from mice with transaortic constriction-induced HF and from HF patients. In left ventricular tissue, hnRNPL was detected predominantly in nuclei. Knockdown of the hnRNPL homolog Smooth in Drosophila induced cardiomyopathy. Computational analysis of predicted mouse and human hnRNPL binding sites suggested hnRNPL-mediated alternative splicing of tropomyosin, which was confirmed in C2C12 myoblasts. These findings identify hnRNPL as a sensor of cardiac dysfunction and suggest that disturbances of hnRNPL affect alternative splicing in HF.
C1 [Draper, Isabelle; Huang, Wanting; Pande, Suchita; Zou, Aaron; Calamaras, Timothy D.; Choe, Richard H.; Mei, Ariel L.; Chen, Howard H.; Blanton, Robert M.] Tufts Med Ctr, Mol Cardiol Res Inst, Boston, MA 02111 USA.
   [Zou, Aaron; Correia-Branco, Ana; Wallingford, Mary C.] Tufts Med Ctr, Mother Infant Res Inst, Boston, MA USA.
   [Littel, Hannah R.; Gunasekaran, Mekala; Wells, Natalya M.; Bruels, Christine C.; Daugherty, Audrey L.; Kang, Peter B.] Univ Minnesota, Dept Neurol, Greg Marzolf Jr Muscular Dystrophy Ctr, Minneapolis, MN USA.
   [Littel, Hannah R.; Gunasekaran, Mekala; Wells, Natalya M.; Bruels, Christine C.; Daugherty, Audrey L.; Kang, Peter B.] Univ Minnesota, Inst Translat Neurosci, Minneapolis, MN USA.
   [Wolf, Matthew J.] Univ Virginia, Div Cardiol, Charlottesville, VA USA.
   [Yang, Vicky K.] Tufts Univ, Cummings Sch Vet Med, North Grafton, MA USA.
   [Slonim, Donna K.] Tufts Univ, Dept Comp Sci, Medford, MA USA.
C3 Tufts Medical Center; Tufts Medical Center; University of Minnesota
   System; University of Minnesota Twin Cities; University of Minnesota
   System; University of Minnesota Twin Cities; University of Virginia;
   Tufts University; Tufts University
RP Blanton, RM (corresponding author), Tufts Med Ctr, Mol Cardiol Res Inst, Boston, MA 02111 USA.
EM robert.blanton@tuftsmedicine.org
RI Chen, Hao Jan Howard/HHY-9856-2022; Kang, Peter/HKF-7815-2023
OI Kang, Peter/0000-0002-4270-7325; Correia-Branco,
   Ana/0000-0001-5353-9665; Wallingford, Mary/0000-0002-3682-156X;
   Daugherty, Audrey/0009-0005-0182-2238
FU Foundation for the National Institutes of Health [K00/R00HL121152,
   1R01HL162919]; National Institutes of Health [932792]; American Heart
   Association Career Development Award; American Heart Association (AHA)
   [932792] Funding Source: American Heart Association (AHA)
FX This work was supported by the National Institutes of Health
   K00/R00HL121152 to H.H.C., 1R01HL162919 to R.M.B., and by the American
   Heart Association Career Development Award 932792 to H.H.C. The funding
   sources had no input into the study design, collection, and
   interpretation of data, in the writing of the manuscript, or in the
   decision to submit this paper.
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NR 42
TC 0
Z9 0
U1 0
U2 0
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0014-5793
EI 1873-3468
J9 FEBS LETT
JI FEBS Lett.
PD NOV
PY 2024
VL 598
IS 21
BP 2670
EP 2682
DI 10.1002/1873-3468.15020
EA SEP 2024
PG 13
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA L7P9K
UT WOS:001316481300001
PM 39300280
DA 2025-04-10
ER

PT J
AU Li, J
   Tu, DY
   Li, SH
   Guo, ZF
   Song, XW
AF Li, Jia
   Tu, Dingyuan
   Li, Songhua
   Guo, Zhifu
   Song, Xiaowei
TI Identification of alternative splicing regulatory patterns and
   characteristic splicing factors in heart failure using RNA-seq data and
   machine learning
SO HELIYON
LA English
DT Article
DE Alternative splicing; Heart failure; Characteristic splicing factor;
   Machine learning
ID TUMOR-SUPPRESSOR; EXPRESSION; PROTEIN; GENES; ISOFORM; ZRANB2; RBM20
AB Heart failure (HF) represents the advanced stage of several cardiovascular disorders. This study aimed to build an alternative splicing regulatory network and identify potential splicing factors involved in HF utilizing RNA-seq data and machine learning algorithms. We performed bioinformatics analysis on RNA-seq datasets containing samples from HF patients and normal individuals to obtain gene expression matrices and identify differently regulated alternative splicing events in HF. By calculating percent spliced-in (PSI) value, we identified 4055 abnormal alternative splicing events of 3142 genes in HF. These genes were significantly enriched in PPAR signaling, regulation of actin cytoskeleton, and muscle contraction. Interestingly, based on abnormal alternative splicing events, two distinct clusters of HF patients with distinct molecular mechanisms and pathways were identified using unsupervised clustering. Additionally, we built a regulatory network consisting of heart failure-related alternative splicing and splicing factors. Subsequently, we identify 203 HF specific pairs between splicing factors and alternative splicing events. Four splicing factors (RBM5, ZRANB2, HnRNPF, and HnRNPA0) were found using LASSO and SVM-RFE algorithms, their expression patterns were confirmed in two other microarray datasets. Our study clarifies involvement of splicing factors and alternative splicing events in HF by thoroughly analyzing RNA-seq data with machine learning methods. The findings may advance our understanding of the regulatory systems underlying biological processes associated with heart failure by providing candidates for further investigation and markers for diagnostic and therapeutic purposes.
C1 [Li, Jia; Tu, Dingyuan; Li, Songhua; Guo, Zhifu; Song, Xiaowei] Naval Med Univ, Changhai Hosp, Dept Cardiovasc Med, Shanghai, Peoples R China.
C3 Naval Medical University
RP Guo, ZF; Song, XW (corresponding author), Naval Med Univ, Changhai Hosp, Dept Cardiovasc Med, Shanghai, Peoples R China.
EM 13918459432@163.com; xiao_wei_song@163.com
RI Guo, Zhifu/AAC-5040-2022
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NR 68
TC 0
Z9 0
U1 4
U2 5
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
EI 2405-8440
J9 HELIYON
JI Heliyon
PD AUG 15
PY 2024
VL 10
IS 15
AR e35408
DI 10.1016/j.heliyon.2024.e35408
EA AUG 2024
PG 13
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA C0W4P
UT WOS:001286652100001
PM 39170450
OA gold
DA 2025-04-10
ER

PT J
AU Kong, SW
   Hu, YW
   Ho, JWK
   Ikeda, S
   Polster, S
   John, R
   Hall, JL
   Bisping, E
   Pieske, B
   dos Remedios, CG
   Pu, WT
AF Kong, Sek Won
   Hu, Yong Wu
   Ho, Joshua W. K.
   Ikeda, Sadakatsu
   Polster, Sean
   John, Ranjit
   Hall, Jennifer L.
   Bisping, Egbert
   Pieske, Burkert
   dos Remedios, Cristobal G.
   Pu, William T.
TI Heart Failure-Associated Changes in RNA Splicing of Sarcomere Genes
SO CIRCULATION-CARDIOVASCULAR GENETICS
LA English
DT Article
DE mRNA splicing; cardiomyopathy; heart failure; genes
ID CARDIAC TROPONIN-T; NONISCHEMIC CARDIOMYOPATHY; BREAST-CANCER;
   MESSENGER-RNA; EXPRESSION; ISOFORMS; IDENTIFICATION; ADULT; MICROARRAYS;
   GENOMICS
AB Background-Alternative mRNA splicing is an important mechanism for regulation of gene expression. Altered mRNA splicing occurs in association with several types of cancer, and a small number of disease-associated changes in splicing have been reported in heart disease. However, genome-wide approaches have not been used to study splicing changes in heart disease. We hypothesized that mRNA splicing is different in diseased hearts compared with control hearts.
   Methods and Results-We used the Affymetrix Exon array to globally evaluate mRNA splicing in left ventricular myocardial RNA from controls (n = 15) and patients with ischemic cardiomyopathy (n = 15). We observed a broad and significant decrease in mRNA splicing efficiency in heart failure, which affected some introns to a greater extent than others. The profile of mRNA splicing separately clustered ischemic cardiomyopathy and control samples, suggesting distinct changes in mRNA splicing between groups. Reverse transcription-polymerase chain reaction validated 9 previously unreported alternative splicing events. Furthermore, we demonstrated that splicing of 4 key sarcomere genes, cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), myosin heavy chain 7 (MYH7), and filamin C, gamma ( FLNC), was significantly altered in ischemic cardiomyopathy and in dilated cardiomyopathy and aortic stenosis. In aortic stenosis samples, these differences preceded the onset of heart failure. Remarkably, the ratio of minor to major splice variants of TNNT2, MYH7, and FLNC classified independent test samples as control or disease with >98% accuracy.
   Conclusions-Our data indicate that mRNA splicing is broadly altered in human heart disease and that patterns of aberrant RNA splicing accurately assign samples to control or disease classes. (Circ Cardiovasc Genet. 2010; 3: 138-146.)
C1 [Kong, Sek Won; Hu, Yong Wu; Ikeda, Sadakatsu; Pu, William T.] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA.
   [Kong, Sek Won] Childrens Hosp, Informat Program, Boston, MA 02115 USA.
   [Hu, Yong Wu] Wenzhou Med Coll, Dept Life Sci, Wenzhou, Peoples R China.
   [Ho, Joshua W. K.] Univ Sydney, Sch Informat Technol, Sydney, NSW 2006, Australia.
   [Ho, Joshua W. K.] NICTA, Sydney, NSW, Australia.
   [Polster, Sean; Hall, Jennifer L.] Univ Minnesota, Dept Med, Lillehei Heart Inst, Minneapolis, MN 55455 USA.
   [Polster, Sean; Hall, Jennifer L.] Univ Minnesota, Lillehei Heart Inst, Ctr Dev Biol, Minneapolis, MN USA.
   [John, Ranjit] Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA.
   [Bisping, Egbert; Pieske, Burkert] Med Univ Graz, Dept Clin Cardiol, Graz, Austria.
   [dos Remedios, Cristobal G.] Univ Sydney, Bosch Inst, Muscle Res Unit, Sydney, NSW 2006, Australia.
   [Pu, William T.] Harvard Stem Cell Inst, Cambridge, MA USA.
C3 Harvard University; Harvard University Medical Affiliates; Boston
   Children's Hospital; Harvard University; Harvard University Medical
   Affiliates; Boston Children's Hospital; Wenzhou Medical University;
   University of Sydney; Australian National University; University of
   Minnesota System; University of Minnesota Twin Cities; University of
   Minnesota System; University of Minnesota Twin Cities; University of
   Minnesota System; University of Minnesota Twin Cities; Medical
   University of Graz; University of Sydney; Harvard University
RP Pu, WT (corresponding author), Childrens Hosp, Dept Cardiol, 300 Longwood Ave, Boston, MA 02115 USA.
EM wpu@enders.tch.harvard.edu
RI dos Remedios, Cristobal/B-3487-2010; Ho, Joshua/AAK-7759-2020; Pieske,
   Burkert/M-8089-2016; Pu, William/AAJ-8301-2020; Polster,
   Sean/HRC-2850-2023
OI Kong, Sek Won/0000-0003-4877-7567; Pu, William/0000-0002-4551-8079; Ho,
   Joshua W. K./0000-0003-2331-7011; Polster, Sean/0000-0002-3229-5021
FU Edward Marram and Karen Carpenter; National Institutes of Health
   [R21HL89417, P50 NS40828, P30 HD18655]; Charles H Hood Foundation;
   University of Sydney
FX This work was funded by a charitable donation from Edward Marram and
   Karen Carpenter (Dr Pu) and grants from the National Institutes of
   Health (NIH R21HL89417) (Dr Pu), the Charles H Hood Foundation (Dr
   Kong), and the University of Sydney (Mr Ho). The Molecular Genetics Core
   Facility at Children's Hospital performed microarray experiments (NIH
   P50 NS40828 and NIH P30 HD18655).
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NR 35
TC 122
Z9 134
U1 0
U2 10
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 1942-325X
EI 1942-3268
J9 CIRC-CARDIOVASC GENE
JI Circ.-Cardiovasc. Genet.
PD APR
PY 2010
VL 3
IS 2
BP 138
EP U72
DI 10.1161/CIRCGENETICS.109.904698
PG 44
WC Cardiac & Cardiovascular Systems; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Genetics & Heredity
GA 586BR
UT WOS:000276876400004
PM 20124440
OA Green Accepted, Bronze
DA 2025-04-10
ER

PT J
AU Hasimbegovic, E
   Schweiger, V
   Kastner, N
   Spannbauer, A
   Traxler, D
   Lukovic, D
   Gyöngyösi, M
   Mester-Tonczar, J
AF Hasimbegovic, Ena
   Schweiger, Victor
   Kastner, Nina
   Spannbauer, Andreas
   Traxler, Denise
   Lukovic, Dominika
   Gyongyosi, Mariann
   Mester-Tonczar, Julia
TI Alternative Splicing in Cardiovascular Disease-A Survey of Recent
   Findings
SO GENES
LA English
DT Review
DE alternative splicing; atherosclerosis; dilated cardiomyopathy;
   myocardial infarction; circular RNAs; heart failure
ID MYOCARDIAL-INFARCTION; CARDIAC-FUNCTION; TISSUE FACTOR; ANTISENSE
   OLIGONUCLEOTIDE; COMMON POLYMORPHISM; EXON 33; ATHEROSCLEROSIS; HEART;
   GENE; RNA
AB Alternative splicing, a driver of posttranscriptional variance, differs from canonical splicing by arranging the introns and exons of an immature pre-mRNA transcript in a multitude of different ways. Although alternative splicing was discovered almost half a century ago, estimates of the proportion of genes that undergo alternative splicing have risen drastically over the last two decades. Deep sequencing methods and novel bioinformatic algorithms have led to new insights into the prevalence of spliced variants, tissue-specific splicing patterns and the significance of alternative splicing in development and disease. Thus far, the role of alternative splicing has been uncovered in areas ranging from heart development, the response to myocardial infarction to cardiac structural disease. Circular RNAs, a product of alternative back-splicing, were initially discovered in 1976, but landmark publications have only recently identified their regulatory role, tissue-specific expression, and transcriptomic abundance, spurring a renewed interest in the topic. The aim of this review is to provide a brief insight into some of the available findings on the role of alternative splicing in cardiovascular disease, with a focus on atherosclerosis, myocardial infarction, heart failure, dilated cardiomyopathy and circular RNAs in myocardial infarction.
C1 [Hasimbegovic, Ena; Schweiger, Victor; Kastner, Nina; Spannbauer, Andreas; Traxler, Denise; Lukovic, Dominika; Gyongyosi, Mariann; Mester-Tonczar, Julia] Med Univ Vienna, Dept Internal Medcine 2, Div Cardiol, A-1090 Vienna, Austria.
C3 Medical University of Vienna
RP Gyöngyösi, M (corresponding author), Med Univ Vienna, Dept Internal Medcine 2, Div Cardiol, A-1090 Vienna, Austria.
EM ena.hasimbegovic@meduniwien.ac.at; victor.schweiger@student.i-med.ac.at;
   nina.kastner@meduniwien.ac.at; andreas.spannbauer@meduniwien.ac.at;
   denise.traxler@gmail.com; dominikalukovic@meduniwien.ac.at;
   mariann.gyongyosi@meduniwien.ac.at;
   julia.mester-tonczar@meduniwien.ac.at
RI Lukovic, Dominika/AAZ-4178-2020
OI Gyongyosi, Mariann/0000-0002-7083-2107; Kastner,
   Nina/0000-0002-1576-9029; Spannbauer, Andreas/0000-0002-9819-0361;
   Mester-Tonczar, Julia/0000-0003-1426-6670
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NR 83
TC 27
Z9 28
U1 0
U2 5
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2073-4425
J9 GENES-BASEL
JI Genes
PD SEP
PY 2021
VL 12
IS 9
AR 1457
DI 10.3390/genes12091457
PG 14
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA UV5AD
UT WOS:000699490200001
PM 34573439
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Varga, ZV
   Pipicz, M
   Baán, JA
   Baranyai, T
   Koncsos, G
   Leszek, P
   Kusmierczyk, M
   Sánchez-Cabo, F
   García-Pavía, P
   Brenner, GJ
   Giricz, Z
   Csont, T
   Mendler, L
   Lara-Pezzi, E
   Pacher, P
   Ferdinandy, P
AF Varga, Zoltan V.
   Pipicz, Marton
   Baan, Julia A.
   Baranyai, Tamas
   Koncsos, Gabor
   Leszek, Przemyslaw
   Kusmierczyk, Mariusz
   Sanchez-Cabo, Fatima
   Garcia-Pavia, Pablo
   Brenner, Gabor J.
   Giricz, Zoltan
   Csont, Tamas
   Mendler, Luca
   Lara-Pezzi, Enrique
   Pacher, Pal
   Ferdinandy, Peter
TI Alternative Splicing of NOX4 in the Failing Human Heart
SO FRONTIERS IN PHYSIOLOGY
LA English
DT Article
DE cardiomyopathy; oxidative stress; cardiac dysfunction; myocardium; aging
ID CHRONIC GRANULOMATOUS-DISEASE; INCREASED OXIDATIVE STRESS; OXIDASE 4
   NOX4; NADPH OXIDASE; CARDIAC-HYPERTROPHY; ISCHEMIA/REPERFUSION INJURY;
   NAD(P)H OXIDASE; UP-REGULATION; RISK-FACTORS; KAPPA-B
AB Increased oxidative stress is a major contributor to the development and progression of heart failure, however, our knowledge on the role of the distinct NADPH oxidase (NOX) isoenzymes, especially on NOX4 is controversial. Therefore, we aimed to characterize NOX4 expression in human samples from healthy and failing hearts. Explanted human heart samples (left and right ventricular, and septal regions) were obtained from patients suffering from heart failure of ischemic or dilated origin. Control samples were obtained from donor hearts that were not used for transplantation. Deep RNA sequencing of the cardiac transcriptome indicated extensive alternative splicing of the NOX4 gene in heart failure as compared to samples from healthy donor hearts. Long distance PCR analysis with a universal 5 '-3' end primer pair, allowing amplification of different splice variants, confirmed the presence of the splice variants. To assess translation of the alternatively spliced transcripts we determined protein expression of NOX4 by using a specific antibody recognizing a conserved region in all variants. Western blot analysis showed up-regulation of the full-length NOX4 in ischemic cardiomyopathy samples and confirmed presence of shorter isoforms both in control and failing samples with disease-associated expression pattern. We describe here for the first time that NOX4 undergoes extensive alternative splicing in human hearts which gives rise to the expression of different enzyme isoforms. The full length NOX4 is significantly upregulated in ischemic cardiomyopathy suggesting a role for NOX4 in ROS production during heart failure.
C1 [Varga, Zoltan V.; Koncsos, Gabor; Brenner, Gabor J.; Giricz, Zoltan; Ferdinandy, Peter] Semmelweis Univ, Dept Pharmacol & Pharmacotherapy, Cardiometab Res Grp, Budapest, Hungary.
   [Varga, Zoltan V.; Baranyai, Tamas; Pacher, Pal] NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, Bethesda, MD USA.
   [Pipicz, Marton; Baan, Julia A.; Csont, Tamas; Ferdinandy, Peter] Univ Szeged, Fac Med, Dept Biochem, Szeged, Hungary.
   [Leszek, Przemyslaw] Cardinal Stefan Wyszynski Inst Cardiol, Dept Heart Failure & Transplantol, Warsaw, Poland.
   [Kusmierczyk, Mariusz] Cardinal Stefan Wyszynski Inst Cardiol, Dept Cardiac Surg & Transplantol, Warsaw, Poland.
   [Sanchez-Cabo, Fatima] Ctr Nacl Invest Cardioavsculares Carlos III, Bioinformat Unit, Madrid, Spain.
   [Garcia-Pavia, Pablo] Hosp Univ Puerta Hierro Majadahonda, Dept Cardiol, Heart Failure & Inherited Cardiac Dis Unit, Madrid, Spain.
   [Giricz, Zoltan; Ferdinandy, Peter] Pharmahungary Grp, Szeged, Hungary.
   [Mendler, Luca] Goethe Univ, Fac Med, Inst Biochem 2, Frankfurt, Germany.
   [Lara-Pezzi, Enrique] Ctr Invest Cardiovasc Carlos II, Madrid, Spain.
C3 Semmelweis University; National Institutes of Health (NIH) - USA; NIH
   National Institute on Alcohol Abuse & Alcoholism (NIAAA); Szeged
   University; Centro Nacional de Investigaciones Cardiovasculares (CNIC);
   Hospital Puerta de Hierro-Majadahonda; Pharmahungary Group; Goethe
   University Frankfurt; Centro Nacional de Investigaciones
   Cardiovasculares (CNIC)
RP Ferdinandy, P (corresponding author), Semmelweis Univ, Dept Pharmacol & Pharmacotherapy, Cardiometab Res Grp, Budapest, Hungary.; Pacher, P (corresponding author), NIAAA, Lab Cardiovasc Physiol & Tissue Injury, NIH, Bethesda, MD USA.; Ferdinandy, P (corresponding author), Univ Szeged, Fac Med, Dept Biochem, Szeged, Hungary.; Ferdinandy, P (corresponding author), Pharmahungary Grp, Szeged, Hungary.
EM pacher@mail.nih.gov; peter.ferdinandy@pharmahungary.com
RI Giricz, Zoltán/B-6990-2008; Garcia-Pavia, Pablo/T-9100-2019; Ferdinandy,
   Péter/H-9181-2019; Sanchez-Cabo, Fatima/IZD-8966-2023; Sanchez-Cabo,
   Fatima/N-5030-2014; Pacher, Pal/B-6378-2008; Varga, Zoltan/J-9264-2017;
   Lara-Pezzi, Enrique/E-2350-2015
OI Sanchez-Cabo, Fatima/0000-0003-1881-1664; Pacher,
   Pal/0000-0001-7036-8108; Leszek, Przemyslaw/0000-0003-4529-2687; Pipicz,
   Marton/0000-0002-0944-1684; Garcia-Pavia, Pablo/0000-0002-5470-2257;
   Varga, Zoltan/0000-0002-2758-0784; Lara-Pezzi,
   Enrique/0000-0002-2743-1033
FU Hungarian Scientific Research Fund [OTKA ANN107803, OTKA K109737];
   National Research, Development and Innovation Fund of Hungary
   [NVKP_16-1-2016-0017, NVKP_16]; National Program of Excellence [TAMOP
   4.2.4.A/1-11-1-2012-0001]; Rosztoczy Foundation; Hungarian Academy of
   Sciences; NIAAA; Ministry of Human Capacities [UNKP-16-3]
FX The study was supported by the grants from the Hungarian Scientific
   Research Fund (OTKA ANN107803, OTKA K109737 to PF) by the National
   Research, Development and Innovation Fund of Hungary (Project no.
   NVKP_16-1-2016-0017 has been implemented with the support provided from
   the National Research, Development and Innovation Fund of Hungary,
   financed under the NVKP_16 funding scheme). ZVV was supported by the
   National Program of Excellence (TAMOP 4.2.4.A/1-11-1-2012-0001) and by
   the Rosztoczy Foundation. PF was a Szentagothai Fellow of the National
   Program of Excellence (TAMOP 4.2.4.A/2-11-1-2012-0001). ZG held a "Janos
   Bolyai Fellowship" from the Hungarian Academy of Sciences (awarded in
   2013 and 2017). TB is supported by the UNKP-16-3 New National Excellence
   Program of The Ministry of Human Capacities. PP is supported by the
   Intramural Research Program of NIAAA. PF is a vice chair, PL and ZG are
   management committee members of the EU-Cardioprotection COST Action
   CA16225.
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NR 52
TC 34
Z9 38
U1 0
U2 6
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA PO BOX 110, EPFL INNOVATION PARK, BUILDING I, LAUSANNE, 1015,
   SWITZERLAND
SN 1664-042X
J9 FRONT PHYSIOL
JI Front. Physiol.
PD NOV 22
PY 2017
VL 8
AR 935
DI 10.3389/fphys.2017.00935
PG 9
WC Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Physiology
GA FN4OW
UT WOS:000415987600001
PM 29204124
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Xu, MZ
   Jin, NN
   Yin, XM
   Gu, QQ
   Liu, F
   Zhu, WJ
   Jiang, TB
   Zhou, YF
AF Xu, Mingzhu
   Jin, Nana
   Yin, Xiaomin
   Gu, Qingqing
   Liu, Fei
   Zhu, W. Jianhua
   Jiang, Tingbo
   Zhou, Yafeng
TI Regulation of the alternative splicing of human cardiac troponin T exon
   5 by splicing factor SF2/ASF
SO EXPERIMENTAL & CLINICAL CARDIOLOGY
LA English
DT Article
DE Alternative splicing; Cardiac troponin T (cTnT); Splicing factor
   2/Alternative splicing factor (SF2/ASF)
ID SKELETAL-MUSCLE; BETA(1)-ADRENERGIC RECEPTOR; FORCE DEVELOPMENT; CA2+
   SENSITIVITY; TRANSGENIC MICE; ISOFORMS AFFECT; ADULT ISOFORMS;
   HEART-FAILURE; FAILING HEART; MESSENGER-RNA
AB BACKGROUND: Cardiac troponin T (cTnT) is crucial in regulating the contraction of striated muscle and plays an important role in cardiomyopathy, which can lead to heart failure. Alternative splicing of exon 5 is developmentally regulated. Exon 5 is included in the embryonic cTnT but is excluded from the adult cTnT. Changes of cTnT isoform expression have been reported in hypothyroidism, cardiac hypertrophy of the left ventricle and, in some cases, heart failure.
   OBJECTIVE: To investigate the underlying mechanism of exon 5 alternative splicing and identify potential therapeutics for heart disease.
   METHODS: A cTnT minigene was constructed and a series of minigene constructions were generated with intron deletions from the full length of cTnT exons 3 to 6.
   RESULTS: Reverse-transcription polymerase chain reaction results demonstrated that the splicing silencers were located in intron 4 and 5. In addition, ASF/SF2, a member of the SR family of splicing factors, was found to promote the inclusion of cTnT exon 5 in a dose-dependent manner. Both dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) and cAMP-dependent kinase (PKA) phosphorylated the splicing factor SF2/ASF and inhibited the inclusion of cTnT exon 5.
   CONCLUSIONS: PKA and Dyrk1A induced changes in the alternative splicing of TNNT2 exon 5 via SF2/ASF, potentially uncovering new avenues for research into the molecular mechanism and aiding in the development of new therapeutics in cardiomyopathy.
C1 [Xu, Mingzhu; Jiang, Tingbo; Zhou, Yafeng] Soochow Univ, Affiliated Hosp 1, Dept Cardiol, Suzhou 215006, Jiangsu, Peoples R China.
   [Jin, Nana; Yin, Xiaomin; Liu, Fei] Jiangsu Key Lab Neuroregenerat, Nantong, Jiangsu, Peoples R China.
   [Gu, Qingqing; Zhu, W. Jianhua] Nantong Univ, Affiliated Hosp, Dept Cardiol, Nantong, Jiangsu, Peoples R China.
C3 Soochow University - China; Nantong University
RP Jiang, TB (corresponding author), Soochow Univ, Affiliated Hosp 1, Dept Cardiol, Suzhou 215006, Jiangsu, Peoples R China.
EM qcysz@sohu.com; zhouyafeng@medmail.com.cn
RI ZHOU, yf/IAO-5497-2023; Xu, Mingzhu/HGE-3639-2022
FU National Natural Science Foundation of China [81170174]; Natural
   Scientific Fund of Jiangsu province [BK2011304]; Jiangsu Province's Key
   Provincial Talents Program [RC2011111]
FX This work was supported by grants from National Natural Science
   Foundation of China (81170174), Natural Scientific Fund of Jiangsu
   province (BK2011304) and Jiangsu Province's Key Provincial Talents
   Program (RC2011111). The funders had no roles in study design, data
   collection and analysis, decision to publish or preparation of the
   manuscript.
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NR 29
TC 0
Z9 0
U1 1
U2 7
PU CARDIOLOGY ACADEMIC PRESS
PI TORONTO
PA 140 YONGE STREET, TORONTO, ONTARIO M5C 1X6, CANADA
SN 1205-6626
EI 1918-1515
J9 EXP CLIN CARDIOL
JI Exp. Clin. Cardiol.
PD WIN
PY 2013
VL 19
IS 1
PG 6
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA AN6TU
UT WOS:000340731600022
DA 2025-04-10
ER

PT J
AU Wang, JJ
   Li, G
   Yu, DJ
   Wong, YP
   Yong, TF
   Liang, MC
   Liao, P
   Foo, R
   Hoppe, UC
   Soong, TW
AF Wang, Juejin
   Li, Guang
   Yu, Dejie
   Wong, Yuk Peng
   Yong, Tan Fong
   Liang, Mui Cheng
   Liao, Ping
   Foo, Roger
   Hoppe, Uta C.
   Soong, Tuck Wah
TI Characterization of CaV1.2 exon 33 heterozygous knockout mice
   and negative correlation between Rbfox1 and CaV1.2
   exon 33 expressions in human heart failure
SO CHANNELS
LA English
DT Article
DE alternative splicing; cardiomyopathy; CaV1.2 calcium channel;
   heterozygous knockout; Rbfox
ID CALCIUM-CHANNEL; MUSCLE; AFTERDEPOLARIZATIONS; HYPERTROPHY; SUBUNIT
AB Recently, we reported that homozygous deletion of alternative exon 33 of Ca(V)1.2 calcium channel in the mouse resulted in ventricular arrhythmias arising from increased Ca(V)1.2(Delta 33) I-CaL current density in the cardiomyocytes. We wondered whether heterozygous deletion of exon 33 might produce cardiac phenotype in a dose-dependent manner, and whether the expression levels of RNA splicing factors known to regulate alternative splicing of exon 33 might change in human heart failure. Unexpectedly, we found that exon 33(+/-) cardiomyocytes showed similar Ca(V)1.2 channel properties as wild-type cardiomyocyte, even though Ca(V)1.2D33 channels exhibit a gain-in-function. In human hearts, we found that the mRNA level of splicing factor Rbfox1, but not Rbfox2, was downregulated in dilated cardiomyopathy, and CACNA1C mRNA level was dramatically decreased in the both of dilated and ischemic cardiomyopathy. These data imply Rbfox1 may be involved in the development of cardiomyopathies via regulating the alternative splicing of Ca(V)1.2 exon 33. (149 words)
C1 [Wang, Juejin; Li, Guang; Yu, Dejie; Wong, Yuk Peng; Yong, Tan Fong; Liang, Mui Cheng; Soong, Tuck Wah] Natl Univ Singapore, Dept Physiol, Singapore 117593, Singapore.
   [Wang, Juejin] Nanjing Med Univ, Dept Physiol, Nanjing, Jiangsu, Peoples R China.
   [Li, Guang] Southwest Med Univ, Inst Cardiovasc Res, Minist Educ, Key Lab Med Electrophysiol, Luzhou, Peoples R China.
   [Liao, Ping; Soong, Tuck Wah] Natl Neurosci Inst, Singapore, Singapore.
   [Foo, Roger] Genome Inst Singapore, Singapore, Singapore.
   [Hoppe, Uta C.] Paracelsus Med Univ, Dept Internal Med 2, Salzburg, Austria.
   [Soong, Tuck Wah] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore, Singapore.
   [Soong, Tuck Wah] Natl Univ Singapore, Neurobiol Ageing Programme, Singapore, Singapore.
C3 National University of Singapore; Nanjing Medical University; Southwest
   Medical University; National Neuroscience Institute (NNI); Agency for
   Science Technology & Research (A*STAR); A*STAR - Genome Institute of
   Singapore (GIS); Paracelsus Private Medical University; National
   University of Singapore; National University of Singapore
RP Soong, TW (corresponding author), Natl Univ Singapore, Dept Physiol, Singapore 117593, Singapore.
EM phsstw@nus.edu.sg
RI Juejin, Wang/JAX-4081-2023; Liao, Ping/LBI-1504-2024; Yu,
   Dejie/AAT-3293-2021
OI Liang, Mui Cheng/0000-0003-1208-0733; Liao, Ping/0000-0002-6205-4042;
   Foo, Roger/0000-0002-8079-4618
FU Singapore National Medical Research Council; Biomedical Research Council
FX The research was supported by funding from the Singapore National
   Medical Research Council and Biomedical Research Council to TWS.
CR Blech-Hermoni Y, 2013, INT J BIOCHEM CELL B, V45, P2467, DOI 10.1016/j.biocel.2013.08.008
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NR 22
TC 15
Z9 16
U1 8
U2 13
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 1933-6950
EI 1933-6969
J9 CHANNELS
JI Channels
PY 2018
VL 12
IS 1
BP 51
EP 57
DI 10.1080/19336950.2017.1381805
PG 7
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA HB3RQ
UT WOS:000450969300008
PM 28949795
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Gao, G
   Xie, A
   Huang, SC
   Zhou, AY
   Zhang, JH
   Herman, AM
   Ghassemzadeh, S
   Jeong, EM
   Kasturirangan, S
   Raicu, M
   Sobieski, MA
   Bhat, G
   Tatooles, A
   Benz, EJ
   Kamp, TJ
   Dudley, SC
AF Gao, Ge
   Xie, An
   Huang, Shu-Ching
   Zhou, Anyu
   Zhang, Jianhua
   Herman, Amanda M.
   Ghassemzadeh, Sassan
   Jeong, Euy-Myoung
   Kasturirangan, Srinivasan
   Raicu, Mihai
   Sobieski, Michael A., II
   Bhat, Geetha
   Tatooles, Antone
   Benz, Edward J., Jr.
   Kamp, Timothy J.
   Dudley, Samuel C., Jr.
TI Role of RBM25/LUC7L3 in Abnormal Cardiac Sodium Channel Splicing
   Regulation in Human Heart Failure
SO CIRCULATION
LA English
DT Article
DE angiotensin II; arrhythmia; cardiomyopathy; gene expression; sodium
ID GENE-EXPRESSION; PROTEIN
AB Background-Human heart failure is associated with decreased cardiac voltage-gated Na+ channel current (encoded by SCN5A), and the changes have been implicated in the increased risk of sudden death in heart failure. Nevertheless, the mechanism of SCN5A downregulation is unclear. A number of human diseases are associated with alternative mRNA splicing, which has received comparatively little attention in the study of cardiac disease. Splicing factor expression profiles during human heart failure and a specific splicing pathway for SCN5A regulation were explored in this study.
   Methods and Results-Gene array comparisons between normal human and heart failure tissues demonstrated that 17 splicing factors, associated with all major spliceosome components, were upregulated. Two of these splicing factors, RBM25 and LUC7L3, were elevated in human heart failure tissue and mediated truncation of SCN5A mRNA in both Jurkat cells and human embryonic stem cell-derived cardiomyocytes. RBM25/LUC7L3-mediated abnormal SCN5A mRNA splicing reduced Na+ channel current 91.1 +/- 9.3% to a range known to cause sudden death. Overexpression of either splicing factor resulted in an increase in truncated mRNA and a concomitant decrease in the full-length SCN5A transcript.
   Conclusions-Of the 17 mRNA splicing factors upregulated in heart failure, RBM25 and LUC7L3 were sufficient to explain the increase in truncated forms and the reduction in full-length Na+ channel transcript. Because the reduction in channels was in the range known to be associated with sudden death, interruption of this abnormal mRNA processing may reduce arrhythmic risk in heart failure. (Circulation. 2011; 124: 1124-1131.)
C1 [Gao, Ge; Xie, An; Jeong, Euy-Myoung; Raicu, Mihai; Dudley, Samuel C., Jr.] Univ Illinois, Cardiol Sect, Div Cardiol, Chicago, IL 60612 USA.
   [Gao, Ge; Xie, An; Jeong, Euy-Myoung; Raicu, Mihai; Dudley, Samuel C., Jr.] Jesse Brown VAMC, Chicago, IL USA.
   [Huang, Shu-Ching; Zhou, Anyu; Benz, Edward J., Jr.] Dana Farber Canc Inst, Boston, MA 02115 USA.
   [Zhang, Jianhua; Herman, Amanda M.; Kamp, Timothy J.] Univ Wisconsin, Div Cardiovasc Med, Dept Med, Sch Med & Publ Hlth, Madison, WI 53706 USA.
   [Ghassemzadeh, Sassan] Univ Illinois, Coll Med, Chicago, IL USA.
   [Kasturirangan, Srinivasan] Univ Illinois, Div Neonatol, Dept Pediat, Chicago, IL 60612 USA.
   [Sobieski, Michael A., II; Bhat, Geetha; Tatooles, Antone] Advocate Christ Med Ctr, Oak Lawn, IL USA.
C3 University of Illinois System; University of Illinois Chicago;
   University of Illinois Chicago Hospital; Harvard University; Harvard
   University Medical Affiliates; Dana-Farber Cancer Institute; University
   of Wisconsin System; University of Wisconsin Madison; University of
   Illinois System; University of Illinois Chicago; University of Illinois
   Chicago Hospital; University of Illinois System; University of Illinois
   Chicago; University of Illinois Chicago Hospital
RP Dudley, SC (corresponding author), Univ Illinois, Cardiol Sect, Div Cardiol, 840 S Wood St,MC 715, Chicago, IL 60612 USA.
EM scdudley@uic.edu
RI Dudley, Samuel/A-7085-2009; Kamp, Timothy/ABD-1343-2020
OI Kamp, Timothy J/0000-0003-2103-7876; Dudley, Samuel/0000-0001-5843-5961
FU National Heart, Lung, and Blood Institute [R01 HL085558, R01 HL073753,
   P01 HL058000]; Veterans Affairs MERIT
FX This work was supported by grants from the National Heart, Lung, and
   Blood Institute (R01 HL085558, R01 HL073753, P01 HL058000) and a
   Veterans Affairs MERIT grant.
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NR 33
TC 69
Z9 83
U1 1
U2 10
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7322
EI 1524-4539
J9 CIRCULATION
JI Circulation
PD SEP 6
PY 2011
VL 124
IS 10
BP 1124
EP U112
DI 10.1161/CIRCULATIONAHA.111.044495
PG 13
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 815VF
UT WOS:000294557400016
PM 21859973
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Dlamini, Z
   Tshidino, SC
   Hull, R
AF Dlamini, Zodwa
   Tshidino, Shonisani C.
   Hull, Rodney
TI Abnormalities in Alternative Splicing of Apoptotic Genes and
   Cardiovascular Diseases
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Review
DE apoptosis; alternative splicing; cardiomyopathies; PUMA; Bcl-2; Bnip3;
   Nix; therapeutic strategies for targeting heart disease associated
   abnormal splicing
ID CELL-DEATH; HEART-FAILURE; CARDIOMYOCYTE APOPTOSIS; CALCIUM HOMEOSTASIS;
   CARDIAC MYOCYTE; CYTOCHROME-C; PUMA; EXPRESSION; PROTEIN; BNIP3
AB Apoptosis is required for normal heart development in the embryo, but has also been shown to be an important factor in the occurrence of heart disease. Alternative splicing of apoptotic genes is currently emerging as a diagnostic and therapeutic target for heart disease. This review addresses the involvement of abnormalities in alternative splicing of apoptotic genes in cardiac disorders including cardiomyopathy, myocardial ischemia and heart failure. Many pro-apoptotic members of the Bcl-2 family have alternatively spliced isoforms that lack important active domains. These isoforms can play a negative regulatory role by binding to and inhibiting the pro-apoptotic forms. Alternative splicing is observed to be increased in various cardiovascular diseases with the level of alternate transcripts increasing elevated in diseased hearts compared to healthy subjects. In many cases these isoforms appear to be the underlying cause of the disease, while in others they may be induced in response to cardiovascular pathologies. Regardless of this, the detection of alternate splicing events in the heart can serve as useful diagnostic or prognostic tools, while those splicing events that seem to play a causative role in cardiovascular disease make attractive future drug targets.
C1 [Dlamini, Zodwa] Mangosuthu Univ Technol, Res Innovat & Engagements, ZA-4026 Durban, South Africa.
   [Tshidino, Shonisani C.] Univ Limpopo, Dept Biochem Microbiol & Biotechnol, ZA-0727 Polokwane, South Africa.
   [Hull, Rodney] Univ South Africa, Dept Life & Consumer Sci, Coll Agr & Environm Sci, ZA-1709 Johannesburg, South Africa.
C3 Mangosuthu University of Technology; University of Limpopo; University
   of South Africa
RP Dlamini, Z (corresponding author), Mangosuthu Univ Technol, Res Innovat & Engagements, ZA-4026 Durban, South Africa.
EM dlaminiz@mut.ac.za; shonisani.tshidino@ul.ac.za; hullr@unisa.ac.za
RI Dlamini, Zodwa/HNB-6090-2023; Hull, Rodney/HJP-0275-2023
OI Hull, Rodney/0000-0002-2001-3453; Dlamini, Zodwa/0000-0002-8012-3646;
   Tshidino, Shonisani Cathphonia/0000-0001-5848-8844
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NR 121
TC 24
Z9 25
U1 1
U2 13
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD NOV
PY 2015
VL 16
IS 11
BP 27171
EP 27190
DI 10.3390/ijms161126017
PG 20
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA CX4DI
UT WOS:000365648300082
PM 26580598
OA gold, Green Published, Green Submitted
DA 2025-04-10
ER

PT J
AU Liu, HY
   Duan, R
   He, XY
   Qi, JC
   Xing, TM
   Wu, YH
   Zhou, LP
   Wang, LL
   Shao, YJ
   Zhang, FL
   Zhou, HX
   Gu, XD
   Lin, BW
   Liu, YN
   Wang, Y
   Liu, Y
   Li, L
   Liang, DN
   Chen, YH
AF Liu, Hongyu
   Duan, Ran
   He, Xiaoyu
   Qi, Jincu
   Xing, Tianming
   Wu, Yahan
   Zhou, Liping
   Wang, Lingling
   Shao, Yujing
   Zhang, Fulei
   Zhou, Huixing
   Gu, Xingdong
   Lin, Bowen
   Liu, Yuanyuan
   Wang, Yan
   Liu, Yi
   Li, Li
   Liang, Dandan
   Chen, Yi-Han
TI Endothelial deletion of PTBP1 disrupts ventricular chamber development
SO NATURE COMMUNICATIONS
LA English
DT Article
ID TRACT-BINDING-PROTEIN; CARDIAC DEVELOPMENT; NON-COMPACTION; SPLICING
   REGULATION; BUILDING PLAN; NONCOMPACTION; REGULATOR; PROLIFERATION;
   MORPHOGENESIS; ACTIVATION
AB The growth and maturation of the ventricular chamber require spatiotemporally precise synergy between diverse cell types. Alternative splicing deeply affects the processes. However, the functional properties of alternative splicing in cardiac development are largely unknown. Our study reveals that an alternative splicing factor polypyrimidine tract-binding protein 1 (PTBP1) plays a key role in ventricular chamber morphogenesis. During heart development, PTBP1 colocalizes with endothelial cells but is almost undetectable in cardiomyocytes. The endothelial-specific knockout of Ptbp1, in either endocardial cells or pan-endothelial cells, leads to a typical phenotype of left ventricular noncompaction (LVNC). Mechanistically, the deletion of Ptbp1 reduces the migration of endothelial cells, disrupting cardiomyocyte proliferation and ultimately leading to the LVNC. Further study shows that Ptbp1 deficiency changes the alternative splicing of beta-arrestin-1 (Arrb1), which affects endothelial cell migration. In conclusion, as an alternative splicing factor, PTBP1 is essential during ventricular chamber development, and its deficiency can lead to congenital heart disease.
   Alternative splicing crucially affects various biological processes, however, its function in heart development is largely unknown. Here, the authors show an essential role of alternative splicing factor PTBP1 in ventricular chamber development.
C1 [Liu, Hongyu; Duan, Ran; He, Xiaoyu; Qi, Jincu; Wu, Yahan; Zhou, Liping; Wang, Lingling; Shao, Yujing; Zhang, Fulei; Zhou, Huixing; Lin, Bowen; Liu, Yi; Li, Li; Liang, Dandan; Chen, Yi-Han] Tongji Univ, Shanghai E Hosp, Dept Cardiol, Sch Med, Shanghai 200120, Peoples R China.
   [Liu, Hongyu; Duan, Ran; He, Xiaoyu; Qi, Jincu; Xing, Tianming; Wu, Yahan; Zhou, Liping; Wang, Lingling; Shao, Yujing; Zhang, Fulei; Zhou, Huixing; Gu, Xingdong; Lin, Bowen; Liu, Yuanyuan; Wang, Yan; Liu, Yi; Li, Li; Liang, Dandan; Chen, Yi-Han] Tongji Univ, Shanghai E Hosp, Sch Med, Key Lab Arrhythmias Minist Educ China, Shanghai 200120, Shanghai, Peoples R China.
   [Xing, Tianming; Gu, Xingdong; Liu, Yuanyuan; Wang, Yan] Jinzhou Med Univ, Jinzhou 121000, Liaoning, Peoples R China.
   [Li, Li; Liang, Dandan; Chen, Yi-Han] Chinese Acad Med Sci, Res Units Origin & Regulat Heart Rhythm, Shanghai 200092, Peoples R China.
   [Li, Li; Chen, Yi-Han] Tongji Univ, Dept Pathol & Pathophysiol, Sch Med, Shanghai 200092, Peoples R China.
C3 Tongji University; Tongji University; Jinzhou Medical University;
   Chinese Academy of Medical Sciences - Peking Union Medical College;
   Tongji University
RP Liang, DN; Chen, YH (corresponding author), Tongji Univ, Shanghai E Hosp, Dept Cardiol, Sch Med, Shanghai 200120, Peoples R China.; Liang, DN; Chen, YH (corresponding author), Tongji Univ, Shanghai E Hosp, Sch Med, Key Lab Arrhythmias Minist Educ China, Shanghai 200120, Shanghai, Peoples R China.; Liang, DN; Chen, YH (corresponding author), Chinese Acad Med Sci, Res Units Origin & Regulat Heart Rhythm, Shanghai 200092, Peoples R China.; Chen, YH (corresponding author), Tongji Univ, Dept Pathol & Pathophysiol, Sch Med, Shanghai 200092, Peoples R China.
EM dandanliang@tongji.edu.cn; yihanchen@tongji.edu.cn
RI Lin, Bowen/IQU-3812-2023; wang, lingling/O-5918-2014
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U1 2
U2 17
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
EI 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD MAR 31
PY 2023
VL 14
IS 1
AR 1796
DI 10.1038/s41467-023-37409-9
PG 14
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA F2NS5
UT WOS:000980769900002
PM 37002228
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Gu, QQ
   Jin, NN
   Sheng, HZ
   Yin, XM
   Zhu, JH
AF Gu, Qingqing
   Jin, Nana
   Sheng, Hongzhuan
   Yin, Xiaomin
   Zhu, Jianhua
TI Cyclic AMP-Dependent Protein Kinase A Regulates the Alternative Splicing
   of CaMKIIδ
SO PLOS ONE
LA English
DT Article
ID HEART-FAILURE; BETA(1)-ADRENERGIC RECEPTOR; DIFFERENTIAL EXPRESSION;
   DILATED CARDIOMYOPATHY; CARDIAC-HYPERTROPHY; TRANSGENIC MICE;
   PHOSPHORYLATION; ISOFORMS; IDENTIFICATION; INHIBITION
AB Ca(2+)/calmodulin-dependent protein kinase (CaMK) II delta is predominantly expressed in the heart. There are three isoforms of CaMKII delta resulting from the alternative splicing of exons 14, 15, and 16 of its pre-mRNA, which is regulated by the splicing factor SF2/ASF. Inclusion of exons 15 and 16 or of exon 14 generates delta A or delta B isoform. The exclusion of all three exons gives rise to delta C isoform, which is selectively increased in pressure-overload-induced hypertrophy. Overexpression of either delta B or delta C induces hypertrophy and heart failure, suggesting their specific role in the pathogenesis of hypertrophy and heart failure. It is well known that the beta-adrenergic-cyclic AMP-dependent protein kinase A (PKA) pathway is implicated in heart failure. To determine the role of PKA in the alternative splicing of CaMKII delta, we constructed mini-CaMKII delta genes and used these genes to investigate the regulation of the alternative splicing of CaMKII delta by PKA in cultured cells. We found that PKA promoted the exclusion of exons 14, 15, and 16 of CaMKII delta, resulting in an increase in delta C isoform. PKA interacted with and phosphorylated SF2/ASF, and enhanced SF2/ASF's activity to promote the exclusion of exons 14, 15, and 16 of CaMKII delta, leading to a further increase in the expression of delta C isoform. These findings suggest that abnormality in beta-adrenergic-PKA signaling may contribute to cardiomyopathy and heart failure through dysregulation in the alternative splicing of CaMKII delta exons 14, 15, and 16 and up-regulation of CaMKII delta C.
C1 [Gu, Qingqing; Sheng, Hongzhuan; Zhu, Jianhua] Nantong Univ, Affiliated Hosp, Dept Cardiol, Nantong, Jiangsu, Peoples R China.
   [Jin, Nana; Yin, Xiaomin] Nantong Univ, Jiangsu Key Lab Neuroregenerat, Nantong, Jiangsu, Peoples R China.
C3 Nantong University; Nantong University
RP Gu, QQ (corresponding author), Nantong Univ, Affiliated Hosp, Dept Cardiol, Nantong, Jiangsu, Peoples R China.
EM jhz323@yahoo.com.cn
FU National Natural Science Foundation of China [30971223, 30971224]
FX This study was supported by grants from the National Natural Science
   Foundation of China (30971223 and 30971224). The funders had no role in
   study design, data collection and analysis, decision to publish, or
   preparation of the manuscript.
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NR 28
TC 8
Z9 12
U1 0
U2 11
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD NOV 22
PY 2011
VL 6
IS 11
AR e25745
DI 10.1371/journal.pone.0025745
PG 8
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 858JH
UT WOS:000297792400001
PM 22132070
OA Green Published, Green Submitted, gold
DA 2025-04-10
ER

PT J
AU Gao, G
   Dudley, SC
AF Gao, Ge
   Dudley, Samuel C., Jr.
TI RBM25/LUC7L3 Function in Cardiac Sodium Channel Splicing Regulation of
   Human Heart Failure
SO TRENDS IN CARDIOVASCULAR MEDICINE
LA English
DT Review
ID IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; NF-KAPPA-B; GENETIC-VARIATION;
   BRUGADA-SYNDROME; EXPRESSION; SCN5A; THERAPY; MUTATIONS; PROTEINS; DEATH
AB Alternative splicing is a posttranscriptional mechanism that can substantially change the pattern of gene expression. Up to 95% of human genes have multiexon alternative spliced forms, suggesting that alternative splicing is one of the most significant components of the functional complexity of the human genome. Nevertheless, alternative splicing regulation has received comparatively little attention in the study of cardiac diseases. When investigating SCN5A splicing abnormalities in heart failure (HF), we found that 47 of 181 known splicing regulators were upregulated in HF compared to controls, which indicates that splicing regulation may play a key role in HF. Our results show that angiotensin II and hypoxia, signals common to HF, result in increased LUC7L3 and RBM25 splicing regulators, increased binding of RBM25 to SCN5A mRNA, increased SCN5A splice variant abundances, decreased full-length SCN5A mRNA and protein, and decreased Na+ current. These observations may shed light on a mechanism whereby cardiac function and arrhythmic risk are associated and allow for refined predictions of which patients may be at highest arrhythmic risk or suffer from Na+ channel blocking anti-arrhythmic drug complications. (Trends Cardiovasc Med 23:5-8) (C) 2012 Elsevier Inc. All rights reserved.
C1 [Dudley, Samuel C., Jr.] Univ Illinois, Cardiol Sect, Dept Med, Chicago, IL 60612 USA.
   Jesse Brown VA Med Ctr, Chicago, IL 60612 USA.
C3 University of Illinois System; University of Illinois Chicago;
   University of Illinois Chicago Hospital; US Department of Veterans
   Affairs; Veterans Health Administration (VHA); Jesse Brown VA Medical
   Center
RP Dudley, SC (corresponding author), Univ Illinois, Cardiol Sect, Dept Med, 840 S Wood S,MC 715, Chicago, IL 60612 USA.
EM scdudley@uic.edu
RI Dudley, Samuel/A-7085-2009
OI Dudley, Samuel/0000-0001-5843-5961
FU NIH [R01 HL106592, R01 HL104025, P01 HL058000]; VA MERIT grant
FX This work was supported by NIH grants R01 HL106592, R01 HL104025, and
   P01 HL058000 (SCD) and a VA MERIT grant.
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NR 37
TC 21
Z9 30
U1 1
U2 10
PU ELSEVIER SCIENCE LONDON
PI LONDON
PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND
SN 1050-1738
J9 TRENDS CARDIOVAS MED
JI Trends Cardiovasc. Med.
PD JAN
PY 2013
VL 23
IS 1
BP 5
EP 8
AR PII S1050-1738(12)00275-7
DI 10.1016/j.tcm.2012.08.003
PG 4
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 074WR
UT WOS:000313846300002
PM 22939879
DA 2025-04-10
ER

PT J
AU Gao, C
   Ren, SX
   Lee, JH
   Qiu, JS
   Chapski, DJ
   Rau, CD
   Zhou, Y
   Abdellatif, M
   Nakano, A
   Vondriska, TM
   Xiao, XS
   Fu, XD
   Chen, JN
   Wang, YB
AF Gao, Chen
   Ren, Shuxun
   Lee, Jae-Hyung
   Qiu, Jinsong
   Chapski, Douglas J.
   Rau, Christoph D.
   Zhou, Yu
   Abdellatif, Maha
   Nakano, Astushi
   Vondriska, Thomas M.
   Xiao, Xinshu
   Fu, Xiang-Dong
   Chen, Jau-Nian
   Wang, Yibin
TI RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart
   failure
SO JOURNAL OF CLINICAL INVESTIGATION
LA English
DT Article
ID TRANSCRIPTION FACTOR; MESSENGER-RNA; MYOTONIC-DYSTROPHY; PROTEIN; RBM20;
   RBFOX1; GENE; EXON; CARDIOMYOPATHY; COMPLEXITY
AB RNA splicing is a major contributor to total transcriptome complexity; however, the functional role and regulation of splicing in heart failure remain poorly understood. Here, we used a total transcriptome profiling and bioinformatic analysis approach and identified a muscle-specific isoform of an RNA splicing regulator, RBFox1 (also known as A2BP1), as a prominent regulator of alternative RNA splicing during heart failure. Evaluation of developing murine and zebrafish hearts revealed that RBFox1 is induced during postnatal cardiac maturation. However, we found that RBFox1 is markedly diminished in failing human and mouse hearts. In a mouse model, RBFox1 deficiency in the heart promoted pressure overload induced heart failure. We determined that RBFox1 is a potent regulator of RNA splicing and is required for a conserved splicing process of transcription factor MEF2 family members that yields different MEF2 isoforms with differential effects on cardiac hypertrophic gene expression. Finally, induction of RBFox1 expression in murine pressure overload models substantially attenuated cardiac hypertrophy and pathological manifestations. Together, this study identifies regulation of RNA splicing by RBFox1 as an important player in transcriptome reprogramming during heart failure that influence pathogenesis of the disease.
C1 [Gao, Chen; Lee, Jae-Hyung; Nakano, Astushi; Vondriska, Thomas M.; Xiao, Xinshu; Chen, Jau-Nian; Wang, Yibin] Univ Calif Los Angeles, David Geffen Sch Med, Inst Mol Biol, Los Angeles, CA 90095 USA.
   [Gao, Chen; Ren, Shuxun; Chapski, Douglas J.; Rau, Christoph D.; Nakano, Astushi; Vondriska, Thomas M.; Chen, Jau-Nian; Wang, Yibin] Univ Calif Los Angeles, David Geffen Sch Med, Cardiovasc Res Labs, Los Angeles, CA 90095 USA.
   [Gao, Chen; Ren, Shuxun; Chapski, Douglas J.; Rau, Christoph D.; Vondriska, Thomas M.; Wang, Yibin] Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol, Div Mol Med, Los Angeles, CA 90095 USA.
   [Gao, Chen; Ren, Shuxun; Chapski, Douglas J.; Rau, Christoph D.; Vondriska, Thomas M.; Wang, Yibin] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Div Mol Med, Los Angeles, CA 90095 USA.
   [Gao, Chen; Ren, Shuxun; Chapski, Douglas J.; Rau, Christoph D.; Vondriska, Thomas M.; Wang, Yibin] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Mol Med, Los Angeles, CA 90095 USA.
   [Lee, Jae-Hyung; Xiao, Xinshu] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA.
   [Qiu, Jinsong; Zhou, Yu; Fu, Xiang-Dong] UCSD Sch Med, Dept Cellular & Mol Med, La Jolla, CA USA.
   [Abdellatif, Maha] Rutgers State Univ, Rutgers New Jersey Med Sch, Dept Cell Biol & Mol Med, Newark, NJ 07102 USA.
   [Nakano, Astushi; Chen, Jau-Nian] Univ Calif Los Angeles, Dept Mol & Cellular Dev Biol, Los Angeles, CA USA.
C3 University of California System; University of California Los Angeles;
   University of California Los Angeles Medical Center; David Geffen School
   of Medicine at UCLA; University of California System; University of
   California Los Angeles; University of California Los Angeles Medical
   Center; David Geffen School of Medicine at UCLA; University of
   California System; University of California Los Angeles; University of
   California Los Angeles Medical Center; David Geffen School of Medicine
   at UCLA; University of California System; University of California Los
   Angeles; University of California Los Angeles Medical Center; David
   Geffen School of Medicine at UCLA; University of California System;
   University of California Los Angeles; University of California Los
   Angeles Medical Center; David Geffen School of Medicine at UCLA;
   University of California System; University of California Los Angeles;
   University of California System; University of California San Diego;
   Rutgers University System; Rutgers University New Brunswick; Rutgers
   University Biomedical & Health Sciences; Rutgers University Newark;
   University of California System; University of California Los Angeles
RP Wang, YB (corresponding author), Univ Calif Los Angeles, David Geffen Sch Med, Inst Mol Biol, Dept Anesthesiol,CHS, Room BH-569, Los Angeles, CA 90095 USA.
EM yibinwang@mednet.ucla.edu
RI Qiu, Jinsong/K-2325-2013; Yimei, Wang/AAE-4083-2019; Lee,
   Jae-Hyung/AAI-9813-2020; Rau, Christoph/AAC-3943-2020; Gao,
   Chen/KZU-1046-2024; Zhou, Yu/AAP-9964-2021; Chen,
   Jau-Nian/AAM-7808-2020; Wang, Yibin/AES-4559-2022
OI Lee, Jae-Hyung/0000-0002-5085-6988; Xiao, Xinshu/0000-0002-9362-8029;
   Chapski, Douglas/0000-0002-6730-7627; Wang, Yibin/0000-0003-0852-0767;
   Chen, Jau-Nian/0000-0001-8807-3607; Zhou, Yu/0000-0002-2102-9377
FU NIH [HL070079, HL103205, HL108186, HL110667, HL096980, HL115238,
   R01HG006264, U01HG007013]; UCLA Clinical and Translational Science
   Institute Cardiovascular Pilot Team Research Grant [UL1TR000124];
   American Heart Association Established Investigator Award; Eli & Edythe
   Broad Center Predoctoral Fellowship in Stem Cell Science; Ruth L.
   Kirschstein National Research Service Award at UCLA [T32 HL-69766]; UCLA
   Cardiovascular Research Laboratories; National Heart Lung and Blood
   Institute [T32HL069766] Funding Source: NIH RePORTER
FX The authors wish to thank Haiying Pu for her technical assistance and
   Douglas L. Black (UCLA) for reagents and discussion. This work was
   supported in part by grants from NIH (HL070079, HL103205, HL108186, and
   HL110667 to Y. Wang; HL096980 to J. Chen; HL115238 to T.M. Vondriska;
   R01HG006264 and U01HG007013 to X. Xiao), UCLA Clinical and Translational
   Science Institute Cardiovascular Pilot Team Research Grant (UL1TR000124
   to Y. Wang, X. Xiao, J. Chen, and T.M. Vondriska), an American Heart
   Association Established Investigator Award (to Y. Wang), an Eli & Edythe
   Broad Center Predoctoral Fellowship in Stem Cell Science (to C. Gao),
   the Ruth L. Kirschstein National Research Service Award at UCLA (T32
   HL-69766 to D.J. Chapski), and UCLA Cardiovascular Research
   Laboratories.
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NR 51
TC 113
Z9 126
U1 1
U2 23
PU AMER SOC CLINICAL INVESTIGATION INC
PI ANN ARBOR
PA 2015 MANCHESTER RD, ANN ARBOR, MI 48104 USA
SN 0021-9738
EI 1558-8238
J9 J CLIN INVEST
JI J. Clin. Invest.
PD JAN
PY 2016
VL 126
IS 1
BP 195
EP 206
DI 10.1172/JCI84015
PG 12
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA DA4JG
UT WOS:000367765600020
PM 26619120
OA Green Published, Green Submitted, Bronze
DA 2025-04-10
ER

PT J
AU He, J
   Yao, J
   Sheng, HZ
   Zhu, JH
AF He, Jing
   Yao, Jian
   Sheng, Hongzhuan
   Zhu, Jianhua
TI Involvement of the Dual-Specificity Tyrosine Phosphorylation-Regulated
   Kinase 1A-Alternative Splicing Factor Calcium/Calmodulin-Dependent
   Protein Kinase 118 Signaling Pathway in Myocardial Infarction-Induced
   Heart Failure of Rats
SO JOURNAL OF CARDIAC FAILURE
LA English
DT Article
DE Heart failure; calcium/calmodulin-dependent protein kinase 11 delta
   (CaMK11 delta); alternative splicing factor (ASF); dual-specificity
   tyrosine phosphorylation-regulated kinase 1A (Dyrk1A)
ID DOWN-SYNDROME; PREMESSENGER RNA; GENE-EXPRESSION; FACTOR ASF/SF2; SR
   PROTEINS; IN-VIVO; DYRK1A; HYPERTROPHY; INHIBITION; ACTIVATION
AB Background: Alternative splicing factor (ASF) regulated alternative splicing of calcium/calmodulin-dependent protein kinase II delta (CaMKII delta) plays an important role in pathologic cardiac remodeling. ASF can be phosphorylated by dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A). This study aimed to investigate the possible involvement of the Dyrk1A-ASF-CaMICII delta signaling pathway in the progression of myocardial infarction (ME)-induced heart failure (HF).
   Methods and Results: MI in rats was induced by means of left anterior descending coronary artery ligation. Seven weeks after MI, the increase in left ventricular internal diameter at end-diastole (LVIDd), and the decrease in both ejection fraction (EF) and fractional shortening (FS) indicated that MI rats had developed HF. Quantitative real time reverse-transcription polymerase chain reaction indicated the dysregulation of CaMICII delta alternative splicing, ie, up-regulation of CaMKII delta A and CaMKII delta C and down-regulation of CaMKII delta B in the hearts of HF rats. Electrophoresis and immunostaining revealed that HF activated the phosphorylation of ASF and affected its subcellular localization. Western blot analysis demonstrated a significant elevation in the activity and expression of Dyrk1A in HF rats. Inversely, treatment of MI-induCed HF rats with Dyrk1A inhibitor, either harmine or EGCG, improved the symptoms of HF, reversed the molecular changes of Dyrk1A and ASF, and regulated alternative splicing of CaMKII delta in HF rats.
   Conclusions: Enhanced activation of Dyrk1A-ASF-CaMICII delta signaling pathway may underlie the mechanisms of BY after MI, and Dyrk1A inhibition may contribute to inactivation of this pathway and thereby retard the progression of MI-induced HF.
C1 [He, Jing; Sheng, Hongzhuan; Zhu, Jianhua] Nantong Univ, Inst Cardiovasc Dis, Nantong, Jiangsu, Peoples R China.
   [He, Jing; Sheng, Hongzhuan; Zhu, Jianhua] Nantong Univ, Affiliated Hosp, Dept Cardiol, Nantong, Jiangsu, Peoples R China.
   [Yao, Jian] Nantong Univ, Dept Histol & Embryol, Nantong, Jiangsu, Peoples R China.
C3 Nantong University; Nantong University; Nantong University
RP Sheng, HZ (corresponding author), Nantong Univ, Affiliated Hosp, Dept Cardiol, Nantong, Jiangsu, Peoples R China.
EM yjshz@ntu.edu.cn; zhujhntheart@163.com
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NR 42
TC 18
Z9 18
U1 1
U2 14
PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS
PI PHILADELPHIA
PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA
SN 1071-9164
EI 1532-8414
J9 J CARD FAIL
JI J. Card. Fail.
PD SEP
PY 2015
VL 21
IS 9
BP 751
EP 760
DI 10.1016/j.cardfail.2015.05.015
PG 10
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA CQ7JD
UT WOS:000360778000010
PM 26067684
DA 2025-04-10
ER

PT J
AU Xu, X
   Zou, RC
   Liu, XY
   Su, QQ
AF Xu, Xiang
   Zou, Renchao
   Liu, Xiaoyong
   Su, Qianqian
TI Alternative splicing signatures of congenital heart disease and induced
   pluripotent stem cell-derived cardiomyocytes from congenital heart
   disease patients
SO MEDICINE
LA English
DT Article
DE alternative splicing; bioinformatics; congenital heart disease; RNA-seq
ID BINDING; HISAT
AB Congenital heart disease (CHD) is the most serious congenital defect in newborns with higher mortality. Alternative splicing (AS) plays an essential role in numerous heart diseases. However, our understanding of the link between mRNA splicing and CHD in humans is limited. Here, we try to investigate the genome-wide AS events in CHD using bioinformatics methods. We collected available RNA-seq datasets of CHD-induced pluripotent stem cell-cardiomyocytes (iPSC-CMs) (including single ventricle disease [SVD] and tetralogy of Fallot [TOF]) and non-CHD from the Gene Expression Omnibus database. Then, we unprecedentedly performed AS profiles in CHD-iPSC-CMs and non-CHD-iPSC-CMs. The rMAPS was used to generate RNA-maps for the analysis of RNA-binding proteins' (RBPs) binding sites. We used StringTie to identify and quantify the transcripts from aligned RNA-Seq reads. A quantification matrix was generated with respect to different groups by extracting the transcripts per million values from StringTie outputs. Then, this matrix was used for correlation analysis between the expression level of RBP and AS level. Finally, we validated our AS results using RNA-seq data from CHD and non-CHD patient tissue samples. We identified CHD-related AS events using CHD-iPSC-CMs and CHD samples from patients. The results showed that functional enrichment of abnormal AS in SVD and TOF was transcription factor-related. Using rMAPS, RNA-binding proteins which regulated these AS were also determined, and RBP-AS regulatory network was constructed. Overall, we identified abnormal AS in CHD-iPSC-CMs and CHD samples from patients. We predicted AS regulators in SVD and TOF, respectively. At last, we concluded that AS played a key role in the pathogenesis of CHD.
C1 [Xu, Xiang; Liu, Xiaoyong] Kunming Med Univ, Affiliated Hosp 2, Dept Cardiol, Kunming, Yunnan, Peoples R China.
   [Zou, Renchao] Kunming Med Univ, Affiliated Hosp 2, Dept Hepatobiliary Surg, Kunming, Yunnan, Peoples R China.
   [Su, Qianqian] Kunming Med Univ, Dept Lab Anim Sci, Kunming, Yunnan, Peoples R China.
C3 Kunming Medical University; Kunming Medical University; Kunming Medical
   University
RP Su, QQ (corresponding author), Kunming Med Univ, Dept Lab Anim Sci, Kunming, Yunnan, Peoples R China.
EM suqianqian@kmmu.edu.cn
OI Su, Qianqian/0000-0002-4476-7321
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NR 41
TC 1
Z9 1
U1 4
U2 14
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0025-7974
EI 1536-5964
J9 MEDICINE
JI Medicine (Baltimore)
PD AUG 19
PY 2022
VL 101
IS 33
AR e30123
DI 10.1097/MD.0000000000030123
PG 8
WC Medicine, General & Internal
WE Science Citation Index Expanded (SCI-EXPANDED)
SC General & Internal Medicine
GA 3V8UT
UT WOS:000841935100055
PM 35984151
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Liu, J
   Kong, X
   Zhang, MK
   Yang, X
   Xu, XQ
AF Liu, Jing
   Kong, Xu
   Zhang, Mengkai
   Yang, Xiao
   Xu, Xiuqin
TI RNA binding protein 24 deletion disrupts global alternative splicing and
   causes dilated cardiomyopathy
SO PROTEIN & CELL
LA English
DT Article
DE RNA binding protein; RBM24; dilated cardiomyopathy; alternative
   splicing; heart failure
ID HIGHLY ENRICHED CARDIOMYOCYTES; CARDIAC-HYPERTROPHY; Z-DISC; HEART;
   RBM24; MUTATIONS; TITIN; REGULATOR; GENE
AB RNA splicing contributes to a broad spectrum of post-transcriptional gene regulation during normal development, as well as pathological manifestation of heart diseases. However, the functional role and regulation of splicing in heart failure remain poorly understood. RNA binding protein (RBP), a major component of the splicing machinery, is a critical factor in this process. RNA binding motif protein 24 (RBM24) is a tissue-specific RBP which is highly expressed in human and mouse heart. Previous studies demonstrated the functional role of RBM24 in the embryonic heart development. However, the role of RBM24 in postnatal heart development and heart disease has not been investigated. In this paper, using conditional RBM24 knockout mice, we demonstrated that ablation of RBM24 in postnatal heart led to rapidly progressive dilated cardiomyopathy (DCM), heart failure, and postnatal lethality. Global splicing profiling revealed that RBM24 regulated a network of genes related to cardiac function and diseases. Knockout of RBM24 resulted in misregulation of these splicing transitions which contributed to the subsequent development of cardiomyopathy. Notably, our analysis identified RBM24 as a splice factor that determined the splicing switch of a subset of genes in the sacomeric Z-disc complex, including Titin, the major disease gene of DCM and heart failure. Together, this study identifies regulation of RNA splicing by RBM24 as a potent player in remodeling of heart during postnatal development, and provides novel mechanistic insights to the pathogenesis of DCM.
C1 [Liu, Jing; Kong, Xu; Zhang, Mengkai; Xu, Xiuqin] Xiamen Univ, Inst Stem Cell & Regenerat Med, Coll Med, Xiamen 361100, Fujian, Peoples R China.
   [Yang, Xiao] Inst Biotechnol, State Key Lab Prote, Genet Lab Dev & Dis, Beijing 100071, Peoples R China.
C3 Xiamen University
RP Xu, XQ (corresponding author), Xiamen Univ, Inst Stem Cell & Regenerat Med, Coll Med, Xiamen 361100, Fujian, Peoples R China.
EM xuxq@xmu.edu.cn
RI Kong, Fanxu/GSI-7088-2022; yang, xiao/HJI-7815-2023
OI Yang, Xiao/0000-0002-0298-9831
FU Major State Basic Research Development Program of China (973 Program)
   [2014CB965101]; National Key R&D program of China [2018YFA0107304];
   National Natural Science Foundation of China (NSFC) [81670286, 81871744,
   81700255]
FX The authors thank Li Wei Hong, Li Yan Guo and Xi Chen for technical
   assistance. This work was supported by the Major State Basic Research
   Development Program of China (973 Program) (Grant No. 2014CB965101),
   National Key R&D program of China (Grant No. 2018YFA0107304), and the
   National Natural Science Foundation of China (NSFC) (Grant Nos.
   81670286, 81871744 and 81700255).
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NR 35
TC 52
Z9 55
U1 1
U2 16
PU SPRINGEROPEN
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 1674-800X
EI 1674-8018
J9 PROTEIN CELL
JI Protein Cell
PD JUN
PY 2019
VL 10
IS 6
BP 405
EP 416
DI 10.1007/s13238-018-0578-8
PG 12
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA IA3ZQ
UT WOS:000469502200004
PM 30267374
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Zhao, YB
   Riching, AS
   Knight, WE
   Chi, CW
   Broadwell, LJ
   Du, YM
   Abdel-Hafiz, M
   Ambardekar, AV
   Irwin, DC
   Proenza, C
   Xu, HY
   Leinwand, LA
   Walker, LA
   Woulfe, KC
   Bristow, MR
   Buttrick, PM
   Song, KH
AF Zhao, Yuanbiao
   Riching, Andrew S.
   Knight, Walter E.
   Chi, Congwu
   Broadwell, Lindsey J.
   Du, Yanmei
   Abdel-Hafiz, Mostafa
   Ambardekar, Amrut, V
   Irwin, David C.
   Proenza, Catherine
   Xu, Hongyan
   Leinwand, Leslie A.
   Walker, Lori A.
   Woulfe, Kathleen C.
   Bristow, Michael R.
   Buttrick, Peter M.
   Song, Kunhua
TI Cardiomyocyte-Specific Long Noncoding RNA Regulates Alternative Splicing
   of the Triadin Gene in the Heart
SO CIRCULATION
LA English
DT Article
DE arrhythmias; cardiac; heart failure; myocytes; cardiac; RNA; long
   noncoding; splicing; alternative
ID RYANODINE RECEPTOR; PROTEIN-PROTEIN; CA2+ RELEASE; CALSEQUESTRIN;
   CONTRACTILITY; EXPRESSION; DOMAIN
AB Background: Abnormalities in Ca2+ homeostasis are associated with cardiac arrhythmias and heart failure. Triadin plays an important role in Ca2+ homeostasis in cardiomyocytes. Alternative splicing of a single triadin gene produces multiple triadin isoforms. The cardiac-predominant isoform, mouse MT-1 or human Trisk32, is encoded by triadin exons 1 to 8. In humans, mutations in the triadin gene that lead to a reduction in Trisk32 levels in the heart can cause cardiac dysfunction and arrhythmias. Decreased levels of Trisk32 in the heart are also common in patients with heart failure. However, mechanisms that maintain triadin isoform composition in the heart remain elusive. Methods: We analyzed triadin expression in heart explants from patients with heart failure and cardiac arrhythmias and in hearts from mice carrying a knockout allele for Trdn-as, a cardiomyocyte-specific long noncoding RNA encoded by the antisense strand of the triadin gene, between exons 9 and 11. Catecholamine challenge with isoproterenol was performed on Trdn-as knockout mice to assess the role of Trdn-as in cardiac arrhythmogenesis, as assessed by ECG. Ca2+ transients in adult mouse cardiomyocytes were measured with the IonOptix platform or the GCaMP system. Biochemistry assays, single-molecule fluorescence in situ hybridization, subcellular localization imaging, RNA sequencing, and molecular rescue assays were used to investigate the mechanisms by which Trdn-as regulates cardiac function and triadin levels in the heart. Results: We report that Trdn-as maintains cardiac function, at least in part, by regulating alternative splicing of the triadin gene. Knockout of Trdn-as in mice downregulates cardiac triadin, impairs Ca2+ handling, and causes premature death. Trdn-as knockout mice are susceptible to cardiac arrhythmias in response to catecholamine challenge. Normalization of cardiac triadin levels in Trdn-as knockout cardiomyocytes is sufficient to restore Ca2+ handling. Last, Trdn-as colocalizes and interacts with serine/arginine splicing factors in cardiomyocyte nuclei and is essential for efficient recruitment of splicing factors to triadin precursor mRNA. Conclusions: These findings reveal regulation of alternative splicing as a novel mechanism by which a long noncoding RNA controls cardiac function. This study indicates potential therapeutics for heart disease by targeting the long noncoding RNA or pathways regulating alternative splicing.
C1 [Zhao, Yuanbiao; Riching, Andrew S.; Knight, Walter E.; Chi, Congwu; Du, Yanmei; Ambardekar, Amrut, V; Walker, Lori A.; Woulfe, Kathleen C.; Bristow, Michael R.; Buttrick, Peter M.; Song, Kunhua] Univ Colorado, Dept Med, Div Cardiol, Anschutz Med Campus, Aurora, CO USA.
   [Riching, Andrew S.; Knight, Walter E.; Chi, Congwu; Song, Kunhua] Univ Colorado, Gates Ctr Regenerat Med & Stem Cell Biol, Anschutz Med Campus, Aurora, CO USA.
   [Riching, Andrew S.; Knight, Walter E.; Chi, Congwu; Ambardekar, Amrut, V; Song, Kunhua] Univ Colorado, Consortium Fibrosis Res & Translat, Anschutz Med Campus, Aurora, CO USA.
   [Abdel-Hafiz, Mostafa] Univ Colorado, Dept Bioengn, Anschutz Med Campus, Aurora, CO USA.
   [Irwin, David C.] Univ Colorado, Dept Med, Cardiovasc & Pulm Res Lab, Anschutz Med Campus, Aurora, CO USA.
   [Proenza, Catherine] Univ Colorado, Dept Physiol & Biophys, Anschutz Med Campus, Aurora, CO USA.
   [Broadwell, Lindsey J.] Univ Colorado, Dept Biochem, Boulder, CO 80309 USA.
   [Broadwell, Lindsey J.; Leinwand, Leslie A.] Univ Colorado, BioFrontiers Inst, Boulder, CO 80309 USA.
   [Leinwand, Leslie A.] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA.
   [Xu, Hongyan] Augusta Univ, Med Coll Georgia, Dept Populat Hlth Sci, Augusta, GA USA.
C3 University of Colorado System; University of Colorado Anschutz Medical
   Campus; University of Colorado System; University of Colorado Anschutz
   Medical Campus; University of Colorado System; University of Colorado
   Anschutz Medical Campus; University of Colorado System; University of
   Colorado Anschutz Medical Campus; University of Colorado System;
   University of Colorado Anschutz Medical Campus; University of Colorado
   System; University of Colorado Anschutz Medical Campus; University of
   Colorado System; University of Colorado Boulder; University of Colorado
   System; University of Colorado Boulder; University of Colorado System;
   University of Colorado Boulder; University System of Georgia; Augusta
   University
RP Song, KH (corresponding author), 12700 E 19th Ave,B-139, Aurora, CO 80045 USA.
EM kunhua.song@cuanschutz.edu
RI zhao, yuanbiao/I-2990-2019; Walker, Lori/J-7098-2013; L, A/HZI-4043-2023
OI Ambardekar, Amrut/0000-0003-3503-4203; Riching,
   Andrew/0000-0001-6797-6487
FU Colorado Clinical & Translational Sciences Institute [TL1 TR001081];
   American Heart Association [18PRE34030030]; National Institutes of
   Health (NIH) Cardiology Training Grant [T32HL007822]; NIH/Colorado
   Clinical & Translational Sciences Institute CO-Pilot Mentored Faculty
   Award [TL1 TR002533]; Boettcher Foundation, University of Colorado
   Department of Medicine Outstanding Early Career Scholar Program; Gates
   Frontiers Fund; NIH [1S10OD018156-01]; NIH/National Center for Advancing
   Translational Sciences Colorado [UL1 TR002535]; American Heart
   Association; National Center for Advancing Translational Sciences
   [UL1TR002535, TL1TR002533] Funding Source: NIH RePORTER; NIH Office of
   the Director [R01HL133230] Funding Source: NIH RePORTER
FX Dr Riching was supported by predoctoral fellowships from Colorado
   Clinical & Translational Sciences Institute (TL1 TR001081) and the
   American Heart Association (18PRE34030030). Dr Knight was supported by
   National Institutes of Health (NIH) Cardiology Training Grant
   T32HL007822, American Heart Association (19POST34380250), and an
   NIH/Colorado Clinical & Translational Sciences Institute CO-Pilot
   Mentored Faculty Award (TL1 TR002533). Dr Song was supported by funds
   from the Boettcher Foundation, University of Colorado Department of
   Medicine Outstanding Early Career Scholar Program, Gates Frontiers Fund,
   American Heart Association, and NIH R01HL133230. REDCap was supported by
   NIH/National Center for Advancing Translational Sciences Colorado (UL1
   TR002535). Echocardiographic analysis was supported by NIH grant
   1S10OD018156-01.
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NR 58
TC 17
Z9 19
U1 0
U2 6
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7322
EI 1524-4539
J9 CIRCULATION
JI Circulation
PD AUG 30
PY 2022
VL 146
IS 9
BP 699
EP 714
DI 10.1161/CIRCULATIONAHA.121.058017
PG 16
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 4A1ON
UT WOS:000844880000008
PM 35862102
OA Bronze
DA 2025-04-10
ER

PT J
AU Guo, W
   Schafer, S
   Greaser, ML
   Radke, MH
   Liss, M
   Govindarajan, T
   Maatz, H
   Schulz, H
   Li, SJ
   Parrish, AM
   Dauksaite, V
   Vakeel, P
   Klaassen, S
   Gerull, B
   Thierfelder, L
   Regitz-Zagrosek, V
   Hacker, TA
   Saupe, KW
   Dec, GW
   Ellinor, PT
   MacRae, CA
   Spallek, B
   Fischer, R
   Perrot, A
   Özcelik, C
   Saar, K
   Hubner, N
   Gotthardt, M
AF Guo, Wei
   Schafer, Sebastian
   Greaser, Marion L.
   Radke, Michael H.
   Liss, Martin
   Govindarajan, Thirupugal
   Maatz, Henrike
   Schulz, Herbert
   Li, Shijun
   Parrish, Amanda M.
   Dauksaite, Vita
   Vakeel, Padmanabhan
   Klaassen, Sabine
   Gerull, Brenda
   Thierfelder, Ludwig
   Regitz-Zagrosek, Vera
   Hacker, Timothy A.
   Saupe, Kurt W.
   Dec, G. William
   Ellinor, Patrick T.
   MacRae, Calum A.
   Spallek, Bastian
   Fischer, Robert
   Perrot, Andreas
   Oezcelik, Cemil
   Saar, Kathrin
   Hubner, Norbert
   Gotthardt, Michael
TI RBM20, a gene for hereditary cardiomyopathy, regulates titin
   splicing
SO NATURE MEDICINE
LA English
DT Article
ID FAMILIAL DILATED CARDIOMYOPATHY; RNA-BINDING PROTEINS; ISOFORM
   EXPRESSION; PASSIVE STIFFNESS; HEART-FAILURE; SR PROTEINS; DISEASE;
   MUTATIONS; RAT; MYOCARDIUM
AB Alternative splicing has a major role in cardiac adaptive responses, as exemplified by the isoform switch of the sarcomeric protein titin, which adjusts ventricular filling. By positional cloning using a previously characterized rat strain with altered titin mRNA splicing, we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression. The phenotype of Rbm20-deficient rats resembled the pathology seen in individuals with dilated cardiomyopathy caused by RBM20 mutations. Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20-dependent regulation of alternative splicing. In addition to titin (TTN), we identified a set of 30 genes with conserved splicing regulation between humans and rats. This network is enriched for genes that have previously been linked to cardiomyopathy, ion homeostasis and sarcomere biology. Our studies emphasize the key role of post-transcriptional regulation in cardiac function and provide mechanistic insights into the pathogenesis of human heart failure.
C1 [Schafer, Sebastian; Radke, Michael H.; Liss, Martin; Govindarajan, Thirupugal; Maatz, Henrike; Schulz, Herbert; Dauksaite, Vita; Vakeel, Padmanabhan; Klaassen, Sabine; Gerull, Brenda; Thierfelder, Ludwig; Saar, Kathrin; Hubner, Norbert; Gotthardt, Michael] Max Delbruck Ctr Mol Med, Berlin, Germany.
   [Guo, Wei; Greaser, Marion L.; Li, Shijun; Parrish, Amanda M.] Univ Wisconsin, Muscle Biol Lab, Madison, WI 53706 USA.
   [Regitz-Zagrosek, Vera] Univ Med Berlin, Charite, Cardiovasc Res Ctr, Berlin, Germany.
   [Regitz-Zagrosek, Vera] Univ Med Berlin, Charite, Inst Gender Med, Berlin, Germany.
   [Hacker, Timothy A.; Saupe, Kurt W.] Univ Wisconsin, Dept Med, Madison, WI USA.
   [Dec, G. William; Ellinor, Patrick T.; MacRae, Calum A.] Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA USA.
   [Spallek, Bastian; Fischer, Robert] Univ Med Berlin, Charite, Univ Kilikum Benjamin Franklin, Berlin, Germany.
   [Perrot, Andreas; Oezcelik, Cemil] Charite, Campus Virchow Klinikum, Dept Cardiol, D-13353 Berlin, Germany.
C3 Helmholtz Association; Max Delbruck Center for Molecular Medicine;
   University of Wisconsin System; University of Wisconsin Madison; Berlin
   Institute of Health; Free University of Berlin; Humboldt University of
   Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health;
   Free University of Berlin; Humboldt University of Berlin; Charite
   Universitatsmedizin Berlin; University of Wisconsin System; University
   of Wisconsin Madison; Harvard University; Harvard University Medical
   Affiliates; Massachusetts General Hospital; Berlin Institute of Health;
   Free University of Berlin; Humboldt University of Berlin; Charite
   Universitatsmedizin Berlin; Berlin Institute of Health; Free University
   of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin
   Berlin
RP Gotthardt, M (corresponding author), Max Delbruck Ctr Mol Med, Berlin, Germany.
EM gotthardt@mdc-berlin.de
RI van Heesch, Sebastiaan/AAT-6595-2020; Greaser, Marion/C-6147-2012;
   Gotthardt, Michael/ABE-8274-2021; guo, wei/E-8906-2012; Govindarajan,
   Thirupugal/A-8758-2015
OI Klaassen, Sabine/0000-0001-5925-9912; Schafer,
   Sebastian/0000-0002-6909-8275; Perrot, Andreas/0000-0002-8800-342X;
   Govindarajan, Thirupugal/0000-0003-2660-9730; guo,
   wei/0000-0002-9158-8107; Liss, Martin/0000-0002-0585-7850; Gotthardt,
   Michael/0000-0003-1788-3172; Regitz-Zagrosek, Vera/0000-0002-3566-3467;
   Govindarajan, Thirupugal/0000-0003-1714-1267; Radke,
   Michael/0000-0003-0112-9917; Saar, Kathrin/0000-0002-4483-1557; Ellinor,
   Patrick/0000-0002-2067-0533
FU US National Institutes of Health [HL77196, HL075431]; Deutsche
   Forschungsgemeinschaft, Bonn, Germany; European Research Council
   [StG282078]; German Ministry of Science and Education (Nationales
   Genomforschungsnetz, NGFN-Plus Heart Failure Network) and EURATRANS
   [HEALTH-F4-2010-241504]; American Heart Association
FX We are grateful to B. Goldbrich, O. Hummel, S. Lubitz, S. Makino, G.
   Patone, S. Blachut, R. Plehm, S. Probst, S. Schmidt and M. Wehle for
   expert technical assistance. R. Hetzer (Deutsches Herzzentrum Berlin)
   generously provided human cardiac tissue. Mammalian expression vectors
   for PTBP1 and HuD were gifts from R. Darnell, The Rockefeller
   University. This work was supported by the US National Institutes of
   Health grants HL77196 (M.L.G.) and HL075431 (C.A.M.), the Deutsche
   Forschungsgemeinschaft, Bonn, Germany and the European Research Council
   grant StG282078 (M.G.), the German Ministry of Science and Education
   (Nationales Genomforschungsnetz, NGFN-Plus Heart Failure Network) and
   EURATRANS (HEALTH-F4-2010-241504) (N.H.) and the American Heart
   Association (P.T.E.).
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NR 51
TC 424
Z9 482
U1 1
U2 24
PU NATURE PUBLISHING GROUP
PI NEW YORK
PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA
SN 1078-8956
J9 NAT MED
JI Nat. Med.
PD MAY
PY 2012
VL 18
IS 5
BP 766
EP U162
DI 10.1038/nm.2693
PG 9
WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research &
   Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental
   Medicine
GA 938WE
UT WOS:000303763500044
PM 22466703
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Li, G
   Wang, JJ
   Liao, P
   Bartels, P
   Zhang, HY
   Yu, DJ
   Liang, MC
   Poh, KK
   Yu, CY
   Jiang, FL
   Yong, TF
   Wong, YP
   Hu, ZY
   Huang, H
   Zhang, GQ
   Galupo, MJ
   Bian, JS
   Ponniah, S
   Trasti, SL
   See, K
   Foo, R
   Hoppe, UC
   Herzig, S
   Soong, TW
AF Li, Guang
   Wang, Juejin
   Liao, Ping
   Bartels, Peter
   Zhang, Hengyu
   Yu, Dejie
   Liang, Mui Cheng
   Poh, Kian Keong
   Yu, Chye Yun
   Jiang, Fengli
   Yong, Tan Fong
   Wong, Yuk Peng
   Hu, Zhenyu
   Huang, Hua
   Zhang, Guangqin
   Galupo, Mary Joyce
   Bian, Jin-Song
   Ponniah, Sathivel
   Trasti, Scott Lee
   See, Kelvin
   Foo, Roger
   Hoppe, Uta C.
   Herzig, Stefan
   Soong, Tuck Wah
TI Exclusion of alternative exon 33 of CaV1.2 calcium channels
   in heart is proarrhythmogenic
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
   AMERICA
LA English
DT Article
DE CaV1.2 channel; alternative splicing; cardiac function; cardiac
   arrhythmia; heart failure
ID CA2+ CHANNEL; EARLY AFTERDEPOLARIZATIONS; VENTRICULAR MYOCYTES; CARDIAC
   MYOCYTES; ALPHA(1) SUBUNIT; SPLICE VARIANTS; PURKINJE-FIBERS; TRANSGENIC
   MICE; FAILURE; CONTRACTION
AB Alternative splicing changes the Ca(V)1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure-function studies of heterologously expressed Ca(V)1.2 channels could not recapitulate channel function in the native milieu of the cardiomyocyte. To address this gap in knowledge, we investigated the role of alternative exon 33 of the Ca(V)1.2 calcium channel in heart function. Exclusion of exon 33 in Ca(V)1.2 channels has been reported to shift the activation potential -10.4 mV to the hyperpolarized direction, and increased expression of Ca(V)1.2.33 channels was observed in rat myocardial infarcted hearts. However, how a change in Ca(V)1.2 channel electrophysiological property, due to alternative splicing, might affect cardiac function in vivo is unknown. To address these questions, we generated mCacna1c exon 33(-/-)-null mice. These mice contained Ca(V)1.2.33 channels with a gain-of-function that included conduction of larger currents that reflects a shift in voltage dependence and a modest increase in single-channel open probability. This altered channel property underscored the development of ventricular arrhythmia, which is reflected in significantly more deaths of exon 33-/-mice from beta-adrenergic stimulation. In vivo telemetric recordings also confirmed increased frequencies in premature ventricular contractions, tachycardia, and lengthened QT interval. Taken together, the significant decrease or absence of exon 33-containing Ca(V)1.2 channels is potentially proarrhythmic in the heart. Of clinical relevance, human ischemic and dilated cardiomyopathy hearts showed increased inclusion of exon 33. However, the possible role that inclusion of exon 33 in Ca(V)1.2 channels may play in the pathogenesis of human heart failure remains unclear.
C1 [Li, Guang; Wang, Juejin; Bartels, Peter; Zhang, Hengyu; Yu, Dejie; Liang, Mui Cheng; Jiang, Fengli; Yong, Tan Fong; Wong, Yuk Peng; Hu, Zhenyu; Huang, Hua; Soong, Tuck Wah] Natl Univ Singapore, Dept Physiol, Singapore 117597, Singapore.
   [Li, Guang] Southwest Med Univ, Inst Cardiovascular Res, Minist Educ, Key Lab Med Electrophysiol, Luzhou 646000, Sichuan, Peoples R China.
   [Wang, Juejin] Nanjing Med Univ, Dept Physiol, Nanjing 211166, Jiangsu, Peoples R China.
   [Liao, Ping; Yu, Chye Yun; Soong, Tuck Wah] Natl Neurosci Inst, Singapore 308433, Singapore.
   [Poh, Kian Keong; Galupo, Mary Joyce] Natl Univ Singapore, Dept Med, Singapore, Singapore.
   [Zhang, Guangqin] China Pharmaceut Univ, Dept Clin Pharm, Nanjing 210009, Jiangsu, Peoples R China.
   [Bian, Jin-Song] Natl Univ Singapore, Dept Pharmacol, Singapore 117600, Singapore.
   [Ponniah, Sathivel] Agcy Sci Technol & Res, Biol Resource Ctr, Singapore 138668, Singapore.
   [Trasti, Scott Lee] Natl Univ Singapore, Comparat Med, Singapore 117601, Singapore.
   [See, Kelvin; Foo, Roger] Genome Inst Singapore, Singapore 138672, Singapore.
   [Hoppe, Uta C.] Paracelsus Med Univ, Dept Internal Med 2, A-5020 Salzburg, Austria.
   [Herzig, Stefan] Univ Cologne, Ctr Mol Med, D-50931 Cologne, Germany.
   [Herzig, Stefan] Univ Cologne, Dept Pharmacol, D-50931 Cologne, Germany.
   [Soong, Tuck Wah] Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 117456, Singapore.
   [Soong, Tuck Wah] Natl Univ Singapore, Neurobiol Ageing Programme, Singapore 117456, Singapore.
C3 National University of Singapore; Southwest Medical University; Nanjing
   Medical University; National Neuroscience Institute (NNI); National
   University of Singapore; China Pharmaceutical University; National
   University of Singapore; Agency for Science Technology & Research
   (A*STAR); National University of Singapore; Agency for Science
   Technology & Research (A*STAR); A*STAR - Genome Institute of Singapore
   (GIS); Paracelsus Private Medical University; University of Cologne;
   University of Cologne; National University of Singapore; National
   University of Singapore
RP Soong, TW (corresponding author), Natl Univ Singapore, Dept Physiol, Singapore 117597, Singapore.; Soong, TW (corresponding author), Natl Neurosci Inst, Singapore 308433, Singapore.; Soong, TW (corresponding author), Natl Univ Singapore, Grad Sch Integrat Sci & Engn, Singapore 117456, Singapore.; Soong, TW (corresponding author), Natl Univ Singapore, Neurobiol Ageing Programme, Singapore 117456, Singapore.
EM phsstw@nus.edu.sg
RI Poh, Kian Keong/KBC-1668-2024; Zhang, hengyo/ITU-4911-2023; Yu,
   Dejie/AAT-3293-2021; Juejin, Wang/JAX-4081-2023; hu,
   zhenyu/KIB-5028-2024; Liao, Ping/LBI-1504-2024; Bartels,
   Peter/AAJ-2857-2021
OI Bartels, Peter/0000-0001-5852-1835; Liang, Mui
   Cheng/0000-0003-1208-0733; Hu, Zhenyu/0000-0002-2392-7533; Li,
   Guang/0009-0005-5017-1937; Bian, Jinsong/0000-0001-8000-3356; Foo,
   Roger/0000-0002-8079-4618; Liao, Ping/0000-0002-6205-4042; Herzig,
   Stefan/0000-0001-8107-5204; Bian, Jinsong/0000-0002-7741-598X
FU Biomedical Research Council; National Medical Research Council of
   Singapore
FX We thank Dr. Carol Tang and Wei-ping Yu for help in karyotyping of ES
   cells. This work was supported by grants from the Biomedical Research
   Council and the National Medical Research Council of Singapore (to
   T.W.S.).
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NR 50
TC 29
Z9 31
U1 12
U2 22
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD MAY 23
PY 2017
VL 114
IS 21
BP E4288
EP E4295
DI 10.1073/pnas.1617205114
PG 8
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA EV5IL
UT WOS:000401797800023
PM 28490495
OA Green Published, Bronze
DA 2025-04-10
ER

PT J
AU Boeckel, JN
   Möbius-Winkler, M
   Müller, M
   Rebs, S
   Eger, N
   Schoppe, L
   Tappu, R
   Kokot, KE
   Kneuer, JM
   Gaul, S
   Bordalo, DM
   Lai, A
   Haas, J
   Ghanbari, M
   Drewe-Boss, P
   Liss, M
   Katus, HA
   Ohler, U
   Gotthardt, M
   Laufs, U
   Streckfuss-Bömeke, K
   Meder, B
AF Boeckel, Jes-Niels
   Moebius-Winkler, Maximilian
   Mueller, Marion
   Rebs, Sabine
   Eger, Nicole
   Schoppe, Laura
   Tappu, Rewati
   Kokot, Karoline E.
   Kneuer, Jasmin M.
   Gaul, Susanne
   Bordalo, Diana M.
   Lai, Alan
   Haas, Jan
   Ghanbari, Mahsa
   Drewe-Boss, Philipp
   Liss, Martin
   Katus, Hugo A.
   Ohler, Uwe
   Gotthardt, Michael
   Laufs, Ulrich
   Streckfuss-Boemeke, Katrin
   Meder, Benjamin
TI SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to
   Dilated Cardiomyopathy
SO GENOMICS PROTEOMICS & BIOINFORMATICS
LA English
DT Article
DE Splicing; Titin; Dilated cardiomyopathy; KHDRBS3; SLM2
ID HNRNP PROTEINS; RNA; GENE; EXPRESSION; MUTATIONS; REGULATOR; DOMAIN;
   RBM20; TITIN
AB Alternative mRNA splicing is a fundamental process to increase the versatility of the gen-ome. In humans, cardiac mRNA splicing is involved in the pathophysiology of heart failure. Mutationsin the splicing factor RNA binding motif protein 20 (RBM20) cause severe forms of cardiomyopathy. To identify novel cardiomyopathy-associated splicing factors, RNA-seq and tissue-enrichment anal-yses were performed, which identified up-regulated expression of Sam68-Like mammalian protein 2 (SLM2) in the left ventricle of dilated cardiomyopathy (DCM) patients. In the human heart, SLM2 binds to important transcripts of sarcomere constituents, such as those encoding myosin light chain 2 (MYL2), troponin I3 (TNNI3), troponin T2 (TNNT2), tropomyosin 1/2 (TPM1/2), and titin (TTN). Mechanistically, SLM2 mediates intron retention, prevents exon exclusion, and thereby medi-ates alternative splicing of the mRNA regions encoding the variable proline-, glutamate-, valine-, and lysine-rich (PEVK) domain and another part of the I-band region of titin. In summary, SLM2 is a novel cardiac splicing regulator with essential functions for maintaining cardiomyocyte integrity by binding to and processing the mRNAs of essential cardiac constituents such as titin.
C1 [Boeckel, Jes-Niels; Mueller, Marion; Eger, Nicole; Schoppe, Laura; Tappu, Rewati; Bordalo, Diana M.; Lai, Alan; Haas, Jan; Katus, Hugo A.; Meder, Benjamin] Univ Hosp Heidelberg, Dept Cardiol Angiol & Pneumol, D-69120 Heidelberg, Germany.
   [Boeckel, Jes-Niels; Moebius-Winkler, Maximilian; Kokot, Karoline E.; Kneuer, Jasmin M.; Gaul, Susanne; Laufs, Ulrich] Univ Krankenhaus Leipzig, Klin & Poliklin Kardiol, D-04103 Leipzig, Germany.
   [Mueller, Marion; Bordalo, Diana M.; Lai, Alan; Haas, Jan; Katus, Hugo A.; Meder, Benjamin] German Ctr Cardiovasc Res DZHK, Partner Site Heidelberg, D-69120 Heidelberg, Germany.
   [Mueller, Marion] Ruhr Univ Bochum, Herz & Diabet Zentrum NRW, Clin Gen & Intervent Cardiol Angiol, D-32545 Bad Oeynhausen, Germany.
   [Rebs, Sabine; Streckfuss-Boemeke, Katrin] Georg August Univ Goettingen, Univ Hosp, Dept Cardiol & Pneumol, D-37075 Gottingen, Germany.
   [Rebs, Sabine; Streckfuss-Boemeke, Katrin] German Ctr Cardiovasc Res DZHK, Partner Site Goettingen, D-37075 Gottingen, Germany.
   [Ghanbari, Mahsa; Drewe-Boss, Philipp; Ohler, Uwe] Max Delbruck Ctr Mol Med, Berlin Inst Med Syst Biol, Helmholtz Assoc, D-10115 Berlin, Germany.
   [Ghanbari, Mahsa; Drewe-Boss, Philipp; Ohler, Uwe] Humboldt Univ, Inst Biol, D-10099 Berlin, Germany.
   [Liss, Martin; Gotthardt, Michael] Max Delbruck Ctr Mol Med, Neuromuscular & Cardiovasc Cell Biol, Helmholtz Assoc, D-13092 Berlin, Germany.
   [Liss, Martin; Gotthardt, Michael] German Ctr Cardiovasc Res DZHK, Partner Site Berlin, D-10117 Berlin, Germany.
   [Meder, Benjamin] Stanford Med Sch, Stanford Genome Technol Ctr, Dept Genet, Palo Alto, CA 94304 USA.
C3 Ruprecht Karls University Heidelberg; German Centre for Cardiovascular
   Research; Ruhr University Bochum; University of Gottingen; UNIVERSITY
   GOTTINGEN HOSPITAL; German Centre for Cardiovascular Research; Helmholtz
   Association; Max Delbruck Center for Molecular Medicine; Humboldt
   University of Berlin; Helmholtz Association; Max Delbruck Center for
   Molecular Medicine; German Centre for Cardiovascular Research; Stanford
   University
RP Meder, B (corresponding author), Univ Hosp Heidelberg, Dept Cardiol Angiol & Pneumol, D-69120 Heidelberg, Germany.; Meder, B (corresponding author), German Ctr Cardiovasc Res DZHK, Partner Site Heidelberg, D-69120 Heidelberg, Germany.; Meder, B (corresponding author), Stanford Med Sch, Stanford Genome Technol Ctr, Dept Genet, Palo Alto, CA 94304 USA.
EM Benjamin.Meder@med.uni-heidelberg.de
RI Streckfuß-Bömeke, Katrin/H-1375-2016; Gotthardt, Michael/ABE-8274-2021;
   Müller, Marion/ISV-5297-2023
OI Mobius-Winkler, Maximilian Nicolas/0000-0002-4400-3508; Gaul,
   Susanne/0000-0003-4780-1844; Rebs, Sabine/0000-0002-9504-0261; Laufs,
   Ulrich/0000-0003-2620-9323; Schoppe, Laura/0000-0003-0047-8760; Kokot,
   Karoline Elizabeth/0000-0002-8130-4289; Muller,
   Marion/0000-0002-8519-0661; Kneuer, Jasmin Marga/0000-0003-0273-3614;
   Gotthardt, Michael/0000-0003-1788-3172
FU Deutsches Zentrum fur Herz-Kreislauf-Forschung (German Center for
   Cardiovascular Research, DZHK, Germany); German Ministry of Education
   and Research [T0395/35973/2020]; Informatics for Life (Klaus Tschira
   Foundation, Germany); Faculty of Medicine of the Leipzig University; Dr.
   Marija Orlovic Stiftung [FP7]; European Union; excellence fellowship of
   the Else Kroner Fresenius Foundation (Germany);  [FKZ 031L0075B]
FX We thank Sabine Herch, Anne Marie Muller, Antje Weber, and Rouven
   Nietsch for excellent technical support. We thank Daniel Ohler for his
   support in retrieving RNA-binding proteins from literature. This work
   was supported by grants from the Deutsches Zentrum fur
   Herz-Kreislauf-Forschung (German Center for Cardiovascular Research,
   DZHK, Germany), the German Ministry of Education and Research (Grant No.
   FKZ 031L0075B, CaRNAtion, Germany), the Informatics for Life (Klaus
   Tschira Foundation, Germany), the Faculty of Medicine of the Leipzig
   University to MMW, the Dr. Marija Orlovic Stiftung (Grant No.
   T0395/35973/2020, Germany) to JNB, and the European Union (Grant No. FP7
   BestAgeing,Europe). BM was supported by an excellence fellowship of the
   Else Kroner Fresenius Foundation (Germany).
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NR 54
TC 13
Z9 14
U1 0
U2 0
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 1672-0229
EI 2210-3244
J9 GENOM PROTEOM BIOINF
JI Genom. Proteomics Bioinformatics
PD FEB
PY 2022
VL 20
IS 1
BP 129
EP 146
DI 10.1016/j.gpb.2021.01.006
PG 18
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 5K2TJ
UT WOS:000869583000006
PM 34273561
OA Green Accepted, Green Published, gold
DA 2025-04-10
ER

PT J
AU Jiang, JX
   Wu, HC
   Ji, YB
   Han, KJ
   Tang, JM
   Hu, SJ
   Lei, W
AF Jiang, Jinxiu
   Wu, Hongchun
   Ji, Yabo
   Han, Kunjun
   Tang, Jun-Ming
   Hu, Shijun
   Lei, Wei
TI Development and disease-specific regulation of RNA splicing in
   cardiovascular system
SO FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
LA English
DT Review
DE alternative splicing; cardiac development; cardiovascular disease; RNA
   binding protein; splicing factor
ID CA(V)1.2 CALCIUM-CHANNELS; MESSENGER-RNA; CARDIAC-FUNCTION; HYPERTROPHIC
   CARDIOMYOPATHY; DILATED CARDIOMYOPATHY; MYOCARDIAL-INFARCTION;
   ENDOTHELIAL-CELLS; GENE-EXPRESSION; HEART; BINDING
AB Alternative splicing is a complex gene regulatory process that distinguishes itself from canonical splicing by rearranging the introns and exons of an immature pre-mRNA transcript. This process plays a vital role in enhancing transcriptomic and proteomic diversity from the genome. Alternative splicing has emerged as a pivotal mechanism governing complex biological processes during both heart development and the development of cardiovascular diseases. Multiple alternative splicing factors are involved in a synergistic or antagonistic manner in the regulation of important genes in relevant physiological processes. Notably, circular RNAs have only recently garnered attention for their tissue-specific expression patterns and regulatory functions. This resurgence of interest has prompted a reevaluation of the topic. Here, we provide an overview of our current understanding of alternative splicing mechanisms and the regulatory roles of alternative splicing factors in cardiovascular development and pathological process of different cardiovascular diseases, including cardiomyopathy, myocardial infarction, heart failure and atherosclerosis.
C1 [Jiang, Jinxiu; Wu, Hongchun; Ji, Yabo; Han, Kunjun; Hu, Shijun; Lei, Wei] Soochow Univ, Affiliated Hosp 1, Suzhou Med Coll, Dept Cardiovasc Surg, Suzhou, Peoples R China.
   [Jiang, Jinxiu; Wu, Hongchun; Ji, Yabo; Han, Kunjun; Hu, Shijun; Lei, Wei] Soochow Univ, Inst Cardiovasc Sci, Suzhou Med Coll, State Key Lab Radiat Med & Protect, Suzhou, Peoples R China.
   [Tang, Jun-Ming] Hubei Univ Med, Hubei Key Lab Embryon Stem Cell Res, Shiyan, Peoples R China.
C3 Soochow University - China; Soochow University - China; Hubei University
   of Medicine
RP Hu, SJ; Lei, W (corresponding author), Soochow Univ, Affiliated Hosp 1, Suzhou Med Coll, Dept Cardiovasc Surg, Suzhou, Peoples R China.; Hu, SJ; Lei, W (corresponding author), Soochow Univ, Inst Cardiovasc Sci, Suzhou Med Coll, State Key Lab Radiat Med & Protect, Suzhou, Peoples R China.; Tang, JM (corresponding author), Hubei Univ Med, Hubei Key Lab Embryon Stem Cell Res, Shiyan, Peoples R China.
EM tangjm416@163.com; shijunhu@suda.edu.cn; leiwei@suda.edu.cn
RI Lei, Wei/N-7611-2013; Hu, Shijun/AAL-3606-2020
FU National Key R&D Program of China [2021YFA1101900, 2022YFA1104300];
   National Natural Science Foundation of China [82241202, 82170364,
   81970223]; Open Project of Hubei Key Laboratory of Embryonic Stem Cell
   Research [ESOF2023008]; Jiangsu Cardiovascular Medicine Innovation
   Center [CXZX202210]; Priority Academic Program Development of Jiangsu
   Higher Education Institutions [2017B01012]
FX The author(s) declare that financial support was received for the
   research, authorship, and/or publication of this article. This work was
   supported by National Key R&D Program of China (2021YFA1101900,
   2022YFA1104300), National Natural Science Foundation of China (82241202,
   82170364, 81970223), Open Project of Hubei Key Laboratory of Embryonic
   Stem Cell Research (ESOF2023008), Jiangsu Cardiovascular Medicine
   Innovation Center (CXZX202210), a Project Funded by the Priority
   Academic Program Development of Jiangsu Higher Education Institutions,
   National Center for International Research (2017B01012).
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NR 123
TC 2
Z9 2
U1 2
U2 7
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2296-634X
J9 FRONT CELL DEV BIOL
JI Front. Cell. Dev. Biol.
PD JUL 9
PY 2024
VL 12
AR 1423553
DI 10.3389/fcell.2024.1423553
PG 15
WC Cell Biology; Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Developmental Biology
GA ZF0N3
UT WOS:001273764700001
PM 39045460
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Giménez-Escamilla, I
   Pérez-Carrillo, L
   González-Torrent, I
   Delgado-Arija, M
   Benedicto, C
   Portolés, M
   Tarazón, E
   Roselló-Lletí, E
AF Gimenez-Escamilla, Isaac
   Perez-Carrillo, Lorena
   Gonzalez-Torrent, Irene
   Delgado-Arija, Marta
   Benedicto, Carlota
   Portoles, Manuel
   Tarazon, Estefania
   Rosello-Lleti, Esther
TI Transcriptomic Alterations in Spliceosome Components in Advanced Heart
   Failure: Status of Cardiac-Specific Alternative Splicing Factors
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Article
DE spliceosome; heart failure; ischaemic cardiomyopathy; dilated
   cardiomyopathy; alternative splicing
ID GENE-EXPRESSION; PROTEIN; DYSREGULATION; CARDIOMYOPATHY; HYPERTROPHY;
   MUTATIONS; REVEALS; DISEASE; GENOME
AB Heart failure (HF) is associated with global changes in gene expression. Alternative mRNA splicing (AS) is a key regulatory mechanism underlying these changes. However, the whole status of molecules involved in the splicing process in human HF is unknown. Therefore, we analysed the spliceosome transcriptome in cardiac tissue (n = 36) from control subjects and HF patients (with ischaemic (ICM) and dilated (DCM) cardiomyopathies) using RNA-seq. We found greater deregulation of spliceosome machinery in ICM. Specifically, we showed widespread upregulation of the E and C complex components, highlighting an increase in SNRPD2 (FC = 1.35, p < 0.05) and DHX35 (FC = 1.34, p < 0.001) mRNA levels. In contrast, we observed generalised downregulation of the A complex and cardiac-specific AS factors, such as the multifunctional protein PCBP2 (FC = -1.29, p < 0.001) and the RNA binding proteins QKI (FC = -1.35, p < 0.01). In addition, we found a relationship between SNPRD2 (an E complex component) and the left ventricular mass index in ICM patients (r = 0.779; p < 0.01). On the other hand, we observed the specific underexpression of DDX46 (FC = -1.29), RBM17 (FC = -1.33), SDE2 (FC = -1.35) and RBFOX1 (FC = -1.33), p < 0.05, in DCM patients. Therefore, these aetiology-related alterations may indicate the differential involvement of the splicing process in the development of ICM and DCM.
C1 [Gimenez-Escamilla, Isaac; Perez-Carrillo, Lorena; Gonzalez-Torrent, Irene; Delgado-Arija, Marta; Benedicto, Carlota; Portoles, Manuel; Tarazon, Estefania; Rosello-Lleti, Esther] Hlth Res Inst Hosp Fe IIS Fe, Clin & Translat Res Cardiol Unit, Avd Fernando Abril Martorell 106, Valencia 46026, Spain.
   [Gimenez-Escamilla, Isaac; Perez-Carrillo, Lorena; Delgado-Arija, Marta; Portoles, Manuel; Tarazon, Estefania; Rosello-Lleti, Esther] Ctr Biomed Res Network Cardiovasc Dis CIBERCV, Avd Monforte Lemos 3-5, Madrid 28029, Spain.
C3 CIBER - Centro de Investigacion Biomedica en Red; CIBERCV
RP Tarazón, E; Roselló-Lletí, E (corresponding author), Hlth Res Inst Hosp Fe IIS Fe, Clin & Translat Res Cardiol Unit, Avd Fernando Abril Martorell 106, Valencia 46026, Spain.; Tarazón, E; Roselló-Lletí, E (corresponding author), Ctr Biomed Res Network Cardiovasc Dis CIBERCV, Avd Monforte Lemos 3-5, Madrid 28029, Spain.
EM isaac_gimenez@iislafe.es; lorena_perezc@iislafe.es;
   irene_gonzalez@iislafe.es; marta_delgado@externos.iislafe.es;
   carlota_benedicto@iislafe.es; drmanuelportoles@gmail.com;
   estefania_tarazon@iislafe.es; esther_rosello@iislafe.es
RI Giménez Escamilla, Isaac/IQV-4707-2023; Pérez Carrillo,
   Lorena/GZL-0411-2022; Tarazón, Estefanía/D-6950-2017; Portoles,
   Manuel/B-4789-2009
OI Gimenez Escamilla, Isaac/0000-0002-0872-1318; Portoles,
   Manuel/0000-0002-4415-7160
FU National Institute of Health "Fondo de Investigaciones Sanitarias del
   Instituto de Salud Carlos III" [PI20/01469, PI20/00071]; European Union
   [CP21/00041, FI21/00186, FI21/00034]; Consorcio Centro de Investigacion
   Biomedica en Red [CIBERCV] [CB16/11/00261]; Ministry of Science and
   Innovation (MCIN); State Investigation Agency (AEI) [CNS2022-135769];
   Conselleria de Educacion, Universidades y Empleo [CIAICO/2022/246,
   CIACIF/2022/429]
FX This work was supported by the National Institute of Health "Fondo de
   Investigaciones Sanitarias del Instituto de Salud Carlos III" (Projects:
   PI20/01469 and PI20/00071) co-funded by the European Union; Miguel
   Servet contract CP21/00041 co-funded by the European Union; contracts
   FI21/00186 and FI21/00034; "Consorcio Centro de Investigacion Biomedica
   en Red" [CIBERCV, under Grant CB16/11/00261]; Ministry of Science and
   Innovation (MCIN, 10.13039/501100011033) and State Investigation Agency
   (AEI) (Project CNS2022-135769) co-funded by the European Union "Next
   Generation EU" and the European Recovery, Transformation and Resilience
   Plan (PRTR); and Conselleria de Educacion, Universidades y Empleo
   (Project CIAICO/2022/246, contract CIACIF/2022/429).
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NR 69
TC 1
Z9 1
U1 3
U2 3
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD SEP
PY 2024
VL 25
IS 17
AR 9590
DI 10.3390/ijms25179590
PG 13
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA F9I6K
UT WOS:001312872200001
PM 39273537
OA gold
DA 2025-04-10
ER

PT J
AU Ma, JP
   Lu, LH
   Guo, W
   Ren, J
   Yang, J
AF Ma, Jipeng
   Lu, Linhe
   Guo, Wei
   Ren, Jun
   Yang, Jian
TI Emerging Role for RBM20 and its Splicing Substrates in Cardiac Function
   and Heart Failure
SO CURRENT PHARMACEUTICAL DESIGN
LA English
DT Review
DE RBM20; heart failure; dilated cardiomyopathy; alternative splicing;
   titin; CaMKII
ID CA2+/CALMODULIN-DEPENDENT PROTEIN-KINASE; FAMILIAL DILATED
   CARDIOMYOPATHY; TITIN ISOFORM EXPRESSION; GTPASE-ACTIVATING PROTEINS; II
   INHIBITION PROTECTS; MUSCLE FILAMENT TITIN; PASSIVE STIFFNESS; GIT
   FAMILY; DIFFERENTIAL EXPRESSION; PRESSURE-OVERLOAD
AB Heart failure is one of the devastating public health problems with high mortality. Among various contributing factors for heart failure, severe dilated cardiomyopathy is the most common indication for cardiac transplantation. Recent evidence revealed that RBM20 mutation represents one main cause for familial dilated cardiomyopathy with a 3% prevalence in all forms of dilated cardiomyopathy. Further scrutiny of molecular mechanisms suggests a role for RBM20 as a functional splicing factor for protein isoform transition, indicating the clinical value of RBM20 mutations in the diagnosis and treatment of heart diseases. RBM20 alternatively splices a set of genes including titin, CaMKIID, and GIT2 at the post transcriptional level to yield diverse isoforms. These target proteins are necessary for cardiac homeostasis including structure and signal transduction. Mutations in RBM20 cause dilated cardiomyopathy along with dysregulated isoform switch. This review aims to summarize the current knowledge of RBM20-related dilated cardiomyopathy and heart failure as well as the underlying mechanism. We will emphasize and thoroughly discuss two splicing targets including titin and CaMKII which are known to play a vital role in dilated cardiomyopathy and heart failure.
C1 [Ma, Jipeng; Lu, Linhe; Yang, Jian] Fourth Mil Med Univ, Xijing Hosp, Dept Cardiovasc Surg, Xian 710032, Peoples R China.
   [Guo, Wei] Univ Wyoming, Coll Agr & Nat Resources, Laramie, WY 82071 USA.
   [Ren, Jun] Univ Wyoming, Coll Hlth Sci, Laramie, WY 82071 USA.
C3 Air Force Medical University; University of Wyoming; University of
   Wyoming
RP Yang, J (corresponding author), Fourth Mil Med Univ, Xijing Hosp, Dept Cardiovasc Surg, Xian 710032, Peoples R China.; Ren, J (corresponding author), Univ Wyoming, Coll Hlth Sci, Laramie, WY 82071 USA.
EM jren@uwyo.edu; yang-jian1212@hotmail.com
RI Lu, Linhe/GOP-2807-2022; Ren, Jun/ACG-5366-2022; guo, wei/E-8906-2012
OI Lu, Linhe/0000-0002-7970-7898; guo, wei/0000-0002-9158-8107; Ren,
   Jun/0000-0002-0275-0783
FU National Natural Science Foundation of China [81470500]; Distinguished
   Young Scholar Cultivation Project of Xijing Hospital [XJZT14J03]
FX This study was supported by funding from the National Natural Science
   Foundation of China (grant No. 81470500), and the Distinguished Young
   Scholar Cultivation Project of Xijing Hospital (XJZT14J03).
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NR 95
TC 11
Z9 12
U1 0
U2 5
PU BENTHAM SCIENCE PUBL LTD
PI SHARJAH
PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB
   EMIRATES
SN 1381-6128
EI 1873-4286
J9 CURR PHARM DESIGN
JI Curr. Pharm. Design
PY 2016
VL 22
IS 31
BP 4744
EP 4751
DI 10.2174/1381612822666160701145322
PG 8
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA EA9BB
UT WOS:000386934100002
PM 27396593
DA 2025-04-10
ER

PT J
AU Montañés-Agudo, P
   Pinto, YM
   Creemers, EE
AF Montanes-Agudo, Pablo
   Pinto, Yigal M.
   Creemers, Esther E.
TI Splicing factors in the heart: Uncovering shared and unique targets
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Article
DE Alternative splicing; Splicing factors; RNA-binding proteins; RNA
   processing; Cardiomyocytes; Heart
ID RNA-BINDING PROTEIN; GENE; CARDIOMYOPATHY; REGULATOR; RBFOX2; RBM20;
   TITIN
AB Alternative splicing generates specialized protein isoforms that allow the heart to adapt during development and disease. The recent discovery that mutations in the splicing factor RNA-binding protein 20 (RBM20) cause a severe form of familial dilated cardiomyopathy has sparked a great interest in alternative splicing in the field of cardiology. Since then, identification of splicing factors controlling alternative splicing in the heart has grown at a rapid pace. Despite the intriguing observation that a certain overlap exists between the targets of some splicing factors, an integrated and systematic analysis of their splicing networks is missing. Here, we compared the splicing networks of individual splicing factors by re-analyzing original RNA-sequencing data from eight previously published mouse models, in which a single splicing factor has been genetically deleted (i.e. HNRNPU, MBNL1/2, QKI, RBM20, RBM24, RBPMS, SRSF3, SRSF4). We show that key splicing events in Camk2d, Ryr2, Tpm1, Tpm2 and Pdlim5 require the combined action of the majority of these splicing factors. Additionally, we identified common targets and pathways among splicing factors, with the largest overlap between the splicing networks of MBNL, QKI and RBM24. We also re-analyzed a large-scale RNA-sequencing study on hearts of 128 heart failure patients. Here, we observed that MBNL1, QKI and RBM24 expression varied greatly. This variation in expression correlated with differential splicing of their downstream targets as found in mice, suggesting that aberrant splicing by MBNL1, QKI and RBM24 might contribute to the disease mechanism in heart failure.
C1 [Montanes-Agudo, Pablo] Locat Univ Amsterdam, Amsterdam UMC, Expt Cardiol, Room K2 112,Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands.
   [Pinto, Yigal M.] Locat Univ Amsterdam, Amsterdam UMC, Expt Cardiol, Room K2 104,Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands.
   [Creemers, Esther E.] Locat Univ Amsterdam, Amsterdam UMC, Expt Cardiol, Room K2 104,Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands.
C3 University of Amsterdam; University of Amsterdam; University of
   Amsterdam
RP Creemers, EE (corresponding author), Locat Univ Amsterdam, Amsterdam UMC, Expt Cardiol, Room K2 104,Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands.
EM p.montanesagudo@amsterdamumc.nl; y.pinto@amsterdamumc.nl;
   e.e.creemers@amsterdamumc.nl
FU Rembrandt Institute for Cardiovascular Sciences
FX This work was supported by grants from the Rembrandt Institute for
   Cardiovascular Sciences to E.E.C. and CVON-ARENA-PRIME to Y.M.P.
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NR 44
TC 11
Z9 11
U1 1
U2 8
PU ELSEVIER SCI LTD
PI London
PA 125 London Wall, London, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD JUN
PY 2023
VL 179
BP 72
EP 79
DI 10.1016/j.yjmcc.2023.04.003
EA APR 2023
PG 8
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA G3EJ5
UT WOS:000988026700001
PM 37059416
OA hybrid
DA 2025-04-10
ER

PT J
AU Vujic, A
   Robinson, EL
   Ito, M
   Haider, S
   Ackers-Johnson, M
   See, K
   Methner, C
   Figg, N
   Brien, P
   Roderick, HL
   Skepper, J
   Ferguson-Smith, A
   Foo, RS
AF Vujic, A.
   Robinson, E. L.
   Ito, M.
   Haider, S.
   Ackers-Johnson, M.
   See, K.
   Methner, C.
   Figg, N.
   Brien, P.
   Roderick, H. L.
   Skepper, J.
   Ferguson-Smith, A.
   Foo, R. S.
TI Experimental heart failure modelled by the cardiomyocyte-specific loss
   of an epigenome modifier, DNMT3B
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Article
DE Epigenome; DNA methylation; Heart failure; Alternative splicing
ID DNA METHYLATION; MECHANISMS; DISEASE
AB Differential DNA methylation exists in the epigenome of end-stage failing human hearts but whether it contributes to disease progression is presently unknown. Here, we report that cardiac specific deletion of Dnmt3b, the predominant DNA methyltransferase in adult mouse hearts, leads to an accelerated progression to severe systolic insufficiency and myocardial thinning without a preceding hypertrophic response. This was accompanied by widespread myocardial interstitial fibrosis and myo-sarcomeric disarray. By targeted candidate gene quantitative RT-PCR, we discovered an over-activity of cryptic splice sites in the sarcomeric gene Myh7, resulting in a transcript with 8 exons missing. Moreover, a region of differential methylation overlies the splice site locus in the hearts of the cardiac-specific conditional knockout (CRO) mice. Although abundant and complex forms of alternative splice variants have been reported in diseased hearts and the contribution of each remains to be understood in further detail, our results demonstrate for the first time that a link may exist between alternative splicing and the cardiac epigenome. In particular, this gives the novel evidence whereby the loss of an epigenome modifier promotes the development and progression of heart disease. (C) 2015 Elsevier Ltd. All rights reserved.
C1 [Vujic, A.; Robinson, E. L.; Ackers-Johnson, M.; Figg, N.; Foo, R. S.] Univ Cambridge, Div Cardiovasc Med, Addenbrookes Ctr Clin Invest Bldg, Cambridge CB2 0QQ, England.
   [Vujic, A.; Ackers-Johnson, M.; Foo, R. S.] Natl Univ Hlth Syst, Cardiovasc Res Inst, Ctr Translat Med MD6, Singapore 117599, Singapore.
   [Ito, M.; Skepper, J.; Ferguson-Smith, A.] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England.
   [Haider, S.] Barts Canc Inst, Ctr Mol Oncol, London EC1M 6BQ, England.
   [Ackers-Johnson, M.; See, K.; Foo, R. S.] Genome Inst Singapore, Singapore 138672, Singapore.
   [Methner, C.] Univ Cambridge, Clin Pharmacol Unit, Addenbrookes Ctr Clin Invest Bldg, Cambridge CB2 0QQ, England.
   [Brien, P.; Roderick, H. L.] Babraham Inst, Epigenet ISP, Cambridge CB22 3AT, England.
C3 University of Cambridge; National University of Singapore; University of
   Cambridge; University of London; Queen Mary University London; Agency
   for Science Technology & Research (A*STAR); A*STAR - Genome Institute of
   Singapore (GIS); University of Cambridge; UK Research & Innovation
   (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC);
   Babraham Institute
RP Foo, RS (corresponding author), Natl Univ Hlth Syst, Cardiovasc Res Inst, Ctr Translat Med MD6, Singapore 117599, Singapore.
EM mdcrfsy@nus.edu.sg
RI Roderick, H/IAN-9761-2023; Vujic, Ana/AAQ-8417-2020; Robinson,
   Emma/K-3391-2015
OI Roderick, Hywel/0000-0001-7065-3523; Vujic, Ana/0000-0002-0559-5299;
   Foo, Roger/0000-0002-8079-4618; Robinson, Emma/0000-0002-4866-731X; See,
   Kelvin/0000-0003-0647-6977
FU Wellcome Trust [086796/Z/08/Z]; British Heart Foundation [PG12/2008];
   National Medical Research Council of Singapore [NMRC/CSA/046/2012];
   BBSRC [BBS/E/B/0000S256, BBS/E/B/0000C237] Funding Source: UKRI; MRC
   [MR/J001597/1] Funding Source: UKRI; Wellcome Trust [086796/Z/08/Z]
   Funding Source: Wellcome Trust
FX This work was supported by a Wellcome Trust (086796/Z/08/Z) PhD
   studentship to A.V. and a British Heart Foundation Project Grant
   (PG12/2008). Further support was also from the National Medical Research
   Council of Singapore (NMRC/CSA/046/2012).
CR [Anonymous], 2002, HEART DIS STROK STAT
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NR 31
TC 47
Z9 50
U1 0
U2 5
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD MAY
PY 2015
VL 82
BP 174
EP 183
DI 10.1016/j.yjmcc.2015.03.007
PG 10
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA CH6KO
UT WOS:000354145700019
PM 25784084
DA 2025-04-10
ER

PT J
AU Liu, SM
   Yue, SS
   Guo, YX
   Han, JY
   Wang, H
AF Liu, Songming
   Yue, Shanshan
   Guo, Yuxuan
   Han, Jing-yan
   Wang, Huan
TI Sorafenib induces cardiotoxicity through RBM20-mediated alternative
   splicing of sarcomeric and mitochondrial genes
SO PHARMACOLOGICAL RESEARCH
LA English
DT Article
DE Sorafenib; Cardiotoxicity; Alternative Splicing; RBM20; Sarcomere;
   Energy metabolism; FHOD3; SLC25A3
ID RBM20; CARDIOMYOPATHY; HEART; VARIANTS; METAANALYSIS; INHIBITION;
   SUNITINIB; ISOFORMS; INSIGHTS; PROMOTE
AB Sorafenib, a multi-targeted tyrosine kinase inhibitor, is a first-line treatment for advanced solid tumors, but it induces many adverse cardiovascular events, including myocardial infarction and heart failure. These cardiac defects can be mediated by alternative splicing of genes critical for heart function. Whether alternative splicing plays a role in sorafenib-induced cardiotoxicity remains unclear. Transcriptome of rat hearts or human cardiomyocytes treated with sorafenib was analyzed and validated to define alternatively spliced genes and their impact on cardiotoxicity. In rats, sorafenib caused severe cardiotoxicity with decreased left ventricular systolic pressure, elongated sarcomere, enlarged mitochondria and decreased ATP. This was associated with alternative splicing of hundreds of genes in the hearts, many of which were targets of a cardiac specific splicing factor, RBM20. Sorafenib inhibited RBM20 expression in both rat hearts and human cardiomyocytes. The splicing of RBM20's targets, SLC25A3 and FHOD3, was altered into fetal isoforms with decreased function. Upregulation of RBM20 during sorafenib treatment reversed the pathogenic splicing of SLC25A3 and FHOD3, and enhanced the phosphate transport into mitochondria by SLC25A3, ATP synthesis and cell survival.We envision this regulation may happen in many drug-induced cardiotoxicity, and represent a potential druggable pathway for mitigating sorafenib-induced cardiotoxicity.
C1 [Liu, Songming; Wang, Huan] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Biomed Informat, Beijing 100191, Peoples R China.
   [Yue, Shanshan; Han, Jing-yan] Peking Univ, Sch Basic Med Sci, Dept Integrat Chinese & Western Med, Beijing 100191, Peoples R China.
   [Yue, Shanshan; Han, Jing-yan] Peking Univ, Hlth Sci Ctr, Tasly Microcirculat Res Ctr, Beijing 100191, Peoples R China.
   [Guo, Yuxuan] Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Inst Cardiovasc Sci, Beijing 100191, Peoples R China.
   [Wang, Huan] Peking Univ, Inst Syst Biomed, Sch Basic Med Sci, Hlth Sci Ctr, Beijing 100191, Peoples R China.
   [Han, Jing-yan] Peking Univ, Sch Basic Med Sci, Dept Integrat Chinese & Western Med, 38 Xueyuan Rd, Beijing 100191, Peoples R China.
   [Wang, Huan] Beijing Vercelldo Cell Technol Co LTD, Zhongguanchun Life Sci Pk, Beijing 102206, Peoples R China.
C3 Peking University; Peking University; Peking University; Tasly Holding
   Group Co Ltd; Peking University; Peking University; Peking University
RP Wang, H (corresponding author), Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Dept Biomed Informat, Beijing 100191, Peoples R China.; Han, JY (corresponding author), Peking Univ, Sch Basic Med Sci, Dept Integrat Chinese & Western Med, 38 Xueyuan Rd, Beijing 100191, Peoples R China.
EM hanjingyan@bjmu.edu.cn; huan_sharon_wang@pku.edu.cn
RI han, jingyan/HJG-6568-2022; Guo, Yuxuan/GLU-7230-2022
FU National Key R & D Program (China) [2022YFA1104800]; National Natural
   Science Foundation (China) [881973403, 81841003]; Peking University
   Health Science Center Start-up Project (China) [BMU2018YJ012,
   BMU2021YJ053]
FX This work was supported by the National Key R & D Program (No.
   2022YFA1104800 to Y.G and H.W, China) , the National Natural Science
   Foundation (No. 881973403, 81841003 to H.W, China) and the Peking
   University Health Science Center Start-up Project (No. BMU2018YJ012,
   BMU2021YJ053 to H.W, China) .
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NR 52
TC 4
Z9 4
U1 0
U2 8
PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
PI LONDON
PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND
SN 1043-6618
EI 1096-1186
J9 PHARMACOL RES
JI Pharmacol. Res.
PD DEC
PY 2023
VL 198
AR 107017
DI 10.1016/j.phrs.2023.107017
EA NOV 2023
PG 15
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA CL8P0
UT WOS:001125500500001
PM 38006979
OA hybrid
DA 2025-04-10
ER

PT J
AU Frese, KS
   Meder, B
   Keller, A
   Just, S
   Haas, J
   Vogel, B
   Fischer, S
   Backes, C
   Matzas, M
   Köhler, D
   Benes, V
   Katus, HA
   Rottbauer, W
AF Frese, Karen S.
   Meder, Benjamin
   Keller, Andreas
   Just, Steffen
   Haas, Jan
   Vogel, Britta
   Fischer, Simon
   Backes, Christina
   Matzas, Mark
   Koehler, Doreen
   Benes, Vladimir
   Katus, Hugo A.
   Rottbauer, Wolfgang
TI RNA splicing regulated by RBFOX1 is essential for cardiac function in
   zebrafish
SO JOURNAL OF CELL SCIENCE
LA English
DT Article
DE Dilated cardiomyopathy; Genetics; Zebrafish; Deep sequencing; Splicing
ID SPINAL MUSCULAR-ATROPHY; IN-SITU HYBRIDIZATION; DILATED CARDIOMYOPATHY;
   BINDING-PROTEIN; CALCIUM-CHANNEL; MYOTONIC-DYSTROPHY; EMBRYONIC HEART;
   CANDIDATE-GENE; TROPONIN-T; EXPRESSION
AB Alternative splicing is one of the major mechanisms through which the proteomic and functional diversity of eukaryotes is achieved. However, the complex nature of the splicing machinery, its associated splicing regulators and the functional implications of alternatively spliced transcripts are only poorly understood. Here, we investigated the functional role of the splicing regulator rbfox1 in vivo using the zebrafish as a model system. We found that loss of rbfox1 led to progressive cardiac contractile dysfunction and heart failure. By using deep-transcriptome sequencing and quantitative real-time PCR, we show that depletion of rbfox1 in zebrafish results in an altered isoform expression of several crucial target genes, such as actn3a and hug. This study underlines that tightly regulated splicing is necessary for unconstrained cardiac function and renders the splicing regulator rbfox1 an interesting target for investigation in human heart failure and cardiomyopathy.
C1 [Frese, Karen S.; Meder, Benjamin; Haas, Jan; Vogel, Britta; Fischer, Simon; Koehler, Doreen; Katus, Hugo A.] Heidelberg Univ, Dept Med 3, D-69120 Heidelberg, Germany.
   [Frese, Karen S.; Meder, Benjamin; Haas, Jan; Vogel, Britta; Fischer, Simon; Katus, Hugo A.] Partner Site Heidelberg Mannheim, German Ctr Cardiovasc Res DZHK, D-69120 Heidelberg, Germany.
   [Keller, Andreas] Univ Saarland, Chair Clin Bioinformat, D-66123 Saarbrucken, Germany.
   [Keller, Andreas; Backes, Christina] Univ Saarland, Dept Human Genet, D-66123 Saarbrucken, Germany.
   [Just, Steffen; Rottbauer, Wolfgang] Univ Ulm, Dept Med 2, D-89081 Ulm, Germany.
   [Matzas, Mark] Comprehens Biomarker Ctr, D-69120 Heidelberg, Germany.
   [Benes, Vladimir] European Mol Biol Lab, Genom Core Facil, D-69117 Heidelberg, Germany.
C3 Ruprecht Karls University Heidelberg; German Centre for Cardiovascular
   Research; Saarland University; Saarland University; Ulm University;
   European Molecular Biology Laboratory (EMBL)
RP Rottbauer, W (corresponding author), Univ Ulm, Dept Med 2, D-89081 Ulm, Germany.
EM wolfgang.rottbauer@uniklinik-ulm.de
RI Just, Steffen/HKO-2417-2023; Benes, Vladimir/M-4755-2017; Keller,
   Andreas/ABB-6412-2021
OI Keller, Andreas/0000-0002-5361-0895
FU Bundesministerium fur Bildung und Forschung [NGFN-plus01GS0836,
   NGFN-transfer 01GR0823]; German Center for Cardiovascular Research
   (DZHK); University of Heidelberg (Innovationsfond FRONTIER); European
   Union (FP7)
FX This work was supported by grants from the 'Bundesministerium fur
   Bildung und Forschung' [grant numbers NGFN-plus01GS0836, NGFN-transfer
   01GR0823]; and the German Center for Cardiovascular Research (DZHK); the
   University of Heidelberg (Innovationsfond FRONTIER); and the European
   Union (FP7 INHERITANCE and BestAgeing). Deposited in PMC for immediate
   release.
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NR 72
TC 21
Z9 24
U1 0
U2 19
PU COMPANY OF BIOLOGISTS LTD
PI CAMBRIDGE
PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL,
   CAMBS, ENGLAND
SN 0021-9533
EI 1477-9137
J9 J CELL SCI
JI J. Cell Sci.
PD AUG 15
PY 2015
VL 128
IS 16
BP 3030
EP 3040
DI 10.1242/jcs.166850
PG 11
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA CP3MG
UT WOS:000359783000011
PM 26116573
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Yin, ZY
   Ren, J
   Guo, W
AF Yin, Zhiyong
   Ren, Jun
   Guo, Wei
TI Sarcomeric protein isoform transitions in cardiac muscle: A journey to
   heart failure
SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
LA English
DT Review
DE Protein isoform transition; Sarcomere proteins; Altemative splicing;
   Heart failure
ID MYOSIN HEAVY-CHAIN; TITIN ISOFORM; TROPONIN-T; C-PROTEIN; ALPHA-MYOSIN;
   VENTRICULAR-FUNCTION; PASSIVE STIFFNESS; BETA-TROPOMYOSIN;
   GENE-EXPRESSION; MYBP-C
AB Sarcomeric protein isoforms are mainly governed by alternative promoter-driven expression, distinct gene expression, gene mutation and alternative mRNA splicing. The transitions of sarcomeric proteins have been implicated to play a role in the onset and development of human heart failure. In this mini-review, we summarized isoform transitions of several most widely examined sarcomeric proteins including myosin, actin, troponin, tropomyosin, titin and myosin binding protein-C, and the consequence of these abnormal isoform transitions. Even though the isoform transitions of sarcomeric proteins have been described in individual sarcomeric protein reviews, no concise summary of these results has been presented previously. This review is intended to fill this gap and discuss possible future perspectives. (C) 2014 Elsevier B.V. All rights reserved.
C1 [Yin, Zhiyong; Guo, Wei] Univ WY, Coll Agr & Nat Resources, Laramie, WY 82071 USA.
   [Yin, Zhiyong] Fourth Mil Med Univ, Xi Jing Hosp, Dept Cardiol, Xian 710032, Peoples R China.
   [Ren, Jun; Guo, Wei] Univ WY, Coll Hlth Sci, Ctr Cardiovasc Res & Alternat Med, Laramie, WY 82071 USA.
C3 Air Force Medical University
RP Guo, W (corresponding author), 1000 E Univ Ave, Laramie, WY 82071 USA.
EM wguo3@uwyo.edu
RI Ren, Jun/ACG-5366-2022; Guo, Wei/KJM-4941-2024
OI guo, wei/0000-0002-9158-8107; Ren, Jun/0000-0002-0275-0783
FU Agricultural Experiment Station at University of Wyoming; Regional Hatch
   Project [NC1184]; NIH [P20-GM-103432]; University of Wyoming
FX We thank Dr. Marion L. Greaser for the critical reading of this review.
   We are grateful to the support of Agricultural Experiment Station at
   University of Wyoming and the Regional Hatch Project (NC1184). This work
   was supported by grants from NIH P20-GM-103432 and Startup Fund from the
   University of Wyoming to W.G.
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NR 88
TC 82
Z9 94
U1 1
U2 24
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0925-4439
EI 1879-260X
J9 BBA-MOL BASIS DIS
JI Biochim. Biophys. Acta-Mol. Basis Dis.
PD JAN
PY 2015
VL 1852
IS 1
BP 47
EP 52
DI 10.1016/j.bbadis.2014.11.003
PG 6
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA AZ8ST
UT WOS:000348485600005
PM 25446994
OA Green Accepted, Bronze
DA 2025-04-10
ER

PT J
AU Cao, J
   Wei, ZY
   Nie, Y
   Chen, HZ
AF Cao, Jun
   Wei, Ziyu
   Nie, Yu
   Chen, Hou-Zao
TI Therapeutic potential of alternative splicing in cardiovascular diseases
SO EBIOMEDICINE
LA English
DT Review
DE Cardiovascular diseases; Splicing; Alternative splicing
ID CONGENITAL HEART-DISEASE; T ISOFORM EXPRESSION; DNA-METHYLATION;
   INTEGRATIVE ANALYSIS; TITIN; GENE; PROTEIN; RBM20; CARDIOMYOPATHY;
   REPRESSION
AB RNA splicing is an important RNA processing step required by multiexon protein-coding mRNAs and some noncoding RNAs. Precise RNA splicing is required for maintaining gene and cell function; however, mis-spliced RNA transcripts can lead to loss- or gain-of-function effects in human diseases. Mis-spliced RNAs induced by gene mutations or the dysregulation of splicing regulators may result in frameshifts, nonsense-mediated decay (NMD), or inclusion/exclusion of exons. Genetic animal models have characterised multiple splicing factors required for cardiac development or function. Moreover, sarcomeric and ion channel genes, which are closely associated with cardiovascular function and disease, are hotspots for AS. Here, we summarise splicing factors and their targets that are associated with cardiovascular diseases, introduce some therapies potentially related to pathological AS targets, and raise outstanding questions and future directions in this field. Copyright (c) 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
C1 [Cao, Jun] Beijing Univ Technol, Coll Chem & Life Sci, Beijing 100124, Peoples R China.
   [Cao, Jun] Univ Texas Med Branch Galveston, Galveston, TX 77555 USA.
   [Chen, Hou-Zao] Chinese Acad Med Sci & Peking Union Med Coll, Inst Basic Med Sci, Dept Biochem & Mol Biol, State Key Lab Common Mech Res Major Dis, Beijing 100005, Peoples R China.
   [Nie, Yu] Chinese Acad Med Sci & Peking Union Med Coll, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing, Peoples R China.
   [Chen, Hou-Zao] Chinese Acad Med Sci, Med Epigenet Res Ctr, Beijing, Peoples R China.
C3 Beijing University of Technology; University of Texas System; University
   of Texas Medical Branch Galveston; Chinese Academy of Medical Sciences -
   Peking Union Medical College; Peking Union Medical College; Chinese
   Academy of Medical Sciences - Peking Union Medical College; Fu Wai
   Hospital - CAMS; Peking Union Medical College; Chinese Academy of
   Medical Sciences - Peking Union Medical College
RP Chen, HZ (corresponding author), Chinese Acad Med Sci & Peking Union Med Coll, Inst Basic Med Sci, Dept Biochem & Mol Biol, State Key Lab Common Mech Res Major Dis, Beijing 100005, Peoples R China.; Nie, Y (corresponding author), Chinese Acad Med Sci & Peking Union Med Coll, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing, Peoples R China.
EM nieyuniverse@126.com; chenhouzao@ibms.cams.cn
RI Cao, Jun/AAK-7312-2021; Wei, Ziyu/GRY-3383-2022
OI Cao, Jun/0000-0003-0211-9227
FU National Natural Science Foundation [82200328, 82030017, 82225007];
   National Key Research and Development Project of China [2019YFA0801500,
   2020YFC2008003]; Chinese Academy of Medical Sciences Innovation Fund for
   Medical Sciences [CIFMS2021-I2M-1-050, CIFMS2022-I2M-2-002]; Beijing
   Natural Science Fund [7242001]
FX We are grateful to Dr. Yao Wei Lu and group members of Dr. De-Pei Liu
   for insightful suggestions. This work was supported by the National
   Natural Science Foundation (82200328, 82030017, 82225007) , National Key
   Research and Development Project of China (2019YFA0801500,
   2020YFC2008003) , Chinese Academy of Medical Sciences Innovation Fund
   for Medical Sciences (CIFMS2021-I2M-1-050, CIFMS2022-I2M-2-002) , and
   the Beijing Natural Science Fund (7242001) . All the funders had no
   roles in paper design, data collection, data analysis, interpreta-tion,
   writing of the paper.
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NR 130
TC 2
Z9 2
U1 9
U2 18
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 2352-3964
J9 EBIOMEDICINE
JI EBioMedicine
PD MAR
PY 2024
VL 101
AR 104995
DI 10.1016/j.ebiom.2024.104995
EA FEB 2024
PG 13
WC Medicine, General & Internal; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC General & Internal Medicine; Research & Experimental Medicine
GA KZ5H8
UT WOS:001183799800001
PM 38350330
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Verma, SK
   Deshmukh, V
   Liu, P
   Nutter, CA
   Espejo, R
   Hung, ML
   Wang, GS
   Yeo, GW
   Kuyumcu-Martinez, MN
AF Verma, Sunil K.
   Deshmukh, Vaibhav
   Liu, Patrick
   Nutter, Curtis A.
   Espejo, Rosario
   Hung, Ming-Lung
   Wang, Guey-Shin
   Yeo, Gene W.
   Kuyumcu-Martinez, Muge N.
TI Reactivation of Fetal Splicing Programs in Diabetic Hearts Is Mediated
   by Protein Kinase C Signaling
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
DE Alternative Splicing; Diabetes; Heart Development; Protein Kinase C
   (PKC); RNA-binding Protein; Signal Transduction
ID CORONARY-ARTERY-DISEASE; PLASMA-MEMBRANE CA2+; GENE-EXPRESSION;
   MESSENGER-RNA; SARCOPLASMIC-RETICULUM; MYOTONIC-DYSTROPHY; CARDIAC
   MYOCYTES; GROWTH-FACTOR; PKC-BETA; CARDIOMYOPATHY
AB Diabetic cardiomyopathy is one of the complications of diabetes that eventually leads to heart failure and death. Aberrant activation of PKC signaling contributes to diabetic cardiomyopathy by mechanisms that are poorly understood. Previous reports indicate that PKC is implicated in alternative splicing regulation. Therefore, we wanted to test whether PKC activation in diabetic hearts induces alternative splicing abnormalities. Here, using RNA sequencing we identified a set of 22 alternative splicing events that undergo a developmental switch in splicing, and we confirmed that splicing reverts to an embryonic pattern in adult diabetic hearts. This network of genes has important functions in RNA metabolism and in developmental processes such as differentiation. Importantly, PKC isozymes / control alternative splicing of these genes via phosphorylation and up-regulation of the RNA-binding proteins CELF1 and Rbfox2. Using a mutant of CELF1, we show that phosphorylation of CELF1 by PKC is necessary for regulation of splicing events altered in diabetes. In summary, our studies indicate that activation of PKC/ in diabetic hearts contributes to the genome-wide splicing changes through phosphorylation and up-regulation of CELF1/Rbfox2 proteins. These findings provide a basis for PKC-mediated cardiac pathogenesis under diabetic conditions.
C1 [Verma, Sunil K.; Deshmukh, Vaibhav; Nutter, Curtis A.; Espejo, Rosario; Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA.
   [Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Dept Neurosci & Cell Biol, Galveston, TX 77555 USA.
   [Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Inst Translat Sci, Galveston, TX 77555 USA.
   [Yeo, Gene W.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92037 USA.
   [Liu, Patrick; Yeo, Gene W.] Univ Calif San Diego, Stem Cell Program, La Jolla, CA 92037 USA.
   [Yeo, Gene W.] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92037 USA.
   [Hung, Ming-Lung; Wang, Guey-Shin] Acad Sinica, Inst Biomed Sci, Taipei 11528, Taiwan.
C3 University of Texas System; University of Texas Medical Branch
   Galveston; University of Texas System; University of Texas Medical
   Branch Galveston; University of Texas System; University of Texas
   Medical Branch Galveston; University of California System; University of
   California San Diego; University of California System; University of
   California San Diego; University of California System; University of
   California San Diego; Academia Sinica - Taiwan
RP Kuyumcu-Martinez, MN (corresponding author), Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA.
EM nmmartin@utmb.edu
RI Verma, Sunil/J-8838-2019; Deshmukh, Vaibhav/HPG-7012-2023; Yeo,
   Gene/AAE-7676-2019; Wang, Guey-Shin/Q-3968-2018
OI Wang, Guey-Shin/0000-0003-4485-1811; Nutter, Curtis/0000-0001-5593-6197;
   Verma, Sunil/0000-0001-9443-2493; Yeo, Eugene/0000-0002-0799-6037
FU National Institutes of Health [HG004659, 3NS075449]; American Heart
   Association [SDG-093022N]; March of Dimes Basil O'Connor Starter Scholar
   Award [5 FY12-21]; University of Texas Medical Branch; National Science
   Council, Taiwan; Institute of Biomedical Sciences, Academia Sinica
FX This work was supported, in whole or in part, by National Institutes of
   Health Grants HG004659 and NS075449 (to G. W. Y.). This work was also
   supported by American Heart Association Grant SDG-093022N, March of
   Dimes Basil O'Connor Starter Scholar Award 5 FY12-21, and University of
   Texas Medical Branch start up funds (to M. N. K.-M.). This work was also
   supported in part by National Science Council, Taiwan, and Institute of
   Biomedical Sciences, Academia Sinica (to G.-S. W.). We thank Dr. David
   Konkel for critically editing the manuscript, Drs. Thai Ho and Rajalaxmi
   Natarajan for critically reading the manuscript, Dr. Thomas Wood for
   technical help in RNA-sequencing, and Dr. Adriana Paulucci for help in
   confocal microscopy. We also thank Dr. Nisha Garg for kindly providing
   control human heart tissues.
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NR 88
TC 54
Z9 58
U1 0
U2 5
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD DEC 6
PY 2013
VL 288
IS 49
BP 35372
EP 35386
DI 10.1074/jbc.M113.507426
PG 15
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 291YA
UT WOS:000329867600034
PM 24151077
OA hybrid, Green Published
DA 2025-04-10
ER

PT J
AU Pilbrow, AP
   Lewis, KA
   Perrin, MH
   Sweet, WE
   Moravec, CS
   Tang, WHW
   Huising, MO
   Troughton, RW
   Cameron, VA
AF Pilbrow, Anna P.
   Lewis, Kathy A.
   Perrin, Marilyn H.
   Sweet, Wendy E.
   Moravec, Christine S.
   Tang, W. H. Wilson
   Huising, Mark O.
   Troughton, Richard W.
   Cameron, Vicky A.
TI Cardiac CRFR1 Expression Is Elevated in Human Heart Failure and
   Modulated by Genetic Variation and Alternative Splicing
SO ENDOCRINOLOGY
LA English
DT Article
ID CORTICOTROPIN-RELEASING-FACTOR; HORMONE-RECEPTOR; CORRELATION-MATRICES;
   DISEASED HEART; UROCORTIN-II; CRHR1 GENE; VARIANT; IDENTIFICATION;
   LIGANDS; CLONING
AB Corticotropin-releasing factor (CRF) and the CRF-related peptides, urocortin (Ucn)-1, Ucn2, and Ucn3 signal through receptors CRFR1 and CRFR2 to restore homeostasis in response to stress. The Ucns exert potent cardioprotective effects and may have clinical utility in heart failure. To explore the activity of this system in the heart, we measured the levels of myocardial gene expression of the CRF/Ucn family of ligands/receptors and investigated genetic variation and alternative splicing of CRFR1 in 110 heart failure patients and 108 heart donors. Using quantitative real-time PCR, we detected CRFR1, CRFR2, CRF, Ucn1, Ucn2, and Ucn3 in all samples. CRFR2 alpha was the most abundant receptor and Ucn3 the most abundant ligand, both in patients and donors. Compared with donors, cardiac expression of CRFR1, CRF, and Ucn3 was higher (P < .001) and CRFR2 alpha lower (P = .012) in patients. In patients and donors, genetic variation within CRFR1, represented by the chromosome 17q21.31 inversion polymorphism, was associated with markedly higher CRFR1 expression (P < .001), making CRFR1 and CRFR2 alpha expression almost equivalent insomepatients. Anovel, truncated splice variant of CRFR1, designated CRFR1j, was identified and shown to exert a dominant-negative effect on CRFR1 signaling in vitro. The novel variant was expressed in a greater proportion of patients (60%) than donors (3%, P < .001). In summary, cardiac expression of CRFR1, CRF, and Ucn3 genes is elevated in heart failure and may contribute to the activation of the CRF/Ucn system in these patients. A common variant within the CRFR1 gene and a novel CRFR1 splice variant may modulate CRFR1 expression and signaling.
C1 [Pilbrow, Anna P.; Lewis, Kathy A.; Perrin, Marilyn H.; Huising, Mark O.] Salk Inst Biol Studies, Peptide Biol Labs, La Jolla, CA 92037 USA.
   [Pilbrow, Anna P.; Troughton, Richard W.; Cameron, Vicky A.] Univ Otago, Christchurch Heart Inst, Dept Med, Christchurch 8011, New Zealand.
   [Sweet, Wendy E.; Moravec, Christine S.; Tang, W. H. Wilson] Cleveland Clin, Kaufman Ctr Heart Failure, Dept Cardiovasc Med, Cleveland, OH 44195 USA.
C3 Salk Institute; University of Otago; Cleveland Clinic Foundation
RP Pilbrow, AP (corresponding author), Univ Otago, Christchurch Heart Inst, POB 4345, Christchurch 8140, New Zealand.
EM anna.pilbrow@otago.ac.nz
RI Tang, Wai Hong/I-1238-2013; Cameron, Vicky/L-4046-2019; Huising,
   Mark/H-3885-2019; Pilbrow, Anna/B-9969-2011
OI Tang, W. H. Wilson/0000-0002-8335-735X; Cameron,
   Vicky/0000-0003-3147-683X; Pilbrow, Anna/0000-0003-1949-9449; Troughton,
   Richard/0000-0001-7484-4036
FU Heart Foundation of New Zealand; Cleveland Clinic Foundation; National
   Institute of Diabetes and Digestive and Kidney Diseases [P01
   DK26741-30]; New Zealand Foundation for Research, Science, and
   Technology Postdoctoral Fellowship; Clayton Medical Research Foundation,
   Inc.
FX This work was supported by the Heart Foundation of New Zealand, the
   Cleveland Clinic Foundation, and the National Institute of Diabetes and
   Digestive and Kidney Diseases (Award P01 DK26741-30). A.P.P. was
   supported by a New Zealand Foundation for Research, Science, and
   Technology Postdoctoral Fellowship and the Clayton Medical Research
   Foundation, Inc.
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NR 40
TC 13
Z9 13
U1 0
U2 0
PU ENDOCRINE SOC
PI WASHINGTON
PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA
SN 0013-7227
EI 1945-7170
J9 ENDOCRINOLOGY
JI Endocrinology
PD DEC
PY 2016
VL 157
IS 12
BP 4865
EP 4874
DI 10.1210/en.2016-1448
PG 10
WC Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Endocrinology & Metabolism
GA EI9PJ
UT WOS:000392840400036
PM 27754786
OA Bronze, Green Published, Green Submitted
DA 2025-04-10
ER

PT J
AU Gotthardt, M
   Badillo-Lisakowski, V
   Parikh, VN
   Ashley, E
   Furtado, M
   Carmo-Fonseca, M
   Schudy, S
   Meder, B
   Grosch, M
   Steinmetz, L
   Crocini, C
   Leinwand, L
AF Gotthardt, Michael
   Badillo-Lisakowski, Victor
   Parikh, Victoria Nicole
   Ashley, Euan
   Furtado, Marta
   Carmo-Fonseca, Maria
   Schudy, Sarah
   Meder, Benjamin
   Grosch, Markus
   Steinmetz, Lars
   Crocini, Claudia
   Leinwand, Leslie
TI Cardiac splicing as a diagnostic and therapeutic target
SO NATURE REVIEWS CARDIOLOGY
LA English
DT Review
ID DIASTOLIC FUNCTION; MOUSE MODEL; TITIN; RBM20; GENE; HEART;
   TRANSCRIPTOME; INSIGHTS; CARDIOMYOPATHY; IDENTIFICATION
AB Alternative splicing determines which exons are included in mature RNA and accounts for the majority of transcriptomic diversity. In this Review, Gotthardt and colleagues discuss how alternative splicing is regulated in the heart and how it differs in cardiac development, physiological adaptation and pathological remodelling. They also summarize technological advances in the field and potential applications of splicing data in cardiovascular medicine.
   Despite advances in therapeutics for heart failure and arrhythmias, a substantial proportion of patients with cardiomyopathy do not respond to interventions, indicating a need to identify novel modifiable myocardial pathobiology. Human genetic variation associated with severe forms of cardiomyopathy and arrhythmias has highlighted the crucial role of alternative splicing in myocardial health and disease, given that it determines which mature RNA transcripts drive the mechanical, structural, signalling and metabolic properties of the heart. In this Review, we discuss how the analysis of cardiac isoform expression has been facilitated by technical advances in multiomics and long-read and single-cell sequencing technologies. The resulting insights into the regulation of alternative splicing - including the identification of cardiac splice regulators as therapeutic targets and the development of a translational pipeline to evaluate splice modulators in human engineered heart tissue, animal models and clinical trials - provide a basis for improved diagnosis and therapy. Finally, we consider how the medical and scientific communities can benefit from facilitated acquisition and interpretation of splicing data towards improved clinical decision-making and patient care.
C1 [Gotthardt, Michael; Badillo-Lisakowski, Victor] Max Delbruck Ctr Mol Med Helmholtz Assoc, Neuromuscular & Cardiovasc Cell Biol, Berlin, Germany.
   [Gotthardt, Michael; Badillo-Lisakowski, Victor] DZHK, German Ctr Cardiovasc Res, Partner Site Berlin, Berlin, Germany.
   [Gotthardt, Michael] Charite Univ Med Berlin, Dept Cardiol, Berlin, Germany.
   [Parikh, Victoria Nicole; Ashley, Euan] Stanford Univ, Stanford Ctr Inherited Cardiovasc Dis, Sch Med, Palo Alto, CA USA.
   [Ashley, Euan; Steinmetz, Lars] Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA USA.
   [Ashley, Euan; Steinmetz, Lars] Stanford Univ, Sch Med, Dept Genet, Stanford, CA USA.
   [Furtado, Marta; Carmo-Fonseca, Maria] Univ Lisbon, Fac Med, Inst Med Mol Joao Lobo Antunes, Lisbon, Portugal.
   [Schudy, Sarah; Meder, Benjamin] Heidelberg Univ, Inst Cardiomyopathies, Dept Med 3, Heidelberg, Germany.
   [Meder, Benjamin] DZHK, German Ctr Cardiovasc Res, Partner Site Heidelberg Mannheim, Heidelberg, Germany.
   [Grosch, Markus; Steinmetz, Lars] European Mol Biol Lab EMBL, Genome Biol Unit, Heidelberg, CO, Germany.
   [Crocini, Claudia; Leinwand, Leslie] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO USA.
C3 Helmholtz Association; Max Delbruck Center for Molecular Medicine;
   German Centre for Cardiovascular Research; Berlin Institute of Health;
   Free University of Berlin; Humboldt University of Berlin; Charite
   Universitatsmedizin Berlin; Stanford University; Stanford University;
   Stanford University; Universidade de Lisboa; Ruprecht Karls University
   Heidelberg; German Centre for Cardiovascular Research; European
   Molecular Biology Laboratory (EMBL); University of Colorado System;
   University of Colorado Boulder
RP Gotthardt, M (corresponding author), Max Delbruck Ctr Mol Med Helmholtz Assoc, Neuromuscular & Cardiovasc Cell Biol, Berlin, Germany.; Gotthardt, M (corresponding author), DZHK, German Ctr Cardiovasc Res, Partner Site Berlin, Berlin, Germany.; Gotthardt, M (corresponding author), Charite Univ Med Berlin, Dept Cardiol, Berlin, Germany.
EM gotthardt@mdc-berlin.de
RI Crocini, Claudia/AAE-2457-2019; Gotthardt, Michael/ABE-8274-2021;
   Crocini, Claudia/F-5429-2016
OI Crocini, Claudia/0000-0001-8231-2726; Badillo Lisakowski,
   Victor/0000-0001-5906-2589; Gotthardt, Michael/0000-0003-1788-3172;
   Carmo-Fonseca, Maria/0000-0002-3402-7143
FU Leducq TAN CASTT [21CVD02]
FX This work was funded by Leducq TAN CASTT grant 21CVD02. Jacobo Lopez
   Carballo (Max Delbrueck Center for Molecular Medicine in the Helmholtz
   Association, Germany) supported the data analysis and generation of the
   supplementary tables.
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NR 112
TC 14
Z9 14
U1 1
U2 15
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 1759-5002
EI 1759-5010
J9 NAT REV CARDIOL
JI Nat. Rev. Cardiol.
PD AUG
PY 2023
VL 20
IS 8
BP 517
EP 530
DI 10.1038/s41569-022-00828-0
EA JAN 2023
PG 14
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA L6FP8
UT WOS:000916484000001
PM 36653465
DA 2025-04-10
ER

PT J
AU Maatz, H
   Jens, M
   Liss, M
   Schafer, S
   Heinig, M
   Kirchner, M
   Adami, E
   Rintisch, C
   Dauksaite, V
   Radke, MH
   Selbach, M
   Barton, PJR
   Cook, SA
   Rajewsky, N
   Gotthardt, M
   Landthaler, M
   Hubner, N
AF Maatz, Henrike
   Jens, Marvin
   Liss, Martin
   Schafer, Sebastian
   Heinig, Matthias
   Kirchner, Marieluise
   Adami, Eleonora
   Rintisch, Carola
   Dauksaite, Vita
   Radke, Michael H.
   Selbach, Matthias
   Barton, Paul J. R.
   Cook, Stuart A.
   Rajewsky, Nikolaus
   Gotthardt, Michael
   Landthaler, Markus
   Hubner, Norbert
TI RNA-binding protein RBM20 represses splicing to orchestrate cardiac
   pre-rnRNA processing
SO JOURNAL OF CLINICAL INVESTIGATION
LA English
DT Article
ID DILATED CARDIOMYOPATHY; MESSENGER-RNA; CA2+ RELEASE; SR PROTEINS; MOUSE
   MODEL; MUTATIONS; IDENTIFICATION; GENE; EXPRESSION; ACTIVATION
AB Mutations in the gene encoding the RNA-binding protein RBM20 have been implicated in dilated cardiomyopathy (DCM), a major cause of chronic heart failure, presumably through altering cardiac RNA splicing. Here, we combined transcriptome-wide crosslinking immunoprecipitation (CLIP-seq), RNA-seq, and quantitative proteomics in cell culture and rat and human hearts to examine how RBM20 regulates alternative splicing in the heart. Our analyses revealed the presence of a distinct RBM20 RNA-recognition element that is predominantly found within intronic binding sites and linked to repression of exon splicing with RBM20 binding near 3 ' and 5 ' splice sites. Proteomic analysis determined that RBM20 interacts with both U1 and U2 small nuclear ribonucleic particles (snRNPs) and suggested that RBM20-dependent splicing repression occurs through spliceosome stalling at complex A. Direct RBM20 targets included several genes previously shown to be involved in DCM as well as genes not typically associated with this disease. In failing human hearts, reduced expression of RBM20 affected alternative splicing of several direct targets, indicating that differences in RBM20 expression may affect cardiac function. Together, these findings identify RBM20-regulated targets and provide insight into the pathogenesis of human heart failure.
C1 [Maatz, Henrike; Schafer, Sebastian; Heinig, Matthias; Adami, Eleonora; Rintisch, Carola; Hubner, Norbert] Max Delbruck Ctr Mol Med MDC, D-13125 Berlin, Germany.
   [Jens, Marvin; Liss, Martin; Dauksaite, Vita; Radke, Michael H.; Rajewsky, Nikolaus; Gotthardt, Michael] MDC, Berlin, Germany.
   [Heinig, Matthias] Max Planck Inst Mol Genet, Dept Computat Biol, D-14195 Berlin, Germany.
   [Kirchner, Marieluise; Selbach, Matthias] MDC, Lab Cell Signalling & Mass Spectrometry, Berlin, Germany.
   [Barton, Paul J. R.; Cook, Stuart A.] Natl Heart & Lung Inst, London, England.
   [Barton, Paul J. R.; Cook, Stuart A.] Royal Brompton NIHR Cardiovasc Biomed Res Unit, London, England.
   [Cook, Stuart A.; Hubner, Norbert] Duke NUS Grad Med Sch, Singapore, Singapore.
   [Cook, Stuart A.] Natl Heart Ctr Singapore, Singapore, Singapore.
   [Gotthardt, Michael; Hubner, Norbert] Partner Site Berlin, DZHK German Ctr Cardiovasc Res, Berlin, Germany.
   [Landthaler, Markus] MDC, RNA Biol & Posttranscript Regulat, Berlin, Germany.
C3 Helmholtz Association; Max Delbruck Center for Molecular Medicine; Max
   Planck Society; Imperial College London; National University of
   Singapore; National Heart Centre Singapore; German Centre for
   Cardiovascular Research
RP Hubner, N (corresponding author), Max Delbruck Ctr Mol Med MDC, Robert Roessle Str 10, D-13125 Berlin, Germany.
EM nhuebner@mdc-berlin.de
RI van Heesch, Sebastiaan/AAT-6595-2020; Heinig, Matthias/IZQ-2092-2023;
   Cook, Stuart/G-9567-2011; Gotthardt, Michael/ABE-8274-2021; Selbach,
   Matthias/C-5988-2008; Landthaler, Markus/A-1427-2010
OI Rajewsky, Nikolaus/0000-0002-4785-4332; Radke,
   Michael/0000-0003-0112-9917; Heinig, Matthias/0000-0002-5612-1720;
   Gotthardt, Michael/0000-0003-1788-3172; Jens,
   Marvin/0000-0002-6660-8743; Landthaler, Markus/0000-0002-1075-8734;
   Schafer, Sebastian/0000-0002-6909-8275; Cook,
   Stuart/0000-0001-6628-194X; Adami, Eleonora/0000-0002-1813-6681; Barton,
   Paul Jeremy Richard/0000-0002-1165-7767; Liss,
   Martin/0000-0002-0585-7850
FU European Union [HEALTH-F4-2010-241504]; Helmholtz Alliance ICEMED;
   Deutsche Forschungsgemeinschaft (Bonn, Germany) [Forschergruppe 1054, HU
   1522/1-1]; European Research Council [StG282078]; Fondation Leducq; NIH
   Research Cardiovascular Biomedical Research Unit at the Royal Brompton
   and Harefield NHS Foundation Trust and Imperial College, London, United
   Kingdom; MRC [MC_U120085815] Funding Source: UKRI
FX We thank G. Patone, S. Blachut, S. Schmidt, and J. Frohlich for expert
   technical assistance and Claudia Langnick and Mirjam Feldkamp for
   performing the sequencing runs. This work was supported by funding from
   the European Union EURATRANS award (HEALTH-F4-2010-241504), the
   Helmholtz Alliance ICEMED, and the Deutsche Forschungsgemeinschaft
   (Forschergruppe 1054, HU 1522/1-1) (to N. Hubner); the Deutsche
   Forschungsgemeinschaf (Bonn, Germany) and the European Research Council
   grant StG282078 (to M. Gotthardt); and by the Fondation Leducq and the
   NIH Research Cardiovascular Biomedical Research Unit at the Royal
   Brompton and Harefield NHS Foundation Trust and Imperial College,
   London, United Kingdom (to S.A. Cook).
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NR 42
TC 159
Z9 179
U1 1
U2 14
PU AMER SOC CLINICAL INVESTIGATION INC
PI ANN ARBOR
PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA
SN 0021-9738
EI 1558-8238
J9 J CLIN INVEST
JI J. Clin. Invest.
PD AUG
PY 2014
VL 124
IS 8
BP 3419
EP 3430
DI 10.1172/JCI74523
PG 12
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA AM6OH
UT WOS:000339984000017
PM 24960161
OA Green Published, Green Accepted, Green Submitted, Bronze
DA 2025-04-10
ER

PT J
AU Rindler, TN
   Hinton, RB
   Salomonis, N
   Ware, SM
AF Rindler, Tara N.
   Hinton, Robert B.
   Salomonis, Nathan
   Ware, Stephanie M.
TI Molecular Characterization of Pediatric Restrictive Cardiomyopathy from
   Integrative Genomics
SO SCIENTIFIC REPORTS
LA English
DT Article
ID NECROSIS-FACTOR-ALPHA; HEART-FAILURE; CARDIAC-HYPERTROPHY; EXPRESSION;
   GENE; RECEPTOR; PATHWAY; MICE; MYOCARDIUM; MICRORNAS
AB Pediatric restrictive cardiomyopathy (RCM) is a genetically heterogeneous heart disease with limited therapeutic options. RCM cases are largely idiopathic; however, even within families with a known genetic cause for cardiomyopathy, there is striking variability in disease severity. Although accumulating evidence implicates both gene expression and alternative splicing in development of dilated cardiomyopathy (DCM), there have been no detailed molecular characterizations of underlying pathways dysregulated in RCM. RNA-Seq on a cohort of pediatric RCM patients compared to other forms of adult cardiomyopathy and controls identified transcriptional differences highly common to the cardiomyopathies, as well as those unique to RCM. Transcripts selectively induced in RCM include many known and novel G-protein coupled receptors linked to calcium handling and contractile regulation. In-depth comparisons of alternative splicing revealed splicing events shared among cardiomyopathy subtypes, as well as those linked solely to RCM. Genes identified with altered alternative splicing implicate RBM20, a DCM splicing factor, as a potential mediator of alternative splicing in RCM. We present the first comprehensive report on molecular pathways dysregulated in pediatric RCM including unique/shared pathways identified compared to other cardiomyopathy subtypes and demonstrate that disruption of alternative splicing patterns in pediatric RCM occurs in the inverse direction as DCM.
C1 [Rindler, Tara N.; Hinton, Robert B.] Cincinnati Childrens Hosp, Inst Heart, Cincinnati, OH USA.
   [Salomonis, Nathan] Cincinnati Childrens Hosp, Biomed Informat, Cincinnati, OH 45229 USA.
   [Ware, Stephanie M.] Indiana Univ Sch Med, Dept Pediat & Med & Mol Genet, Indianapolis, IN 46202 USA.
C3 Cincinnati Children's Hospital Medical Center; Cincinnati Children's
   Hospital Medical Center; Indiana University System; Indiana University
   Bloomington
RP Salomonis, N (corresponding author), Cincinnati Childrens Hosp, Biomed Informat, Cincinnati, OH 45229 USA.; Ware, SM (corresponding author), Indiana Univ Sch Med, Dept Pediat & Med & Mol Genet, Indianapolis, IN 46202 USA.
EM Nathan.Salomonis@cchmc.org; stware@iu.edu
FU American Heart Association Established Investigators Award; National
   Institutes of Health T32 Pulmonary and Cardiovascular Developmental
   Training Grant [HL007752-16]
FX This research was supported by the American Heart Association
   Established Investigators Award (to S.M.W). T.N.R. is supported by a
   National Institutes of Health T32 Pulmonary and Cardiovascular
   Developmental Training Grant (HL007752-16 to J.A.W.).
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NR 51
TC 19
Z9 22
U1 0
U2 5
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD JAN 18
PY 2017
VL 7
AR 39276
DI 10.1038/srep39276
PG 12
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA EI0GD
UT WOS:000392150100001
PM 28098235
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Anderson, ES
   Lin, CH
   Xiao, XS
   Stoilov, P
   Burge, CB
   Black, DL
AF Anderson, Erik S.
   Lin, Chia-Ho
   Xiao, Xinshu
   Stoilov, Peter
   Burge, Christopher B.
   Black, Douglas L.
TI The cardiotonic steroid digitoxin regulates alternative splicing through
   depletion of the splicing factors SRSF3 and TRA2B
SO RNA
LA English
DT Article
DE alternative splicing; cardiotonic steroid; SRp20; Tra2-beta
ID PRE-MESSENGER-RNA; EXOGENOUS CARDIAC-GLYCOSIDES; SR PROTEINS;
   FRONTOTEMPORAL DEMENTIA; GENE-EXPRESSION; TAU EXON-10; HTRA2-BETA-1;
   ENHANCERS; INCLUSION; SMN
AB Modulation of alternative pre-mRNA splicing is a potential approach to therapeutic targeting for a variety of human diseases. We investigated the mechanism by which digitoxin, a member of the cardiotonic steroid class of drugs, regulates alternative splicing. Transcriptome-wide analysis identified a large set of alternative splicing events that change after digitoxin treatment. Within and adjacent to these regulated exons, we identified enrichment of potential binding sites for the splicing factors SRp20 (SRSF3/SFRS3) and Tra2-beta (SFRS10/TRA2B). We further find that both of these proteins are depleted from cells by digitoxin treatment. Characterization of SRp20 and Tra2-beta splicing targets revealed that many, but not all, digitoxin-induced splicing changes can be attributed to the depletion of one or both of these factors. Re-expression of SRp20 or Tra2-beta after digitoxin treatment restores normal splicing of their targets, indicating that the digitoxin effect is directly due to these factors. These results demonstrate that cardiotonic steroids, long prescribed in the clinical treatment of heart failure, have broad effects on the cellular transcriptome through these and likely other RNA binding proteins. The approach described here can be used to identify targets of other potential therapeutics that act as alternative splicing modulators.
C1 [Lin, Chia-Ho; Black, Douglas L.] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA.
   [Anderson, Erik S.] Univ Calif Los Angeles, Mol Biol Interdept Grad Program, Los Angeles, CA 90095 USA.
   [Anderson, Erik S.] Univ Calif Los Angeles, Med Scientist Training Program, Los Angeles, CA 90095 USA.
   [Xiao, Xinshu] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA 90095 USA.
   [Xiao, Xinshu; Black, Douglas L.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA.
   [Stoilov, Peter] W Virginia Univ, Dept Biochem, Morgantown, WV 26506 USA.
   [Burge, Christopher B.] MIT, Dept Biol, Cambridge, MA 02139 USA.
C3 University of California System; University of California Los Angeles;
   Howard Hughes Medical Institute; University of California System;
   University of California Los Angeles; University of California System;
   University of California Los Angeles; University of California System;
   University of California Los Angeles; University of California System;
   University of California Los Angeles; West Virginia University;
   Massachusetts Institute of Technology (MIT)
RP Black, DL (corresponding author), Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA.
EM dougb@microbio.ucla.edu
RI Burge, Christopher/AAH-2177-2020
OI Xiao, Xinshu/0000-0002-9362-8029; Anderson, Erik/0000-0001-5014-8706
FU National Institutes of Health [4F30AG033993, R01 GM084317]; National
   Institute of General Medical Sciences [T32GM008042] Funding Source: NIH
   RePORTER
FX We thank Dr. Alan Cochrane for helpful discussion and generous sharing
   of unpublished data and Dr. Benoit Chabot for reagents. We received
   helpful assistance from Naphat Chantaravisoot, Chen Cheng, Elisa Glubok,
   and Shi Xiaoxian. Additionally, we thank Traci Toy and Alison Schwartz
   in the UCLA DNA Microarray Facility for microarray assistance. This work
   was supported by National Institutes of Health grants 4F30AG033993 (to
   E.S.A.), and R01 GM084317 (to D.L.B., Manuel Ares, Xiang-Dong Fu, and
   Eugene Yeo). D.L.B. is an investigator of the Howard Hughes Medical
   Institute.
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NR 43
TC 55
Z9 65
U1 1
U2 12
PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
PI COLD SPRING HARBOR
PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA
SN 1355-8382
EI 1469-9001
J9 RNA
JI RNA
PD MAY
PY 2012
VL 18
IS 5
BP 1041
EP 1049
DI 10.1261/rna.032912.112
PG 9
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 927LM
UT WOS:000302909000014
PM 22456266
OA Green Accepted, Green Published, Bronze
DA 2025-04-10
ER

PT J
AU Gu, MY
   Zhao, YY
   Wang, H
   Cheng, WW
   Liu, J
   Ouyang, KF
   Wei, CL
AF Gu, Mingyao
   Zhao, Yuying
   Wang, Hong
   Cheng, Wanwen
   Liu, Jie
   Ouyang, Kunfu
   Wei, Chaoliang
TI Suppression of RBFox2 by Multiple MiRNAs in Pressure Overload-Induced
   Heart Failure
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Article
DE RBFox2; miRNAs; E-C coupling; alternative splicing; heart failure
ID CARDIAC-HYPERTROPHY; GENE-EXPRESSION; DILATED CARDIOMYOPATHY; MICROARRAY
   ANALYSIS; MICRORNA SIGNATURE; REGULATOR; RNA; MODELS; LET-7;
   PATHOPHYSIOLOGY
AB Heart failure is the final stage of various cardiovascular diseases and seriously threatens human health. Increasing mediators have been found to be involved in the pathogenesis of heart failure, including the RNA binding protein RBFox2. It participates in multiple aspects of the regulation of cardiac function and plays a critical role in the process of heart failure. However, how RBFox2 itself is regulated remains unclear. Here, we dissected transcriptomic signatures, including mRNAs and miRNAs, in a mouse model of heart failure after TAC surgery. A global analysis showed that an asymmetric alternation in gene expression and a large-scale upregulation of miRNAs occurred in heart failure. An association analysis revealed that the latter not only contributed to the degradation of numerous mRNA transcripts, but also suppressed the translation of key proteins such as RBFox2. With the aid of Ago2 CLIP-seq data, luciferase assays verified that RBFox2 was targeted by multiple miRNAs, including Let-7, miR-16, and miR-200b, which were significantly upregulated in heart failure. The overexpression of these miRNAs suppressed the RBFox2 protein and its downstream effects in cardiomyocytes, which was evidenced by the suppressed alternative splicing of the Enah gene and impaired E-C coupling via the repression of the Jph2 protein. The inhibition of Let-7, the most abundant miRNA family targeting RBFox2, could restore the RBFox2 protein as well as its downstream effects in dysfunctional cardiomyocytes induced by ISO treatment. In all, these findings revealed the molecular mechanism leading to RBFox2 depression in heart failure, and provided an approach to rescue RBFox2 through miRNA inhibition for the treatment of heart failure.
C1 [Gu, Mingyao; Zhao, Yuying; Liu, Jie; Wei, Chaoliang] Shenzhen Univ, Hlth Sci Ctr, Shenzhen Key Lab Metab & Cardiovasc Homeostasis, Shenzhen 518060, Peoples R China.
   [Wang, Hong; Ouyang, Kunfu] Peking Univ, Shenzhen Hosp, Dept Cardiovasc Surg, Shenzhen 518036, Peoples R China.
   [Cheng, Wanwen; Liu, Jie] Shenzhen Univ, Hlth Sci Ctr, Dept Pathophysiol, Shenzhen 518060, Peoples R China.
C3 Shenzhen University; Peking University; Shenzhen University
RP Wei, CL (corresponding author), Shenzhen Univ, Hlth Sci Ctr, Shenzhen Key Lab Metab & Cardiovasc Homeostasis, Shenzhen 518060, Peoples R China.
EM weicl@szu.edu.cn
RI ouyang, kunfu/B-3073-2011; Wei, Chaoliang/KPB-6289-2024
OI ouyang, kunfu/0000-0003-0292-375X
FU National Natural Science Funds of the People's Republic of China
   [81770227, 81970250]; Shenzhen Science and Technology Innovation
   Committee Project [JCYJ20180507182239272]; Shenzhen Key Laboratory of
   Metabolism and Cardiovascular Homeostasis [ZDSYS20190902092903237];
   Shenzhen Basic Research Foundation [JCYJ20190808174001746,
   JCYJ20210324105407019]
FX The authors are grateful to members of the Wei lab for their
   cooperation, reagent sharing, and technical support. This work was
   supported by the National Natural Science Funds of the People's Republic
   of China (81770227 to C.W. and 81970250 to J.L.), the Shenzhen Science
   and Technology Innovation Committee Project (JCYJ20180507182239272 to
   C.W.), the Shenzhen Key Laboratory of Metabolism and Cardiovascular
   Homeostasis (ZDSYS20190902092903237 to C.W.), and the Shenzhen Basic
   Research Foundation (JCYJ20190808174001746 and JCYJ20210324105407019 to
   K.O.)
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NR 69
TC 7
Z9 9
U1 1
U2 7
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD JAN
PY 2023
VL 24
IS 2
AR 1283
DI 10.3390/ijms24021283
PG 21
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA 8C5ET
UT WOS:000917632000001
PM 36674797
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Ladd, AN
   Taffet, G
   Hartley, C
   Kearney, DL
   Cooper, TA
AF Ladd, AN
   Taffet, G
   Hartley, C
   Kearney, DL
   Cooper, TA
TI Cardiac tissue-specific repression of CELF activity disrupts alternative
   splicing and causes cardiomyopathy
SO MOLECULAR AND CELLULAR BIOLOGY
LA English
DT Article
ID RNA-BINDING PROTEINS; PRE-MESSENGER-RNA; MYOTONIC-DYSTROPHY;
   GENE-EXPRESSION; CANDIDATE GENE; HEART-FAILURE; EDEN-BP; MUSCLE; ETR-3;
   DEADENYLATION
AB Members of the CELF family of RNA binding proteins have been implicated in alternative splicing regulation in developing heart. Transgenic mice that express a nuclear dominant-negative CELF protein specifically in the heart (MHC-CELF Delta) develop cardiac hypertrophy and dilated cardiomyopathy with defects in alternative splicing beginning as early as 3 weeks after birth. MHC-CELFA mice exhibit extensive cardiac fibrosis, severe cardiac dysfunction, and premature death. Interestingly, the penetrance of the phenotype is greater in females than in males despite similar levels of dominant-negative expression, suggesting that there is sex-specific modulation of splicing activity. The cardiac defects in MHC-CELF Delta mice are directly attributable to reduced levels of CELF activity, as crossing these mice with mice overexpressing CUG-BP1, a wild-type CELF protein, rescues defects in alternative splicing, the severity and incidence of cardiac hypertrophy, and survival. We conclude that CELF protein activity is required for normal alternative splicing in the heart in vivo and that normal CELF-mediated alternative splicing regulation is in turn required for normal cardiac function.
C1 Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA.
   Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
   Baylor Coll Med, Dept Med, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Baylor College of Medicine; Baylor College
   of Medicine
RP 1 Baylor Pl,Rm 268B, Houston, TX 77030 USA.
EM tcooper@bcm.tmc.edu
OI Ladd, Andrea/0000-0003-4725-5644
FU NHLBI NIH HHS [R01HL22512, R01HL45653, R01 HL022512] Funding Source:
   Medline; NIAMS NIH HHS [F32 AR008618, 5F32AR008618] Funding Source:
   Medline; NIA NIH HHS [R01AG17899, R01 AG017899] Funding Source: Medline
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NR 44
TC 65
Z9 74
U1 0
U2 14
PU AMER SOC MICROBIOLOGY
PI WASHINGTON
PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA
SN 0270-7306
EI 1098-5549
J9 MOL CELL BIOL
JI Mol. Cell. Biol.
PD JUL
PY 2005
VL 25
IS 14
BP 6267
EP 6278
DI 10.1128/MCB.25.14.6267-6278.2005
PG 12
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 942EZ
UT WOS:000230267000039
PM 15988035
OA Green Published, Bronze
DA 2025-04-10
ER

PT J
AU Schumann, H
   Morawietz, H
   Hakim, K
   Zerkowski, HR
   Eschenhagen, T
   Holtz, J
   Darmer, D
AF Schumann, H
   Morawietz, H
   Hakim, K
   Zerkowski, HR
   Eschenhagen, T
   Holtz, J
   Darmer, D
TI Alternative splicing of the primary Fas transcript generating soluble
   fas antagonists is suppressed in the failing human ventricular
   myocardium
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
ID MYOCYTE CELL-DEATH; CARDIAC TROPONIN-T; HEART-FAILURE; MESSENGER-RNA;
   PRESSURE-OVERLOAD; APOPTOSIS; EXPRESSION; ANTIGEN; CDNA; RAT
AB Apoptosis of cardiomyocytes has been proposed as a facto ar contributing to severe heart failure, Since the trigger for apoptotic cellular suicide in nonischemic myocardium is unknown, we analyzed in human myocardial tissue the expression of the apoptosis-inducing membrane receptor Fas/APO-1 and of its alternatively spliced soluble isoforms which antagonize Fas by binding of the Fas ligand. Using reverse transcription polymerase chain reaction (RT-PCR) we found mRNA for Fas and 5 isoforms in nonfailing left ventricles, whereas Fas and only one isoform (FasEXo6DeI) were detectable in failing left ventricles, Standard calibrated, competitive BT-PCR revealed no significant increase of Fas mRNA in failing compared to nonfailing ventricles. However, title mRNA for FasExo6Del, expressed nearly on the same level as Fas in nonfailing ventricles, was decreased about 3-fold in failing ventricles. WE propose that this altered expression of the Fas system renders the myocardium more susceptible for Fas-mediated apoptosis ire end-stage heart failure. (C) 1997 Academic Press.
C1 UNIV HALLE WITTENBERG, CARDIOVASC SURG CLIN, HALLE, GERMANY.
   UNIV HAMBURG, HOSP EPPENDORF, INST PHARMACOL, D-20246 HAMBURG, GERMANY.
C3 Martin Luther University Halle Wittenberg; University of Hamburg
RP UNIV HALLE WITTENBERG, INST PATHOPHYSIOL, HALLE, GERMANY.
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NR 34
TC 34
Z9 37
U1 0
U2 2
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD OCT 29
PY 1997
VL 239
IS 3
BP 794
EP 798
DI 10.1006/bbrc.1997.7555
PG 5
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA YG931
UT WOS:A1997YG93100029
PM 9367848
DA 2025-04-10
ER

PT J
AU Torrado, M
   Iglesias, R
   Centeno, A
   López, E
   Mikhailov, AT
AF Torrado, Mario
   Iglesias, Raquel
   Centeno, Alberto
   Lopez, Eduardo
   Mikhailov, Alexander T.
TI Exon-skipping brain natriuretic peptide variant is overexpressed in
   failing myocardium and attenuates brain natriuretic peptide production
   in vitro
SO EXPERIMENTAL BIOLOGY AND MEDICINE
LA English
DT Article
DE NPPB; exon skipping; post-transcriptional regulation; heart failure;
   myocardium
ID DIASTOLIC HEART-FAILURE; BNP GENE-EXPRESSION; WALL STRESS;
   MESSENGER-RNA; ACTIVATION; CARDIOMYOPATHY; CALCINEURIN; SECRETION;
   NONSENSE; DISEASES
AB Brain natriuretic peptide/natriuretic peptide precursor B (NPPB) is one of the most studied genes in relation to heart failure (HF) conditions. However, it is still unclear as to whether alternative splicing could create NPPB mRNA variants, which may be expressed in normal and diseased myocardium. We aimed to identify and characterize a novel alternatively spliced variant of porcine and human NPPB resulting from exon 2 skipping (designated as Delta E2-NPPB). A variety of conventional molecular, biochemical and immunochemical methods were used to examine the expression and functional consequences of Delta E2-NPPB in vitro and in vivo. The pig Delta E2-NPPB mRNA is effectively translated into stable protein in cell-based assays but, in contrast to normally spliced NPPB, the Delta E2-NPPB protein is not secreted into the media. Co-transfection assays demonstrate that Delta E2-NPPB attenuates production and secretion of normally spliced NPPB, suggesting a negative feedback loop of NPPB signaling through generation of Delta E2-NPPB. The inhibitory effects of Delta E2-NPPB on the expression of NPPB are associated with sequence elements residing in exon 3 of Delta E2-NPPB. In piglets, Delta E2-NPPB gene expression is downregulated in both ventricles after birth, but it is markedly re-activated in the postnatal myocardium in experimental diastolic heart failure. In addition, we demonstrate that the exon-skipped NPPB variants are expressed in the postnatal and adult human myocardium and upregulated at end-stage HF due to dilated cardiomyopathy. Our work uncovers an important role of alternative exon skipping in the regulation of NPPB gene expression, thereby pinpointing a putative new mechanism for post-transcriptional regulation of NPPB production and secretion.
C1 [Torrado, Mario; Iglesias, Raquel; Mikhailov, Alexander T.] Univ A Coruna, Inst Hlth Sci, Dev Biol Unit, La Coruna 15006, Spain.
   [Centeno, Alberto; Lopez, Eduardo] Univ Hosp Ctr La Coruna, Expt Surg Unit, La Coruna 15006, Spain.
C3 Universidade da Coruna; Complejo Hospitalario Universitario A Coruna
RP Mikhailov, AT (corresponding author), Univ A Coruna, Inst Hlth Sci, Dev Biol Unit, Campus Oza,Bldg El Fortin,As Xubias Str S-N, La Coruna 15006, Spain.
EM margot@udc.es
RI Mikhailov, Alexander/H-1897-2012; Iglesias, Raquel/D-3212-2019
OI Torrado, Mario/0000-0001-9762-7018; Mikhailov,
   Alexander/0000-0002-1146-4113; Iglesias, Raquel/0000-0002-0212-3616;
   Centeno Cortes, Alberto/0000-0002-9442-5733
FU Spanish Ministry of Science and Innovation [SAF2004-01462,
   SAF-200800337]; Autonomic Government of Galicia [08CSA008161PR]
FX The authors thank Drs Marisa Crespo, Javier Muniz and Constancio Medrano
   (University Hospital Centre of La Coruna, La Coruna, Spain) for their
   help in sampling and characterization of human heart tissues. Special
   thanks to Cristina Trillo (Roche, Spain) and Javier Aldama (Roche,
   Spain) for the opportunity to use the RTCA SP Station (Roche) in our
   cell-transfection experiments. This work was supported by grants
   (SAF2004-01462 and SAF-200800337) from the Spanish Ministry of Science
   and Innovation and partially by a grant (08CSA008161PR) from the
   Autonomic Government of Galicia.
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NR 30
TC 5
Z9 5
U1 0
U2 0
PU SAGE PUBLICATIONS LTD
PI LONDON
PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND
SN 1535-3702
EI 1535-3699
J9 EXP BIOL MED
JI Exp. Biol. Med.
PD AUG
PY 2010
VL 235
IS 8
BP 941
EP 951
DI 10.1258/ebm.2010.010078
PG 11
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA 634MQ
UT WOS:000280586600006
PM 20660094
OA Green Submitted
DA 2025-04-10
ER

PT J
AU Dumont, AA
   Dumont, L
   Berthiaume, J
   Auger-Messier, M
AF Dumont, Audrey-Ann
   Dumont, Lauralyne
   Berthiaume, Jonathan
   Auger-Messier, Mannix
TI p38α MAPK proximity assay reveals a regulatory mechanism of alternative
   splicing in cardiomyocytes
SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
LA English
DT Article
DE Alternative splicing; APEX2; Cardiomyocytes; p38 MAPK; SRSF3
ID PROTEIN-INTERACTION NETWORKS; PRE-MESSENGER-RNA; SR PROTEINS; P38 MAPK;
   PRESSURE-OVERLOAD; LIVING CELLS; HNRNP A1; KINASE; ACTIVATION;
   PHOSPHORYLATION
AB The p38 mitogen-activated protein kinase (MAPK) signaling pathway is essential for normal heart function. However, p38 also contributes to heart failure pathogenesis by affecting cardiomyocytes contractility and survival. To unravel part of the complex role of p38 in cardiac function, we performed an APEX2-based proximity assay in cultured neonatal rat ventricular myocytes and identified the protein interaction networks (interactomes) of two highly expressed p38 isoforms in the heart. We found that p38 alpha and p38 gamma have distinct interactomes in cardiomyocytes under both basal and osmotic stress-activated states. Interestingly, the activated p38 alpha interactome contains many RNA-binding proteins implicated in splicing, including the serine/arginine-rich splicing factor 3 (SRSF3). Its interaction with the activated p38 alpha was validated by co-immunoprecipitation. The cytoplasmic abundance and alternative splicing function of SRSF3 are also both modulated by the p38 signaling pathway. Our findings reveal a new function for p38 as a specific regulator of SRSF3 in cardiomyocytes.
C1 [Dumont, Audrey-Ann; Dumont, Lauralyne; Berthiaume, Jonathan; Auger-Messier, Mannix] Univ Sherbrooke, Ctr Rech CHUS, Fac Med & Sci Sante, Serv Cardiol,Dept Med, Sherbrooke, PQ, Canada.
C3 University of Sherbrooke
RP Auger-Messier, M (corresponding author), Univ Sherbrooke, Ctr Rech CHUS, Fac Med & Sci Sante, Serv Cardiol,Dept Med, Sherbrooke, PQ, Canada.
EM Mannix.Auger-Messier@USherbrooke.ca
RI Auger-Messier, Mannix/AFL-8844-2022
OI Auger-Messier, Mannix/0000-0001-8600-5440
FU Canadian Institutes of Health Research [301131]; Fonds de Recherche du
   Quebec - Sante (FRQS); Canadian Institutes of Health Research; Faculte
   de Medecine et des Sciences de la Sante - Domenico-Regoli; FRQS-Junior 1
   New Investigator award; Heart and Stroke Foundation of Canada (HSFC)
FX This work was supported by a grant from the Canadian Institutes of
   Health Research (grant number 301131 to M.A.-M.), training awards from
   Fonds de Recherche du Quebec - Sante (FRQS) and Canadian Institutes of
   Health Research to A.-A.D., a training award from the Faculte de
   Medecine et des Sciences de la Sante - Domenico-Regoli to L.D., and
   FRQS-Junior 1 and Heart and Stroke Foundation of Canada (HSFC) New
   Investigator awards both awarded to M.A.-M.
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NR 78
TC 15
Z9 15
U1 1
U2 6
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0167-4889
EI 1879-2596
J9 BBA-MOL CELL RES
JI Biochim. Biophys. Acta-Mol. Cell Res.
PD DEC
PY 2019
VL 1866
IS 12
AR 118557
DI 10.1016/j.bbamcr.2019.118557
PG 12
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA JQ1YM
UT WOS:000498748700025
PM 31505169
OA Bronze
DA 2025-04-10
ER

PT J
AU Tian, X
   Zhou, GL
   Li, H
   Zhang, XT
   Zhao, LM
   Zhang, KY
   Wang, LQ
   Liu, MW
   Liu, C
   Yang, P
AF Tian, Xin
   Zhou, Guangli
   Li, Hao
   Zhang, Xueting
   Zhao, Lingmin
   Zhang, Keyi
   Wang, Luqiao
   Liu, Mingwei
   Liu, Chen
   Yang, Ping
TI RBM25 binds to and regulates alternative splicing levels of
   Slc38a9, Csf1, and Coro6 to affect immune and
   inflammatory processes in H9c2 cells
SO PEERJ
LA English
DT Article
DE RBM25; Alternative splicing; RNA-seq; Improved RNA immunoprecipitation
   sequencing; Inflammation; H9c2 cell; Heart failure
ID HEART-FAILURE; GENE-EXPRESSION; PROTEIN; IDENTIFICATION; HYPERTROPHY;
   MECHANISMS; APOPTOSIS
AB Background. Alternative splicing (AS) is a biological process that allows genes to be translated into diverse proteins. However, aberrant AS can predispose cells to aberrations in biological mechanisms. RNA binding proteins (RBPs), closely affiliated with AS, have gained increased attention in recent years. Among these RBPs, RBM25 has been reported to participate in the cardiac pathological mechanism through regulating AS; however, the involvement of RBM25 as a splicing factor in heart failure remains unclarified. Methods. RBM25 was overexpressed in H9c2 cells to explore the target genes bound and regulated by RBM25 during heart failure. RNA sequencing (RNA-seq) was used to scrutinize the comprehensive transcriptional level before identifying AS events influenced by RBM25. Further, improved RNA immunoprecipitation sequencing (iRIP-seq) was employed to pinpoint RBM25-binding sites, and RT-qPCR was used to validate specific genes modulated by RBM25. Results. RBM25 was found to upregulate the expression of genes pertinent to the inflammatory response and viral processes, as well as to mediate the AS of genes associated with cellular apoptosis and inflammation. Overlap analysis between RNA-seq and iRIP-seq suggested that RBM25 bound to and manipulated the AS of genes associated with inflammation in H9c2 cells. Moreover, qRT-PCR confirmed Slc38a9, Csf1, and Coro6 as the binding and AS regulatory targets of RBM25. Conclusion. Our research implies that RBM25 plays a contributory role in cardiac inflammatory responses via its ability to bind to and regulate the AS of related genes. This study offers preliminary evidence of the influence of RBM25 on inflammation in H9c2 cells.
C1 [Tian, Xin; Zhou, Guangli; Li, Hao; Zhang, Xueting; Zhao, Lingmin; Zhang, Keyi; Wang, Luqiao; Liu, Mingwei; Yang, Ping] Kunming Med Univ, Affiliated Hosp 1, Dept Cardiol, Kunming, Peoples R China.
   [Liu, Chen] Yunnan Univ, Affiliated Hosp, Dept Radiol, Kunming, Peoples R China.
C3 Kunming Medical University; Yunnan University
RP Yang, P (corresponding author), Kunming Med Univ, Affiliated Hosp 1, Dept Cardiol, Kunming, Peoples R China.; Liu, C (corresponding author), Yunnan Univ, Affiliated Hosp, Dept Radiol, Kunming, Peoples R China.
EM 25997055@qq.com; 15877990331@163.com
RI Liu, Ming-Wei/AFL-8981-2022
FU National Natural Science Foundation of China [82360082, 81760074];
   Special Foundation Projects of Joint Applied Basic Research of Yunnan
   Provincial Department of Science and Technology with Kunming Medical
   University [202201AY070001-064, 2017FE468 (-043)]; Yunnan Health
   Training Project of High-Level Talents [D-2018020]; Clinical Medical
   Center for Cardiovascular and Cerebrovascular Disease of Yunnan Province
   [ZX2019-03-01]; Foundation Projects of young and middleaged academic and
   technical leaders reserve talent of Yunnan province [202305AC160048]
FX The following grant information was disclosed by the authors: National
   Natural Science Foundation of China: 82360082, 81760074. Special
   Foundation Projects of Joint Applied Basic Research of Yunnan Provincial
   Department of Science and Technology with Kunming Medical University:
   202201AY070001-064, 2017FE468 (-043) . Yunnan Health Training Project of
   High-Level Talents: D-2018020. Clinical Medical Center for
   Cardiovascular and Cerebrovascular Disease of Yunnan Province:
   ZX2019-03-01. Foundation Projects of young and middleaged academic and
   technical leaders reserve talent of Yunnan province: 202305AC160048.
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NR 55
TC 2
Z9 2
U1 4
U2 9
PU PEERJ INC
PI LONDON
PA 341-345 OLD ST, THIRD FLR, LONDON, EC1V 9LL, ENGLAND
SN 2167-8359
J9 PEERJ
JI PeerJ
PD NOV 7
PY 2023
VL 11
AR e16312
DI 10.7717/peerj.16312
PG 22
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA Y6NC2
UT WOS:001106397700003
PM 37953772
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Montañés-Agudo, P
   Aufiero, S
   Schepers, EN
   van der Made, I
   Cócera-Ortega, L
   Ernault, AC
   Richard, S
   Kuster, DWD
   Christoffels, VM
   Pinto, YM
   Creemers, EE
AF Montanes-Agudo, Pablo
   Aufiero, Simona
   Schepers, Eva N.
   van der Made, Ingeborg
   Cocera-Ortega, Lucia
   Ernault, Auriane C.
   Richard, Stephane
   Kuster, Diederik W. D.
   Christoffels, Vincent M.
   Pinto, Yigal M.
   Creemers, Esther E.
TI The RNA-binding protein QKI governs a muscle-specific alternative
   splicing program that shapes the contractile function of cardiomyocytes
SO CARDIOVASCULAR RESEARCH
LA English
DT Article
DE Alternative splicing; RNA-binding proteins; Quaking; Cardiomyocytes
ID QUAKING; GENE; CARDIOMYOPATHY; EXPRESSION; REGULATOR; TERMINUS; INJURY;
   ADULT; RBM20
AB Aims In the heart, splicing factors orchestrate the functional properties of cardiomyocytes by regulating the alternative splicing of multiple genes. Work in embryonic stem cells has shown that the splicing factor Quaking (QKI) regulates alternative splicing during cardiomyocyte differentiation. However, the relevance and function of QKI in adult cardiomyocytes remains unknown. In this study, we aim to identify the in vivo function of QKI in the adult mouse heart. Methods and results We generated mice with conditional deletion of QKI in cardiomyocytes by the Cre-Lox system. Mice with cardiomyocyte-specific deletion of QKI died during the foetal period (E14.5), without obvious anatomical abnormalities of the heart. Adult mice with tamoxifen-inducible QKI deletion rapidly developed heart failure associated with severe disruption of sarcomeres, already 7 days after knocking out QKI. RNA sequencing revealed that QKI regulates the alternative splicing of more than 1000 genes, including sarcomere and cytoskeletal components, calcium-handling genes, and (post-)transcriptional regulators. Many of these splicing changes corresponded to the loss of muscle-specific isoforms in the heart. Forced overexpression of QKI in cultured neonatal rat ventricular myocytes directed these splicing events in the opposite direction and enhanced contractility of cardiomyocytes. Conclusion Altogether, our findings show that QKI is an important regulator of the muscle-specific alternative splicing program that builds the contractile apparatus of cardiomyocytes.
C1 [Montanes-Agudo, Pablo; Aufiero, Simona; Schepers, Eva N.; van der Made, Ingeborg; Cocera-Ortega, Lucia; Ernault, Auriane C.; Pinto, Yigal M.; Creemers, Esther E.] Univ Amsterdam, Amsterdam UMC, Dept Expt Cardiol, Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands.
   [Aufiero, Simona] Univ Amsterdam, Amsterdam UMC, Dept Clin Epidemiol Biostat & Bioinformat, Meibergdreef 9, Amsterdam, Netherlands.
   [Richard, Stephane] McGill Univ, Segal Canc Ctr, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada.
   [Richard, Stephane] McGill Univ, Dept Biochem Human Genet & Med, Montreal, PQ H3T 1E2, Canada.
   [Richard, Stephane] McGill Univ, Gerald Bronfman Dept Oncol, Montreal, PQ H3T 1E2, Canada.
   [Kuster, Diederik W. D.] Vrije Univ Amsterdam, Amsterdam UMC, Dept Med Physiol, De Boelelaan 1117, Amsterdam, Netherlands.
   [Christoffels, Vincent M.] Univ Amsterdam, Amsterdam UMC, Dept Med Biol, Meibergdreef 9, Amsterdam, Netherlands.
C3 University of Amsterdam; University of Amsterdam; Lady Davis Institute;
   McGill University; McGill University; McGill University; Vrije
   Universiteit Amsterdam; University of Amsterdam
RP Creemers, EE (corresponding author), Univ Amsterdam, Amsterdam UMC, Dept Expt Cardiol, Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands.
EM e.e.creemers@amsterdamumc.nl
RI Kuster, Diederik/AAD-9272-2019; RICHARD, Stéphane/O-1005-2017
OI van der Made, Ingeborg/0000-0001-6251-8161; Montanes-Agudo,
   Pablo/0000-0002-8873-1937; Kuster, Diederik/0000-0003-1498-6862
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NR 52
TC 20
Z9 20
U1 2
U2 10
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0008-6363
EI 1755-3245
J9 CARDIOVASC RES
JI Cardiovasc. Res.
PD MAY 22
PY 2023
VL 119
IS 5
BP 1161
EP 1174
DI 10.1093/cvr/cvad007
EA JAN 2023
PG 14
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA H1XJ0
UT WOS:000918490500001
PM 36627242
OA hybrid, Green Published
DA 2025-04-10
ER

PT J
AU Hu, ZY
   Liang, MC
   Soong, TW
AF Hu, Zhenyu
   Liang, Mui Cheng
   Soong, Tuck Wah
TI Alternative Splicing of L-type CaV1.2 Calcium Channels:
   Implications in Cardiovascular Diseases
SO GENES
LA English
DT Review
DE L-type Ca(V)1.2 calcium channel; alternative splicing; cardiovascular
   diseases
ID CA2+ CHANNELS; UP-REGULATION; CARDIAC-HYPERTROPHY; BETA-SUBUNITS; HUMAN
   HEART; EXPRESSION; CAV1.2; VARIANT; RBM20; RAT
AB L-type Ca(V)1.2 calcium channels are the major pathway for Ca2+ influx to initiate the contraction of smooth and cardiac muscles. Alteration of Ca(V)1.2 channel function has been implicated in multiple cardiovascular diseases, such as hypertension and cardiac hypertrophy. Alternative splicing is a post-transcriptional mechanism that expands Ca(V)1.2 channel structures to modify function, pharmacological and biophysical property such as calcium/voltage-dependent inactivation (C/VDI), or to influence its post-translational modulation by interacting proteins such as Galectin-1. Alternative splicing has generated functionally diverse Ca(V)1.2 isoforms that can be developmentally regulated in the heart, or under pathophysiological conditions such as in heart failure. More importantly, alternative splicing of certain exons of Ca(V)1.2 has been reported to be regulated by splicing factors such as RNA-binding Fox-1 homolog 1/2 (Rbfox 1/2), polypyrimidine tract-binding protein (PTBP1) and RNA-binding motif protein 20 (RBM20). Understanding how Ca(V)1.2 channel function is remodelled in disease will provide better information to guide the development of more targeted approaches to discover therapeutic agents for cardiovascular diseases.
C1 [Hu, Zhenyu; Liang, Mui Cheng; Soong, Tuck Wah] Natl Univ Singapore, Dept Physiol, Yong Loo Lin Sch Med, Singapore 117593, Singapore.
   [Soong, Tuck Wah] NUS Grad Sch Integrat Sci & Engn, Neurobiol Ageing Programme, Ctr Life Sci, Singapore 117456, Singapore.
   [Soong, Tuck Wah] Natl Univ Singapore, Neurobiol Ageing Programme, Ctr Life Sci, Singapore 117456, Singapore.
C3 National University of Singapore; National University of Singapore;
   Center Life Science - NUS; National University of Singapore; Center Life
   Science - NUS
RP Soong, TW (corresponding author), Natl Univ Singapore, Dept Physiol, Yong Loo Lin Sch Med, Singapore 117593, Singapore.; Soong, TW (corresponding author), NUS Grad Sch Integrat Sci & Engn, Neurobiol Ageing Programme, Ctr Life Sci, Singapore 117456, Singapore.; Soong, TW (corresponding author), Natl Univ Singapore, Neurobiol Ageing Programme, Ctr Life Sci, Singapore 117456, Singapore.
EM phshz@nus.edu.sg; phslmc@nus.edu.sg; phsstw@nus.edu.sg
RI hu, zhenyu/KIB-5028-2024
OI Liang, Mui Cheng/0000-0003-1208-0733; Hu, Zhenyu/0000-0002-2392-7533
FU National University Health Systems [NUHSRO/2014/086/AF-Partner/02];
   Ministry of Education NUSMed Post-Doctoral Fellowship
FX This work was supported by the National University Health Systems
   (NUHSRO/2014/086/AF-Partner/02 to T.W.S.) and Ministry of Education
   NUSMed Post-Doctoral Fellowship (Z.H.). The University of California
   Santa Cruz (UCSC) Genome Browser was used to describe the chromosome
   coordinates of the spliced exons in this review.
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NR 66
TC 46
Z9 50
U1 0
U2 14
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2073-4425
J9 GENES-BASEL
JI Genes
PD DEC
PY 2017
VL 8
IS 12
AR 344
DI 10.3390/genes8120344
PG 12
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA FR6YC
UT WOS:000419212400005
PM 29186814
OA gold, Green Submitted, Green Published
DA 2025-04-10
ER

PT J
AU Zahr, HC
   Jaalouk, DE
AF Zahr, Hind C.
   Jaalouk, Diana E.
TI Exploring the Crosstalk Between LMNA and Splicing Machinery Gene
   Mutations in Dilated Cardiomyopathy
SO FRONTIERS IN GENETICS
LA English
DT Review
DE lamins; splicing; RNA binding proteins; cardiomyopathies; DCM; RBM20
ID LAMIN A/C GENE; RNA-POLYMERASE-II; HEART-FAILURE; MESSENGER-RNA; TITIN
   ISOFORM; BINDING-PROTEIN; ATRIOVENTRICULAR-BLOCK; SCIENTIFIC STATEMENT;
   FACTOR COMPARTMENTS; POSITION STATEMENT
AB Mutations in the LMNA gene, which encodes for the nuclear lamina proteins lamins A and C, are responsible for a diverse group of diseases known as laminopathies. One type of laminopathy is Dilated Cardiomyopathy (DCM), a heart muscle disease characterized by dilation of the left ventricle and impaired systolic function, often leading to heart failure and sudden cardiac death. LMNA is the second most commonly mutated gene in DCM. In addition to LMNA, mutations in more than 60 genes have been associated with DCM. The DCM-associated genes encode a variety of proteins including transcription factors, cytoskeletal, Ca2+-regulating, ion-channel, desmosomal, sarcomeric, and nuclear-membrane proteins. Another important category among DCM-causing genes emerged upon the identification of DCM-causing mutations in RNA binding motif protein 20 (RBM20), an alternative splicing factor that is chiefly expressed in the heart. In addition to RBM20, several essential splicing factors were validated, by employing mouse knock out models, to be embryonically lethal due to aberrant cardiogenesis. Furthermore, heart-specific deletion of some of these splicing factors was found to result in aberrant splicing of their targets and DCM development. In addition to splicing alterations, advances in next generation sequencing highlighted the association between splice-site mutations in several genes and DCM. This review summarizes LMNA mutations and splicing alterations in DCM and discusses how the interaction between LMNA and splicing regulators could possibly explain DCM disease mechanisms.
C1 [Zahr, Hind C.; Jaalouk, Diana E.] Amer Univ Beirut, Fac Arts & Sci, Dept Biol, Beirut, Lebanon.
C3 American University of Beirut
RP Jaalouk, DE (corresponding author), Amer Univ Beirut, Fac Arts & Sci, Dept Biol, Beirut, Lebanon.
EM dj11@aub.edu.lb
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NR 155
TC 28
Z9 32
U1 1
U2 7
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 1664-8021
J9 FRONT GENET
JI Front. Genet.
PD JUL 9
PY 2018
VL 9
AR 231
DI 10.3389/fgene.2018.00231
PG 14
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA GM2EV
UT WOS:000437896200001
PM 30050558
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Pan, SC
   Chen, HH
   Dickey, DM
   Boerrigter, G
   Lee, C
   Kleppe, LS
   Hall, JL
   Lerman, A
   Redfield, MM
   Potter, LR
   Burnett, JC
   Simari, RD
AF Pan, Shuchong
   Chen, Horng H.
   Dickey, Deborah M.
   Boerrigter, Guido
   Lee, Candace
   Kleppe, Laurel S.
   Hall, Jennifer L.
   Lerman, Amir
   Redfield, Margaret M.
   Potter, Lincoln R.
   Burnett, John C., Jr.
   Simari, Robert D.
TI Biodesign of a renal-protective peptide based on alternative splicing of
   B-type natriuretic peptide
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
   AMERICA
LA English
DT Article
DE vasoactive; myocardial; kidney
ID CONGESTIVE-HEART-FAILURE; GROWTH-FACTOR; IN-VITRO; NESIRITIDE; SYSTEM;
   BRAIN
AB Alternative RNA splicing may provide unique opportunities to identify drug targets and therapeutics. We identified an alternative spliced transcript for B-type natriuretic peptide (BNP) resulting from intronic retention. This transcript is present in failing human hearts and is reduced following mechanical unloading. The intron-retained transcript would generate a unique 34 amino acid (aa) carboxyl terminus while maintaining the remaining structure of native BNP. We generated antisera to this carboxyl terminus and identified immunoreactivity in failing human heart tissue. The alternatively spliced peptide (ASBNP) was synthesized and unlike BNP, failed to stimulate cGMP in vascular cells or vasorelax pre-constricted arterial rings. This suggests that ASBNP may lack the dose-limiting effects of recombinant BNP. Given structural considerations, a carboxyl-terminal truncated form of ASBNP was generated (ASBNP. 1) and was determined to retain the ability of BNP to stimulate cGMP in canine glomerular isolates and cultured human mesangial cells but lacked similar effects in vascular cells. In a canine-pacing model of heart failure, systemic infusion of ASBNP. 1 did not alter mean arterial pressure but increased the glomerular filtration rate (GFR), suppressed plasma renin and angiotensin, while inducing natriuresis and diuresis. Consistent with its distinct in vivo effects, the activity of ASBNP. 1 may not be explained through binding and activation of NPR-A or NPR-B. Thus, the biodesigner peptide ASBNP. 1 enhances GFR associated with heart failure while lacking the vasoactive properties of BNP. These findings demonstrate that peptides with unique properties may be designed based on products of alternatively splicing.
C1 [Pan, Shuchong; Chen, Horng H.; Boerrigter, Guido; Lee, Candace; Kleppe, Laurel S.; Lerman, Amir; Redfield, Margaret M.; Burnett, John C., Jr.; Simari, Robert D.] Mayo Clin, Div Cardiovasc Dis & Internal Med, Rochester, MN 55905 USA.
   [Dickey, Deborah M.; Potter, Lincoln R.] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA.
   [Hall, Jennifer L.] Univ Minnesota, Div Cardiol, Minneapolis, MN 55455 USA.
C3 Mayo Clinic; University of Minnesota System; University of Minnesota
   Twin Cities; University of Minnesota System; University of Minnesota
   Twin Cities
RP Simari, RD (corresponding author), Mayo Clin, Div Cardiovasc Dis & Internal Med, 200 1st St SW, Rochester, MN 55905 USA.
EM simari.robert@mayo.edu
RI Redfield, Margaret/JQW-3307-2023
FU Anexon, Inc.,; Mayo Foundation; National Institutes of Health [HL 76611]
FX This work was funded in part by grants from Anexon, Inc., the Mayo
   Foundation, and the National Institutes of Health ( HL 76611).
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NR 19
TC 39
Z9 48
U1 0
U2 3
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD JUL 7
PY 2009
VL 106
IS 27
BP 11282
EP 11287
DI 10.1073/pnas.0811851106
PG 6
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 468DX
UT WOS:000267796100075
PM 19541613
OA Green Published
DA 2025-04-10
ER

PT J
AU Matkovich, SJ
AF Matkovich, Scot J.
TI Transcriptome analysis in heart failure
SO CURRENT OPINION IN CARDIOLOGY
LA English
DT Review
DE heart failure; hypertrophy; microRNA; mRNA; RNA sequencing; splicing
ID RNA-SEQ EXPERIMENTS; DIFFERENTIAL EXPRESSION; CARDIAC-HYPERTROPHY;
   SEQUENCING DATA; MICRORNA; GENE; DISEASE; REPRODUCIBILITY;
   CARDIOMYOPATHY; IDENTIFICATION
AB Purpose of review
   Genome-wide analysis of RNA abundances (transcriptome analysis) offers great potential to identify biomarkers of disease and to gain insight into mechanisms underlying the development of heart failure. I will discuss key factors in generating and evaluating transcriptome data, and recent studies that have contributed to the understanding of cardiac disease in humans and animal models.
   Recent findings
   Thorough assessments of RNA-sequencing performance performed across multiple laboratories have demonstrated its primacy in measuring differential RNA abundances, due in part to its wide dynamic range and accuracy. In combination with network and pathway analysis tools, this enables greater understanding of heart failure mechanisms than previously possible, and renders possible current and future investigations into the role of RNA alternative splicing.
   Summary
   Current and future acquisition of accurate, unbiased, and comprehensive transcriptome data will continue to inform the understanding of heart failure, enabling hypothesis testing as well as hypothesis generation. Transcriptome data represent a vital bridge between genomic and epigenomic variation and proteomic output; progressive integration of data from these and other domains will fully realize the potential inherent in transcriptome analyses.
C1 [Matkovich, Scot J.] Washington Univ, Sch Med, Dept Internal Med, Ctr Pharmacogenom, St Louis, MO 63110 USA.
C3 Washington University (WUSTL)
RP Matkovich, SJ (corresponding author), Washington Univ, Sch Med, Ctr Pharmacogenom, 660 S Euclid Ave,Campus Box 8220, St Louis, MO 63110 USA.
EM smatkovi@dom.wustl.edu
RI Matkovich, Scot/B-9077-2009
OI Matkovich, Scot/0000-0002-7398-6857
FU American Heart Association [14GRNT20410000]; Department of Medicine
   (Center for Pharmacogenomics) at Washington University; American Heart
   Association (AHA) [14GRNT20410000] Funding Source: American Heart
   Association (AHA)
FX This work was supported by Grant-in-Aid 14GRNT20410000 from the American
   Heart Association, and by funds from the Department of Medicine (Center
   for Pharmacogenomics) at Washington University.
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NR 66
TC 8
Z9 8
U1 0
U2 23
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0268-4705
EI 1531-7080
J9 CURR OPIN CARDIOL
JI Curr. Opin. Cardiol.
PD MAY
PY 2016
VL 31
IS 3
BP 242
EP 248
DI 10.1097/HCO.0000000000000275
PG 7
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA DK2TD
UT WOS:000374766400002
PM 27054504
DA 2025-04-10
ER

PT J
AU Yuen, M
   Worgan, L
   Iwanski, J
   Pappas, CT
   Joshi, H
   Churko, JM
   Arbuckle, S
   Kirk, EP
   Zhu, Y
   Roscioli, T
   Gregorio, CC
   Cooper, ST
AF Yuen, Michaela
   Worgan, Lisa
   Iwanski, Jessika
   Pappas, Christopher T.
   Joshi, Himanshu
   Churko, Jared M.
   Arbuckle, Susan
   Kirk, Edwin P.
   Zhu, Ying
   Roscioli, Tony
   Gregorio, Carol C.
   Cooper, Sandra T.
TI Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor
   splice-site variant
SO EUROPEAN JOURNAL OF HUMAN GENETICS
LA English
DT Article
ID MYOD
AB Dilated cardiomyopathy (DCM) is characterized by cardiac enlargement and impaired ventricular contractility leading to heart failure. A single report identified variants in leiomodin-2 (LMOD2) as a cause of neonatally-lethal DCM. Here, we describe two siblings with DCM who died shortly after birth due to heart failure. Exome sequencing identified a homozygous LMOD2 variant in both siblings, (GRCh38)chr7:g.123656237G > A; NM_207163.2:c.273 + 1G > A, ablating the donor 5 ' splice-site of intron-1. Pre-mRNA splicing studies and western blot analysis on cDNA derived from proband cardiac tissue, MyoD-transduced proband skin fibroblasts and HEK293 cells transfected with LMOD2 gene constructs established variant-associated absence of canonically spliced LMOD2 mRNA and full-length LMOD2 protein. Immunostaining of proband heart tissue unveiled abnormally short actin-thin filaments. Our data are consistent with LMOD2 c.273 + 1G > A abolishing/reducing LMOD2 transcript expression by: (1) variant-associated perturbation in initiation of transcription due to ablation of the intron-1 donor; and/or (2) degradation of aberrant LMOD2 transcripts (resulting from use of alternative transcription start-sites or cryptic splice-sites) by nonsense-mediated decay. LMOD2 expression is critical for life and the absence of LMOD2 is associated with thin filament shortening and severe cardiac contractile dysfunction. This study describes the first splice-site variant in LMOD2 and confirms the role of LMOD2 variants in DCM.
C1 [Yuen, Michaela; Joshi, Himanshu; Cooper, Sandra T.] Childrens Hosp Westmead, Kids Neurosci Ctr, Westmead, NSW, Australia.
   [Yuen, Michaela; Cooper, Sandra T.] Univ Sydney, Sydney Med Sch, Discipline Child & Adolescent Hlth, Camperdown, NSW, Australia.
   [Worgan, Lisa] Royal Prince Alfred Hosp, Dept Med Genom, Camperdown, NSW, Australia.
   [Iwanski, Jessika; Pappas, Christopher T.; Churko, Jared M.; Gregorio, Carol C.] Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ USA.
   [Iwanski, Jessika; Pappas, Christopher T.; Churko, Jared M.; Gregorio, Carol C.] Univ Arizona, Sarver Mol Cardiovasc Res Program, Tucson, AZ USA.
   [Arbuckle, Susan] Childrens Hosp Westmead, Dept Histopathol, Westmead, NSW, Australia.
   [Kirk, Edwin P.; Zhu, Ying; Roscioli, Tony] Randwick Genom Lab, New South Wales Hlth Pathol, Randwick, NSW, Australia.
   [Kirk, Edwin P.] Univ New South Wales, Sch Womens & Childrens Hlth, Randwick, NSW, Australia.
   [Kirk, Edwin P.; Roscioli, Tony] Sydney Childrens Hosp, Ctr Clin Genet, Randwick, NSW, Australia.
   [Roscioli, Tony] Univ New South Wales, Neurosci Res Australia NeuRA, Sydney, NSW, Australia.
   [Cooper, Sandra T.] Childrens Med Res Inst, Westmead, NSW, Australia.
C3 NSW Health; The Children's Hospital at Westmead; University of Sydney;
   Sydney Childrens Hospitals Network; University of Sydney; University of
   Sydney; NSW Health; Royal Prince Alfred Hospital; University of Arizona;
   University of Arizona; NSW Health; The Children's Hospital at Westmead;
   Sydney Childrens Hospitals Network; University of Sydney; University of
   New South Wales Sydney; NSW Health; Sydney Childrens Hospitals Network;
   Neuroscience Research Australia; University of New South Wales Sydney;
   Children's Medical Research Institute - Australia
RP Yuen, M (corresponding author), Childrens Hosp Westmead, Kids Neurosci Ctr, Westmead, NSW, Australia.; Yuen, M (corresponding author), Univ Sydney, Sydney Med Sch, Discipline Child & Adolescent Hlth, Camperdown, NSW, Australia.
EM michaela.yuen@sydney.edu.au
RI Yuen, Michaela/AFU-7887-2022; Pappas, Christopher/AAS-3981-2021
OI Kirk, Edwin/0000-0002-4662-0024; Iwanski, Jessika/0000-0003-2482-5376;
   Yuen, Michaela/0000-0002-5007-4548; Pappas,
   Christopher/0000-0002-7475-6949
FU National Health and Medical Research Council (NHMRC) fellowships [MY
   APP1121651, STC APP1136197]; NHMRC [STC APP2002640]; Medical Research
   Future Fund (MRFF) Rapid Applied Research Translation Program grant;
   National Heart, Lung, And Blood Institute of the National Institutes of
   Health [F30HL151139, T32HL007249, R01HL123078]; Czarina and Humberto
   Lopez Endowed Chair; CAUL; National Heart Lung and Blood Institute
   [F30HL151139, R01HL123078] Funding Source: NIH RePORTER
FX This study was supported by National Health and Medical Research Council
   (NHMRC) fellowships (MY APP1121651; STC APP1136197), NHMRC Project Grant
   (STC APP2002640) and Medical Research Future Fund (MRFF) Rapid Applied
   Research Translation Program grant awarded to Sydney Health Partners (PI
   Cooper). This work was supported by the National Heart, Lung, And Blood
   Institute of the National Institutes of Health F30HL151139 and
   T32HL007249 to JI, and R01HL123078 to CCG and CTP as well as the Czarina
   and Humberto Lopez Endowed Chair. Open Access funding enabled and
   organized by CAUL and its Member Institutions.
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NR 22
TC 12
Z9 15
U1 0
U2 1
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 1018-4813
EI 1476-5438
J9 EUR J HUM GENET
JI Eur. J. Hum. Genet.
PD APR
PY 2022
VL 30
IS 4
BP 450
EP 457
DI 10.1038/s41431-022-01043-8
EA JAN 2022
PG 8
WC Biochemistry & Molecular Biology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Genetics & Heredity
GA 0I4BY
UT WOS:000748674400002
PM 35082396
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Pereira, AHM
   Cardoso, AC
   Consonni, SR
   Oliveira, RR
   Saito, A
   Vaggione, MLB
   Matos-Souza, JR
   Carazzolle, MF
   Gonçalves, A
   Fernandes, JL
   Ribeiro, GCA
   Lopes, MM
   Molkentin, JD
   Franchini, KG
AF Pereira, Ana Helena M.
   Cardoso, Alisson C.
   Consonni, Silvio R.
   Oliveira, Renata R.
   Saito, Angela
   Vaggione, Maria Luisa B.
   Matos-Souza, Jose R.
   Carazzolle, Marcelo F.
   Goncalves, Anderson
   Fernandes, Juliano L.
   Ribeiro, Gustavo C. A.
   Lopes, Mauricio M.
   Molkentin, Jeffery D.
   Franchini, Kleber G.
TI MEF2C repressor variant deregulation leads to cell cycle re-entry and
   development of heart failure
SO EBIOMEDICINE
LA English
DT Article
DE MEF2; Splicing; Heart failure; Dedifferentiation; Cell cycle re-entry;
   Cardiomyocyte; Sarcomere disassembly
ID TRANSCRIPTION FACTOR; NEONATAL CARDIOMYOCYTES; GENE-EXPRESSION; MUSCLE;
   MECHANISMS; 2C; DEDIFFERENTIATION; PHOSPHORYLATION; CARDIOMYOPATHY;
   THERAPIES
AB Background: A pathophysiological link exists between dysregulation of MEF2C transcription factors and heart failure (HF), but the underlying mechanisms remain elusive. Alternative splicing of MEF2C exons alpha, beta and and gamma provides transcript diversity with gene activation or repression functionalities.
   Methods: Neonatal and adult rat ventricular myocytes were used to overexpress MEF2C splicing variants gamma+ (repressor) or gamma-, or the inactive MEF2C gamma+23/24 (K23T/R24L). Phenotypic alterations in cardiomyocytes were determined by confocal and electron microscopy, flow cytometry and DNA microarray. We used transgenic mice with cardiac-specific overexpression of MEF2C gamma+ or MEF2C gamma-to explore the impact of MEF2C variants in cardiac phenotype. Samples of non-infarcted areas of the left ventricle from patients and mouse model of myocardial infarction were used to detect the expression of MEF2C gamma+ in failing hearts.
   Findings: We demonstrate a previously unrealized upregulation of the transrepressor MEF2C gamma+ isoform in human and mouse failing hearts. We show that adenovirus-mediated overexpression of MEF2C gamma+ downregulates multiple MEF2-target genes, and drives incomplete cell-cycle reentry, partial dedifferentiation and apoptosis in the neonatal and adult rat. None of these changes was observed in cardiomyocytes overexpressing MEF2C gamma-. Transgenic mice overexpressing MEF2C gamma+, but not the MEF2C gamma-, developed dilated cardiomyopathy, correlated to cell-cycle reentry and apoptosis of cardiomyocytes.
   Interpretation: Our results provide a mechanistic link between MEF2C gamma+ and deleterious abnormalities in cardiomyocytes, supporting the notion that splicing dysregulation in MEF2C towards the selection of the MEF2C gamma+ variant contributes to the pathogenesis of HF by promoting cardiomyocyte dropout. (C) 2019 The Authors. Published by Elsevier B.V.
C1 [Pereira, Ana Helena M.; Cardoso, Alisson C.; Oliveira, Renata R.; Saito, Angela; Vaggione, Maria Luisa B.; Goncalves, Anderson; Franchini, Kleber G.] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, BR-13083970 Campinas, SP, Brazil.
   [Consonni, Silvio R.] Univ Estadual Campinas, Dept Biochem & Tissue Biol, Campinas, Brazil.
   [Matos-Souza, Jose R.; Franchini, Kleber G.] Univ Estadual Campinas, Dept Internal Med, Campinas, Brazil.
   [Carazzolle, Marcelo F.] Univ Estadual Campinas, Genom & Express Lab, Campinas, Brazil.
   [Fernandes, Juliano L.] Jose Michel Kalaf Res Inst, Campinas, Brazil.
   [Ribeiro, Gustavo C. A.] Pontificia Univ Catolica Campinas, Cardiovasc Surg, Campinas, Brazil.
   [Lopes, Mauricio M.] Pontificia Univ Catolica Campinas, Cardiol, Campinas, Brazil.
   [Molkentin, Jeffery D.] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA.
C3 Universidade Estadual de Campinas; Universidade Estadual de Campinas;
   Universidade Estadual de Campinas; Pontificia Universidade Catolica de
   Campinas; Pontificia Universidade Catolica de Campinas; University
   System of Ohio; University of Cincinnati; Cincinnati Children's Hospital
   Medical Center
RP Franchini, KG (corresponding author), Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, BR-13083970 Campinas, SP, Brazil.
EM kleber.franchini@lnbio.cnpem.br
RI Ribeiro, Gustavo/KSM-5356-2024; Saito, Angela/AAY-9404-2020; Consonni,
   Sílvio/R-9281-2019; Carazzolle, Marcelo/C-6503-2012; Matos-Souza, Jose
   Roberto/JPL-1608-2023; de Oliveira, Renata/W-3115-2019
OI Cardoso, Alisson/0000-0002-3051-9976; Franchini,
   Kleber/0000-0002-0190-6635; Boldim Vaggione, Maria
   Luisa/0000-0002-9319-3475; Molkentin, Jeffery/0000-0002-3558-6529;
   Consonni, Silvio Roberto/0000-0003-3149-021X; Rocha de Oliveira,
   Renata/0000-0003-3092-838X; Saito, Angela/0000-0003-4421-9226; PEREIRA,
   ANA HELENA/0000-0001-7421-0877
FU Sao Paulo Research Foundation (FAPESP) [2008/53519-5, 2008/53583-5];
   Brazilian National Research Council (CNPq) [304366/2009-9,
   312203/2012-8, 310536/2014-6]
FX This work was funded by Sao Paulo Research Foundation (FAPESP; Grants
   2008/53519-5, 2008/53583-5) and Brazilian National Research Council
   (CNPq; Grants 304366/2009-9, 312203/2012-8 and 310536/2014-6). The
   funding agencies had no involvement in the design, performance, or
   analysis of the study.
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NR 39
TC 15
Z9 15
U1 0
U2 1
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 2352-3964
J9 EBIOMEDICINE
JI EBioMedicine
PD JAN
PY 2020
VL 51
AR 102571
DI 10.1016/j.ebiom.2019.11.032
PG 12
WC Medicine, General & Internal; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC General & Internal Medicine; Research & Experimental Medicine
GA KK7FV
UT WOS:000512904900015
PM 31911274
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Jia, KN
   Cheng, HM
   Ma, WQ
   Zhuang, LF
   Li, H
   Li, ZG
   Wang, ZY
   Sun, H
   Cui, YK
   Zhang, H
   Xie, HY
   Yi, L
   Chen, ZY
   Sano, M
   Fukuda, K
   Lu, L
   Pu, J
   Zhang, Y
   Gao, L
   Zhang, RY
   Yan, XX
AF Jia, Kangni
   Cheng, Haomai
   Ma, Wenqi
   Zhuang, Lingfang
   Li, Hao
   Li, Zhigang
   Wang, Ziyang
   Sun, Hang
   Cui, Yuke
   Zhang, Hang
   Xie, Hongyang
   Yi, Lei
   Chen, Zhiyong
   Sano, Motoaki
   Fukuda, Keiichi
   Lu, Lin
   Pu, Jun
   Zhang, Yan
   Gao, Ling
   Zhang, Ruiyan
   Yan, Xiaoxiang
TI RNA Helicase DDX5 Maintains Cardiac Function by Regulating
   CamkIIδ Alternative Splicing
SO CIRCULATION
LA English
DT Article
DE alternative splicing; calcium signaling; cardiomyocytes; heart failure;
   RNA helicases
ID MULTIPLE FUNCTIONS; HEART; CALCIUM; MECHANISMS; PROTEINS; P68;
   CARDIOMYOPATHY; HYPERTROPHY; ROLES; DEATH
AB BACKGROUND: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. RNA-binding proteins are identified as regulators of cardiac disease; DDX5 (dead-box helicase 5) is a master regulator of many RNA processes, although its function in heart physiology remains unclear. METHODS: We assessed DDX5 expression in human failing hearts and a mouse HF model. To study the function of DDX5 in heart, we engineered cardiomyocyte-specific Ddx5 knockout mice. We overexpressed DDX5 in cardiomyocytes using adeno-associated virus serotype 9 and performed transverse aortic constriction to establish the murine HF model. The mechanisms underlined were subsequently investigated using immunoprecipitation-mass spectrometry, RNA-sequencing, alternative splicing analysis, and RNA immunoprecipitation sequencing. RESULTS: We screened transcriptome databases of murine HF and human dilated cardiomyopathy samples and found that DDX5 was significantly downregulated in both. Cardiomyocyte-specific deletion of Ddx5 resulted in HF with reduced cardiac function, an enlarged heart chamber, and increased fibrosis in mice. DDX5 overexpression improved cardiac function and protected against adverse cardiac remodeling in mice with transverse aortic constriction-induced HF. Furthermore, proteomics revealed that DDX5 is involved in RNA splicing in cardiomyocytes. We found that DDX5 regulated the aberrant splicing of Ca2+/calmodulin-dependent protein kinase II delta (CamkII delta), thus preventing the production of CaMKII delta A, which phosphorylates L-type calcium channel by serine residues of Cacna1c, leading to impaired Ca2+ homeostasis. In line with this, we found increased intracellular Ca2+ transients and increased sarcoplasmic reticulum Ca2+ content in DDX5-depleted cardiomyocytes. Using adeno-associated virus serotype 9 knockdown of CaMKII delta A partially rescued the cardiac dysfunction and HF in Ddx5 knockout mice. CONCLUSIONS: These findings reveal a role for DDX5 in maintaining calcium homeostasis and cardiac function by regulating alternative splicing in cardiomyocytes, identifying the DDX5 as a potential target for therapeutic intervention in HF.
C1 [Jia, Kangni; Cheng, Haomai; Ma, Wenqi; Zhuang, Lingfang; Li, Zhigang; Wang, Ziyang; Sun, Hang; Xie, Hongyang; Yi, Lei; Chen, Zhiyong; Lu, Lin; Zhang, Ruiyan; Yan, Xiaoxiang] Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Cardiovasc Med, Sch Med, 197 Ruijin 2nd Rd, Shanghai 200025, Peoples R China.
   [Li, Hao; Gao, Ling] Tongji Univ, Sch Med, Shanghai East Hosp, Translat Med Ctr Stem Cell Therapy, 1800 Yuntai Rd, Shanghai 200123, Peoples R China.
   [Li, Hao; Gao, Ling] Tongji Univ, Shanghai East Hosp, Inst Regenerat Med, Sch Med, 1800 Yuntai Rd, Shanghai 200123, Peoples R China.
   [Jia, Kangni; Cheng, Haomai; Ma, Wenqi; Zhuang, Lingfang; Li, Zhigang; Wang, Ziyang; Sun, Hang; Cui, Yuke; Zhang, Hang; Xie, Hongyang; Yi, Lei; Chen, Zhiyong; Zhang, Ruiyan] Shanghai Jiao Tong Univ, Inst Cardiovascular Dis, Sch Med, Shanghai, Peoples R China.
   [Pu, Jun] Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Cardiol,State Key Lab Syst Med Canc,Shanghai, Shanghai, Peoples R China.
   [Sano, Motoaki; Fukuda, Keiichi] Keio Univ, Sch Med, Dept Cardiol, Tokyo, Japan.
   [Zhang, Yan] Peking Univ, Inst Mol Med, State Key Lab Membrane Biol, Beijing, Peoples R China.
C3 Shanghai Jiao Tong University; Tongji University; Tongji University;
   Shanghai Jiao Tong University; Shanghai Jiao Tong University; Keio
   University; Peking University
RP Zhang, RY; Yan, XX (corresponding author), Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Cardiovasc Med, Sch Med, 197 Ruijin 2nd Rd, Shanghai 200025, Peoples R China.; Gao, L (corresponding author), Tongji Univ, Sch Med, Shanghai East Hosp, Translat Med Ctr Stem Cell Therapy, 1800 Yuntai Rd, Shanghai 200123, Peoples R China.; Gao, L (corresponding author), Tongji Univ, Shanghai East Hosp, Inst Regenerat Med, Sch Med, 1800 Yuntai Rd, Shanghai 200123, Peoples R China.
EM lingfangzhuang@163.com; happylag5@163.com; happylag5@163.com;
   wangziyang127@foxmail.com; 182026596@qq.com; cyk64coco@gmail.com;
   398135390@qq.com; yilei1996@126.com; 490489218@qq.com; msano@a8.keio.jp;
   kfukuda@a2.keio.jp; rjlulin1965@163.com; pujun310@hotmail.com;
   gaoleng5@126.com; zhangruiyan@263.net; cardexyanxx@hotmail.com
RI Cui, Yuke/AEP-2733-2022; Gao, Ling/KHV-2583-2024; Zhang,
   Ruiyan/HHC-5329-2022; Jia, Kangni/HCH-0443-2022; Yi, Lei/AAI-6290-2020;
   zhuang, lingfang/JAC-4440-2023; Chen, Zhiyong/LRD-1561-2024
FU National Natural Science Foundation of China [82070510, 82370239,
   82325005, 82120108003, 82270261, 82070260]; Shanghai Municipal Education
   Commission-Gaofeng Clinical Medicine Grant; Shanghai Education
   Development Foundation; Shanghai Municipal Education Commission
   [20SG15]; Program of Shanghai Academic/Technology Research Leader
   [21XD1422500]; Peak Disciplines (Type IV) of Institutions of Higher
   Learning in Shanghai
FX This study was supported by the National Natural Science Foundation of
   China (No. 82070510 and No. 82370239 to Dr Zhang; No. 82325005 and No.
   82120108003 to Dr Yan; No. 82270261 and No. 82070260 to Dr Gao), a
   Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant,
   the "Shuguang Program" supported by the Shanghai Education Development
   Foundation and Shanghai Municipal Education Commission (No. 20SG15 to Dr
   Yan) and Program of Shanghai Academic/Technology Research Leader (No.
   21XD1422500), and the Peak Disciplines (Type IV) of Institutions of
   Higher Learning in Shanghai (to Dr Gao).
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NR 51
TC 1
Z9 1
U1 25
U2 39
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7322
EI 1524-4539
J9 CIRCULATION
JI Circulation
PD OCT 1
PY 2024
VL 150
IS 14
BP 1121
EP 1139
DI 10.1161/CIRCULATIONAHA.123.064774
PG 19
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA H9W7Q
UT WOS:001326871200003
PM 39056171
DA 2025-04-10
ER

PT J
AU Holzem, KM
   Efimov, IR
AF Holzem, Katherine M.
   Efimov, Igor R.
TI Arrhythmogenic remodelling of activation and repolarization in the
   failing human heart
SO EUROPACE
LA English
DT Article
DE Heart failure; Remodelling; Arrhythmias; Human heart; Conduction;
   Repolarization; Ion channels; Action potential
ID HUMAN VENTRICULAR MYOCYTES; OUTWARD POTASSIUM CURRENT; CURRENT
   DOWN-REGULATION; SODIUM CURRENT; CARDIAC REPOLARIZATION; NA+-CA2+
   EXCHANGER; HUMAN MYOCARDIUM; CURRENT-DENSITY; CELLULAR BASIS;
   UP-REGULATION
AB Heart failure is a major cause of disability and death worldwide, and approximately half of heart failure-related deaths are sudden and presumably due to ventricular arrhythmias. Patients with heart failure have been shown to be at 6- to 9-fold increased risk of sudden cardiac death compared to the general population. (AHA. Heart Disease and Stroke Statistics-2003 Update. Heart and Stroke Facts. Dallas, TX: American Heart Association; 2002) Thus, electrophysiological remodelling associated with heart failure is a leading cause of disease mortality and has been a major investigational focus examined using many animal models of heart failure. While these studies have provided an important foundation for understanding the arrhythmogenic pathophysiology of heart failure, the need for corroborating studies conducted on human heart tissue has been increasingly recognized. Many human heart studies of conduction and repolarization remodelling have now been published and shed some light on important, potentially arrhythmogenic, changes in human heart failure. These studies are being conducted at multiple experimental scales from isolated cells to whole-tissue preparations and have provided insight into regulatory mechanisms such as decreased protein expression, alternative mRNA splicing of ion channel genes, and defective cellular trafficking. Further investigations of heart failure in the human myocardium will be essential for determining possible therapeutic targets to prevent arrhythmia in heart failure and for facilitating the translation of basic research findings to the clinical realm.
C1 [Holzem, Katherine M.; Efimov, Igor R.] Washington Univ, Dept Biomed Engn, St Louis, MO 63130 USA.
C3 Washington University (WUSTL)
RP Efimov, IR (corresponding author), Washington Univ, Dept Biomed Engn, 390E Whitaker Hall,1 Brookings Dr, St Louis, MO 63130 USA.
EM igor@wustl.edu
RI Efimov, Igor/IUQ-0500-2023; Holzem, Katherine/C-2060-2014; Efimov,
   Igor/B-8040-2010
OI Efimov, Igor/0000-0002-1483-5039
FU NHLBI NIH HHS [R01 HL114395] Funding Source: Medline
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NR 75
TC 15
Z9 17
U1 0
U2 7
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 1099-5129
J9 EUROPACE
JI Europace
PD NOV
PY 2012
VL 14
SU 5
BP V50
EP V57
DI 10.1093/europace/eus275
PG 8
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 031KA
UT WOS:000310636800008
PM 23104915
OA Bronze, Green Published
DA 2025-04-10
ER

PT J
AU Yao, J
   Qin, XT
   Zhu, JH
   Sheng, HZ
AF Yao, Jian
   Qin, Xiaotong
   Zhu, Jianhua
   Sheng, Hongzhuan
TI Dyrk1A-ASF-CaMKIIδ Signaling Is Involved in Valsartan Inhibition of
   Cardiac Hypertrophy in Renovascular Hypertensive Rats
SO CARDIOLOGY
LA English
DT Article
DE Valsartan; Cardiac hypertrophy; Renovascular hypertension;
   Ca2+/calmodulin-dependent protein kinase II delta; Dual-specificity
   tyrosine phosphorylation-regulated kinase 1A; Alternative splicing
   factor
ID RENIN-ANGIOTENSIN SYSTEM; LEFT-VENTRICULAR HYPERTROPHY; CAM KINASE-II;
   HEART-FAILURE; PROTEIN-KINASE; DILATED CARDIOMYOPATHY;
   PRESSURE-OVERLOAD; INCREASED DOSAGE; DOWN-SYNDROME; DYRK1A
AB Objectives: It is known that the expression, activity and alternative splicing of Ca2+/calmodulin-dependent protein kinase II delta (CaMKII delta) are dysregulated in the cardiac remodeling process. Recently, we found a further signaling pathway, by which dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) regulates the alternative splicing of CaMKII delta via the alternative splicing factor (ASF), i.e. Dyrk1A-ASF-CaMKII delta. In this study, we aimed to investigate whether Dyrk1A-ASF-CaMKII delta signaling was involved in valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats. Methods: Rats were subjected to two kidney-one clip (2K1C) surgery and then treated with valsartan (30 mg/kg/day) for 8 weeks. Hypertrophic parameter analysis was then performed. Western blot analysis was used to determine the protein expression of Dyrk1A and ASF and RT-PCR was used to analyze the alternative splicing of CaMKII delta in the left ventricular (LV) sample. Results: Valsartan attenuated cardiac hypertrophy in 2K1C rats but without impairment of cardiac systolic function. Increased protein expression of Dyrk1A and decreased protein expression of ASF were observed in the LV sample of 2K1C rats. Treatment of 2K1C rats with valsartan reversed the changes in Dyrk1A and ASF expression in the LV sample. Valsartan adjusted the 2K1C-induced imbalance in alternative splicing of CaMKII delta by upregulating the mRNA expression of CaMKII delta C and downregulating the mRNA expression of CaMKII delta A and CaMKII delta B. Conclusions: Valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats was mediated, at least partly, by Dyrk1A-ASF-CaMKII delta signaling. (C) 2015 S. Karger AG, Basel
C1 [Qin, Xiaotong; Zhu, Jianhua; Sheng, Hongzhuan] Nantong Univ, Affiliated Hosp, Dept Cardiol, Nantong, Jiangsu, Peoples R China.
   [Yao, Jian] Nantong Univ, Sch Med, Dept Histol & Embryol, Nantong, Peoples R China.
C3 Nantong University; Nantong University
RP Sheng, HZ (corresponding author), Nantong Univ, Affiliated Hosp, Dept Cardiol, Nantong, Jiangsu, Peoples R China.
EM yjshz@ntu.edu.cn
FU National Natural Science Foundation of China [30971223, 30971224]; 333
   talent project from Jiangsu Province, China [BRA2012213];  [WS-054]
FX The authors gratefully thank Dr. Fei Liu for offering mouse anti-rat
   Dyrk1A antibody and excellent technical assistance. This study was
   supported by grants from the National Natural Science Foundation of
   China (30971223 and 30971224) and funding for the top talent project
   (grant No. WS-054) and the 333 talent project from Jiangsu Province
   (grant No. BRA2012213), China.
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NR 34
TC 7
Z9 7
U1 1
U2 8
PU KARGER
PI BASEL
PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND
SN 0008-6312
EI 1421-9751
J9 CARDIOLOGY
JI Cardiology
PY 2016
VL 133
IS 3
BP 198
EP 204
DI 10.1159/000441695
PG 7
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA DE2OI
UT WOS:000370466200011
PM 26619200
DA 2025-04-10
ER

PT J
AU Gao, G
   Xie, A
   Zhang, JH
   Herman, AM
   Jeong, EM
   Gu, LZ
   Liu, M
   Yang, KC
   Kamp, TJ
   Dudley, SC
AF Gao, Ge
   Xie, An
   Zhang, Jianhua
   Herman, Amanda M.
   Jeong, Euy-Myoung
   Gu, Lianzhi
   Liu, Man
   Yang, Kai-Chien
   Kamp, Timothy J.
   Dudley, Samuel C.
TI Unfolded Protein Response Regulates Cardiac Sodium Current in Systolic
   Human Heart Failure
SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY
LA English
DT Article
DE heart failure; humans; PERK kinase; sodium channels
ID ENDOPLASMIC-RETICULUM STRESS; BRUGADA SYNDROME; ANGIOTENSIN-II;
   EXPRESSION; HYPOXIA; CELLS; ACTIVATION; MECHANISM; PATHWAY; RATS
AB Background Human heart failure (HF) increases alternative mRNA splicing of the type V, voltage-gated cardiac Na+ channel -subunit (SCN5A), generating variants encoding truncated, nonfunctional channels that are trapped in the endoplasmic reticulum. In this work, we tested whether truncated Na+ channels activate the unfolded protein response (UPR), contributing to SCN5A electric remodeling in HF.
   Methods and Results UPR and SCN5A were analyzed in human ventricular systolic HF tissue samples and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Cells were exposed to angiotensin II (AngII) and hypoxia, known activators of abnormal SCN5A mRNA splicing, or were induced to overexpress SCN5A variants. UPR effectors, protein kinase R-like ER kinase (PERK), calreticulin, and CHOP, were increased in human HF tissues. Induction of SCN5A variants with AngII or hypoxia or the expression of exogenous variants induced the UPR with concomitant downregulation of Na+ current. PERK activation destabilized SCN5A and, surprisingly, K(v)4.3 channel mRNAs but not transient receptor potential cation channel M7 (TRPM7) channel mRNA. PERK inhibition prevented the loss of full-length SCN5A and K(v)4.3 mRNA levels resulting from expressing Na+ channel mRNA splice variants.
   Conclusions UPR can be initiated by Na+ channel mRNA splice variants and is involved in the reduction of cardiac Na+ current during human HF. Because the effect is not entirely specific to the SCN5A transcript, the UPR may play an important role in downregulation of multiple cardiac genes in HF.
C1 [Gao, Ge; Xie, An; Jeong, Euy-Myoung; Gu, Lianzhi; Liu, Man; Yang, Kai-Chien; Dudley, Samuel C.] Brown Univ, Lifespan Cardiovasc Inst, Warren Alpert Sch Med, Providence, RI 02903 USA.
   [Gao, Ge; Xie, An; Jeong, Euy-Myoung; Gu, Lianzhi; Liu, Man; Yang, Kai-Chien; Dudley, Samuel C.] Providence Vet Adm Med Ctr, Providence, RI USA.
   [Zhang, Jianhua; Herman, Amanda M.; Kamp, Timothy J.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Div Cardiovasc Med, Madison, WI USA.
C3 Lifespan Health Rhode Island; Brown University; US Department of
   Veterans Affairs; Veterans Health Administration (VHA); Providence VA
   Medical Center; University of Wisconsin System; University of Wisconsin
   Madison
RP Dudley, SC (corresponding author), Brown Univ, Ruth & Paul Levinger Chair Med, Warren Alpert Med Sch, Lifespan Cardiovasc Inst, 593 Eddy St,APC 730, Providence, RI 02903 USA.
EM samuel_dudley@brown.edu
RI Dudley, Samuel/A-7085-2009; Kamp, Timothy/ABD-1343-2020; Yang,
   Kai-Chien/AAO-6991-2021; Liu, Man/GXH-3184-2022
OI Yang, Kai-Chien/0000-0002-9128-9166; Dudley, Samuel/0000-0001-5843-5961;
   Liu, Man/0000-0002-1390-7862; Kamp, Timothy J/0000-0003-2103-7876
FU National Institutes of Health [P01 HL058000, R01 HL1024025, R01
   HL106592, R41 HL112355, R01 HL078878, U01HL099773]
FX This work was supported by the National Institutes of Health grants P01
   HL058000 (Dr Dudley), R01 HL1024025 (Dr Dudley), R01 HL106592 (Dr
   Dudley), Veterans Administration Merit Award (Dr Dudley), R41 HL112355
   (Dr Dudley), R01 HL078878 (Dr Kamp), and U01HL099773 (Dr Kamp).
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NR 33
TC 55
Z9 61
U1 1
U2 13
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 1941-3149
EI 1941-3084
J9 CIRC-ARRHYTHMIA ELEC
JI Circ.-Arrhythmia Electrophysiol.
PD OCT
PY 2013
VL 6
IS 5
BP 1018
EP 1024
DI 10.1161/CIRCEP.113.000274
PG 7
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 292SW
UT WOS:000329923700034
PM 24036084
OA Green Accepted, Bronze
DA 2025-04-10
ER

PT J
AU D'Antonio, M
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AF D'Antonio, Matteo
   Nguyen, Jennifer P.
   Arthur, Timothy D.
   Matsui, Hiroko
   Donovan, Margaret K. R.
   D'Antonio-Chronowska, Agnieszka
   Frazer, Kelly A.
TI In heart failure reactivation of RNA-binding proteins is associated with
   the expression of 1,523 fetal-specific isoforms
SO PLOS COMPUTATIONAL BIOLOGY
LA English
DT Article
ID CELL-DERIVED CARDIOMYOCYTES; CARDIAC TROPONIN-T; GENE-EXPRESSION;
   TUMOR-GROWTH; STEM; TITIN; INSIGHTS; MOUSE; SCN5A; HUR
AB Reactivation of fetal-specific genes and isoforms occurs during heart failure. However, the underlying molecular mechanisms and the extent to which the fetal program switch occurs remains unclear. Limitations hindering transcriptome-wide analyses of alternative splicing differences (i.e. isoform switching) in cardiovascular system (CVS) tissues between fetal, healthy adult and heart failure have included both cellular heterogeneity across bulk RNA-seq samples and limited availability of fetal tissue for research. To overcome these limitations, we have deconvoluted the cellular compositions of 996 RNA-seq samples representing heart failure, healthy adult (heart and arteria), and fetal-like (iPSC-derived cardiovascular progenitor cells) CVS tissues. Comparison of the expression profiles revealed that reactivation of fetal-specific RBPs, and the accompanied re-expression of 1,523 fetal-specific isoforms, contribute to the transcriptome differences between heart failure and healthy adult heart. Of note, isoforms for 20 different RBPs were among those that reverted in heart failure to the fetal-like expression pattern. We determined that, compared with adult-specific isoforms, fetal-specific isoforms encode proteins that tend to have more functions, are more likely to harbor RBP binding sites, have canonical sequences at their splice sites, and contain typical upstream polypyrimidine tracts. Our study suggests that compared with healthy adult, fetal cardiac tissue requires stricter transcriptional regulation, and that during heart failure reversion to this stricter transcriptional regulation occurs. Furthermore, we provide a resource of cardiac developmental stage-specific and heart failure-associated genes and isoforms, which are largely unexplored and can be exploited to investigate novel therapeutics for heart failure.
C1 [D'Antonio, Matteo; D'Antonio-Chronowska, Agnieszka; Frazer, Kelly A.] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA.
   [Nguyen, Jennifer P.; Donovan, Margaret K. R.] Univ Calif San Diego, Bioinformat & Syst Biol Grad Program, La Jolla, CA 92093 USA.
   [Nguyen, Jennifer P.; Arthur, Timothy D.; Donovan, Margaret K. R.] Univ Calif San Diego, Dept Biomed Informat, La Jolla, CA 92093 USA.
   [Arthur, Timothy D.] Univ Calif San Diego, Biomed Sci Grad Program, San Diego, CA 92103 USA.
   [Matsui, Hiroko; Frazer, Kelly A.] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA.
C3 University of California System; University of California San Diego;
   University of California System; University of California San Diego;
   University of California System; University of California San Diego;
   University of California System; University of California San Diego;
   University of California System; University of California San Diego
RP Frazer, KA (corresponding author), Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA.; Frazer, KA (corresponding author), Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92093 USA.
EM kafrazer@health.ucsd.edu
RI D'Antonio, Matteo/H-5245-2019
OI D'Antonio, Matteo/0000-0001-5844-6433; Donovan,
   Margaret/0000-0001-5240-4216; Frazer, Kelly/0000-0002-6060-8902;
   D'Antonio-Chronowska, Agnieszka/0000-0003-1653-4106; Arthur,
   Timothy/0000-0002-3393-1691
FU California Institute for Regenerative Medicine [GC1R-06673-B]; National
   Science Foundation - Civil, Mechanical and Manufacturing Innovation
   division award [1728497]; NIH [F31HL158198, HG008118, HL107442];
   National Library of Medicine [T15LM011271]; National Heart Lung and
   Blood Institute [F31HL158198] Funding Source: NIH RePORTER; National
   Human Genome Research Institute [RM1HG011558] Funding Source: NIH
   RePORTER
FX This work was supported by a California Institute for Regenerative
   Medicine grant GC1R-06673-B, National Science Foundation -Civil,
   Mechanical and Manufacturing Innovation division award 1728497, and NIH
   grants HG008118 and HL107442 awarded to KAF. JPN, MKRD and TDA were
   supported in part by National Library of Medicine grant T15LM011271. TDA
   was supported in part by NIH grant F31HL158198. The funders had no role
   in study design, data collection and analysis, decision to publish, or
   preparation of the manuscript.
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NR 104
TC 23
Z9 23
U1 0
U2 1
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1553-734X
EI 1553-7358
J9 PLOS COMPUT BIOL
JI PLoS Comput. Biol.
PD FEB
PY 2022
VL 18
IS 2
AR e1009918
DI 10.1371/journal.pcbi.1009918
PG 41
WC Biochemical Research Methods; Mathematical & Computational Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Mathematical & Computational Biology
GA O5IC7
UT WOS:001044135600003
PM 35226669
OA Green Published, gold, Green Submitted
DA 2025-04-10
ER

PT J
AU Stoilov, P
   Lin, CH
   Damoiseaux, R
   Nikolic, J
   Black, DL
AF Stoilov, Peter
   Lin, Chia-Ho
   Damoiseaux, Robert
   Nikolic, Julia
   Black, Douglas L.
TI A high-throughout screening strategy identifies cardiotonic steroids as
   alternative splicing modulators
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
   AMERICA
LA English
DT Article
DE digoxin; fluorescent reporter; plant steroids; MAPT; FTDP-17
ID SPINAL MUSCULAR-ATROPHY; TAU EXON-10; CARDIAC-GLYCOSIDES; MESSENGER-RNA;
   EXPRESSION; REPORTER; TAU-EXON-10; PATHWAYS; SIGNALS; ROLES
AB Alternative splicing has emerged as a promising therapeutic target in a number of human disorders. However, the discovery of compounds that target the splicing reaction has been hindered by the lack of suitable high-throughput screening assays. Conversely, the effects of known drugs on the splicing reaction are mostly unclear and not routinely assessed. We have developed a two-color fluorescent reporter for cellular assays of exon inclusion that can accommodate nearly any cassette exon and minimizes interfering effects from changes in transcription and translation. We used microtubule-associated protein tau (MAPT) exon 10, whose missplicing causes frontotemporal dementia, to test the reporter in screening libraries of known bioactive compounds. These screens yielded several compounds that alter the splicing of the exon, both in the reporter and in the endogenous MAPT mRNA. One compound, digoxin, has long been used in the treatment of heart failure, but was not known to modulate splicing. The positive compounds target different signal transduction pathways, and microarray analysis shows that each compound affects the splicing of a different set of exons in addition to MAPT exon 10. Our results identify currently prescribed cardiotonic steroids as modulators of alternative splicing and demonstrate the feasibility of screening for drugs that alter exon inclusion.
C1 [Stoilov, Peter; Lin, Chia-Ho; Nikolic, Julia; Black, Douglas L.] Univ Calif Los Angeles, Dept Microbiol Mol Genet & Immunol, Los Angeles, CA 90095 USA.
   [Nikolic, Julia; Black, Douglas L.] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA.
C3 University of California System; University of California Los Angeles;
   University of California System; University of California Los Angeles;
   Howard Hughes Medical Institute
RP Black, DL (corresponding author), Univ Calif Los Angeles, Dept Microbiol Mol Genet & Immunol, 5-748 MacDonald Res Labs,675 Charles E Young Dr S, Los Angeles, CA 90095 USA.
EM dougb@microbio.ucla.edu
RI Damoiseaux, Robert/F-1086-2011
FU National Institutes of Health [RO1 GM49662, R24 GM070857]; Muscular
   Dystrophy Association Development [MDA4260]
FX We thank Stefan Stamm, Tom Cooper, Tim Nilsen, and our anonymous
   reviewers for helpful comments on the manuscript; Drs. Lily Shiue
   (University of California, Santa Cruz) and Manuel Ares, Jr. (University
   of California, Santa Cruz), for providing the human splicing
   microarrays; Dr. Roger Tsien (Howard Hughes Medical Institute,
   University of California at San Diego, La Jolla) for the pRSET-B m
   Strawberry clone; and James Weiss (University of California, Los
   Angeles) for information on Digoxin. This work was supported in part by
   National Institutes of Health Grants RO1 GM49662 and R24 GM070857 (to
   D.L.B.) and Muscular Dystrophy Association Development Grant MDA4260 (to
   P.S.). D.L.B. is an investigator of the Howard Hughes Medical Institute.
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NR 30
TC 113
Z9 142
U1 1
U2 16
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD AUG 12
PY 2008
VL 105
IS 32
BP 11218
EP 11223
DI 10.1073/pnas.0801661105
PG 6
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 339EK
UT WOS:000258560700035
PM 18678901
OA Green Published
DA 2025-04-10
ER

PT J
AU Wan, XX
   Belanger, K
   Widen, SG
   Kuyurncu-Martinez, MN
   Garg, NJ
AF Wan, Xianxiu
   Belanger, KarryAnne
   Widen, Steven G.
   Kuyurncu-Martinez, Muge N.
   Garg, Nisha J.
TI Genes of the cGMP-PKG-Ca<SUP>2+</SUP> signaling pathway are
   alternatively spliced in cardiomyopathy: Role of RBFOX2
SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
LA English
DT Article
DE Cardiomyopathy; Alternative splicing; RNA-binding protein RBFOX2;
   Protein kinase G; Calcium homeostasis; Chagas; Diabetes
ID TRYPANOSOMA-CRUZI; CHAGAS-DISEASE; ADIPOSE-TISSUE; DIABETIC
   CARDIOMYOPATHY; HEART-FAILURE; EXPRESSION; PATHOGENESIS; REGULATOR;
   INFECTION; PROTEINS
AB Aberrations in the cGMP-PKG-Ca(2+)pathway are implicated in cardiovascular complications of diverse etiologies, though involved molecular mechanisms are not understood. We performed RNA-Seq analysis to profile global changes in gene expression and exon splicing in Chagas disease (ChD) murine myocardium. IngenuityPathway-Analysis of transcriptome dataset identified 26 differentially expressed genes associated with increased mobilization and cellular levels of Ca2+ in ChD hearts. Mixture-of-isoforms and Enrichr KEGG pathway analyses of the RNA-Seq datasets from ChD (this study) and diabetic (previous study) murine hearts identified alternative splicing (AS) in eleven genes (Arligef10, Atp2b1, Atp2a3, Cacna1, Itpr1, Mef2a, Mef2d, Pde2a, Plcb1, Plcb4, and Ppp1r12a) of the cGMP-PKG-Ca2+ pathway in diseased hearts. AS of these genes was validated by an exon exclusion-inclusion assay. Further, Arhgef10, Atp2b1, Mef2a, Mef2d, Plcb1, and Ppp1r12a genes consisted RBFOX2 (RNA-binding protein) binding-site clusters, determined by analyzing the RBFOX2 CLIP-Seq dataset. H9c2 rat heart cells transfected with Rbfox2 (vs. scrambled) siRNA confirmed that expression of Rbfox2 is essential for proper exon splicing of genes of the cGMP-PKG-Ca2+ pathway. We conclude that changes in gene expression may influence the Ca2+ mobilization pathway in ChD, and AS impacts the genes involved in cGMP/PKG/Ca2+ signaling pathway in ChD and diabetes. Our findings suggest that ChD patients with diabetes may be at increased risk of cardiomyopathy and heart failure and provide novel ways to restore cGMP-PKG regulated signaling networks via correcting splicing patterns of key factors using oligonucleotide-based therapies for the treatment of cardiovascular complications.
C1 [Wan, Xianxiu; Garg, Nisha J.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA.
   [Belanger, KarryAnne; Widen, Steven G.; Kuyurncu-Martinez, Muge N.] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA.
   [Garg, Nisha J.] Univ Texas Med Branch, Inst Human Infect & Immun, Galveston, TX 77555 USA.
C3 University of Texas System; University of Texas Medical Branch
   Galveston; University of Texas System; University of Texas Medical
   Branch Galveston; University of Texas System; University of Texas
   Medical Branch Galveston
RP Garg, NJ (corresponding author), Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA.; Kuyurncu-Martinez, MN (corresponding author), Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA.
EM nmmartin@utmb.edu; nigarg@utmb.edu
FU National Institutes of Health, National Institute of Allergy and
   Infectious Diseases [R01 AI054578, R01 AI136031]; National Heart Lung
   Blood Institute [1R01HL135031]; Jeane B Kempner Postdoctoral Fellowship,
   UTMB
FX This work was supported, in part, by grants from of the National
   Institutes of Health, National Institute of Allergy and Infectious
   Diseases (R01 AI054578; R01 AI136031) to NJG and National Heart Lung
   Blood Institute (1R01HL135031) to MKM. XW was the recipient of Jeane B
   Kempner Postdoctoral Fellowship, UTMB. We are thankful to Dr. Sunil
   Verma and Dr. Jun Cao for help in designing the primers for
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NR 77
TC 13
Z9 15
U1 0
U2 21
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29a, 1043 NX AMSTERDAM, NETHERLANDS
SN 0925-4439
EI 1879-260X
J9 BBA-MOL BASIS DIS
JI Biochim. Biophys. Acta-Mol. Basis Dis.
PD MAR 1
PY 2020
VL 1866
IS 3
AR 165620
DI 10.1016/j.bbadis.2019.165620
PG 14
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA KH2UY
UT WOS:000510504400025
PM 31778749
OA Bronze, Green Accepted
DA 2025-04-10
ER

PT J
AU Gregorich, ZR
   Zhang, YH
   Kamp, TJ
   Granzier, HL
   Guo, W
AF Gregorich, Zachery R.
   Zhang, Yanghai
   Kamp, Timothy J.
   Granzier, Henk L.
   Guo, Wei
TI Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems
SO CIRCULATION-GENOMIC AND PRECISION MEDICINE
LA English
DT Review
DE alternative splicing; biomolecular condensates; cardiomyopathy, dilated;
   heart failure; induced pluripotent stem cell
ID FAMILIAL DILATED CARDIOMYOPATHY; GENOTYPE-PHENOTYPE CORRELATIONS;
   PROTEIN-PROTEIN INTERACTIONS; GENETIC-DETERMINANTS; CLINICAL GENETICS;
   SPLICING FACTORS; NUCLEAR IMPORT; HEART-FAILURE; EARLY-ONSET; TITIN
AB RBM20 (RNA-binding motif protein 20) is a vertebrate- and muscle-specific RNA-binding protein that belongs to the serine-arginine-rich family of splicing factors. The RBM20 gene was first identified as a dilated cardiomyopathy-linked gene over a decade ago. Early studies in Rbm20 knockout rodents implicated disrupted splicing of RBM20 target genes as a causative mechanism. Clinical studies show that pathogenic variants in RBM20 are linked to aggressive dilated cardiomyopathy with early onset heart failure and high mortality. Subsequent studies employing pathogenic variant knock-in animal models revealed that variants in a specific portion of the arginine-serine-rich domain in RBM20 not only disrupt splicing but also hinder nucleocytoplasmic transport and lead to the formation of RBM20 biomolecular condensates in the sarcoplasm. Conversely, mice harboring a disease-associated variant in the RRM (RNA recognition motif) do not show evidence of adverse remodeling or exhibit sudden death despite disrupted splicing of RBM20 target genes. Thus, whether disrupted splicing, biomolecular condensates, or both contribute to dilated cardiomyopathy is under debate. Beyond this, additional questions remain, such as whether there is sexual dimorphism in the presentation of RBM20 cardiomyopathy. What are the clinical features of RBM20 cardiomyopathy and why do some individuals develop more severe disease than others? In this review, we summarize the reported observations and discuss potential mechanisms of RBM20 cardiomyopathy derived from studies employing in vivo animal models and in vitro human-induced pluripotent stem cell-derived cardiomyocytes. Potential therapeutic strategies to treat RBM20 cardiomyopathy are also discussed.
C1 [Gregorich, Zachery R.; Zhang, Yanghai; Guo, Wei] Univ Wisconsin, Dept Anim & Dairy Sci, Madison, WI 53706 USA.
   [Kamp, Timothy J.] Univ Wisconsin, Cellular & Mol Arrhythmia Res Program, Madison, WI 53706 USA.
   [Kamp, Timothy J.] Univ Wisconsin, Dept Med, Madison, WI 53706 USA.
   [Kamp, Timothy J.; Guo, Wei] Univ Wisconsin, Cardiovasc Res Ctr, Madison, WI 53706 USA.
   [Granzier, Henk L.] Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ USA.
   [Guo, Wei] Univ Wisconsin, Cardiovasc Res Ctr, Dept Anim & Dairy Sci, 1933 Observ Dr, Madison, WI 53706 USA.
C3 University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison;
   University of Arizona; University of Wisconsin System; University of
   Wisconsin Madison
RP Guo, W (corresponding author), Univ Wisconsin, Cardiovasc Res Ctr, Dept Anim & Dairy Sci, 1933 Observ Dr, Madison, WI 53706 USA.
EM zhang2485@wisc.edu; tjk@medicine.wisc.edu; granzier@arizona.edu;
   wguo2@wisc.edu
RI Guo, Wei/KJM-4941-2024; Kamp, Timothy/ABD-1343-2020
OI ZHANG, YANGHAI/0009-0003-5307-6148; Kamp, Timothy J/0000-0003-2103-7876;
   Granzier, Henk/0000-0002-9516-407X; guo, wei/0000-0002-9158-8107
FU National Institute of Health (NIH) National Heart Lung and Blood
   Institute [HL148733]; American Heart Association Foundation
   [19TPA3480072]; Wisconsin Alumni Research Foundation [AAH4884];
   University of Wisconsin Foundation [AAH5964]; United States Department
   of Agriculture-National Institute of Food and Agriculture Hatch
   [AAI4642]; NIH [U01 HL148690, U01 HL134764, R35HL144998]; National
   Science Foundation [EEC-1648035]
FX This work was supported by the National Institute of Health (NIH)
   National Heart Lung and Blood Institute grant HL148733, the American
   Heart Association Foundation grant 19TPA3480072, the Wisconsin Alumni
   Research Foundation grant AAH4884, the University of Wisconsin
   Foundation grant AAH5964, and the United States Department of
   Agriculture-National Institute of Food and Agriculture Hatch grant
   AAI4642 to Dr Guo. This work was also supported by NIH grants U01
   HL148690 and U01 HL134764 and National Science Foundation grant
   EEC-1648035 to Dr Kamp and NIH grant R35HL144998 to Dr Granzier.
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NR 121
TC 8
Z9 9
U1 4
U2 6
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 2574-8300
J9 CIRC-GENOM PRECIS ME
JI Circ.-Genom. Precis. Med.
PD FEB
PY 2024
VL 17
IS 1
AR e004355
DI 10.1161/CIRCGEN.123.004355
PG 20
WC Cardiac & Cardiovascular Systems; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Genetics & Heredity
GA IE3R1
UT WOS:001164616400001
PM 38288598
DA 2025-04-10
ER

PT J
AU David, LS
   Garcia, E
   Cain, SM
   Thau, EM
   Tyson, JR
   Snutch, TP
AF David, Laurence S.
   Garcia, Esperanza
   Cain, Stuart M.
   Thau, Elana M.
   Tyson, John R.
   Snutch, Terrance P.
TI Splice-variant changes of the CaV3.2 T-type calcium channel
   mediate voltage-dependent facilitation and associate with cardiac
   hypertrophy and development
SO CHANNELS
LA English
DT Article
DE voltage-dependent facilitation; alternative splicing; T-type calcium
   channel; hypertension; cardiac hypertrophy
ID CA2+ CHANNEL; ALTERNATIVE STRUCTURES; GENE-EXPRESSION; MOLECULAR-BASIS;
   HEART-FAILURE; MESSENGER-RNA; RAT; IDENTIFICATION; CURRENTS; MUSCLE
AB Low voltage-activated T-type calcium (Ca) channels contribute to the normal development of the heart and are also implicated in pathophysiological states such as cardiac hypertrophy. Functionally distinct T-type Ca channel isoforms can be generated by alternative splicing from each of three different T-type genes (Ca(V)3.1, Ca(V)3.2, Ca(V)3.3), although it remains to be described whether specific splice variants are associated with developmental states and pathological conditions. We aimed to identify and functionally characterize Ca(V)3.2 T-type Ca channel alternatively spliced variants from newborn animals and to compare with adult normotensive and spontaneously hypertensive rats (SHR). DNA sequence analysis of full-length Ca(V)3.2 cDNA generated from newborn heart tissue identified ten major regions of alternative splicing, the more common variants of which were analyzed by quantitative real-time PCR (qRT-PCR) and also subject to functional examination by whole-cell patch clamp. The main findings are that: (1) cardiac Ca(V)3.2 T-type Ca channels are subject to considerable alternative splicing, (2) there is preferential expression of Ca(V)3.2(-25) splice variant channels in newborn rat heart with a developmental shift in adult heart that results in approximately equal levels of expression of both (+25) and (-25) exon variants, (3) in the adult stage of hypertensive rats there is both an increase in overall Ca(V)3.2 expression and a shift towards expression of Ca(V)3.2(+25) containing channels as the predominant form and (4) alternative splicing confers a variant-specific voltage-dependent facilitation of Ca(V)3.2 channels. We conclude that Ca(V)3.2 alternative splicing generates significant T-type Ca channel structural and functional diversity with potential implications relevant to cardiac developmental and pathophysiological states.
C1 [David, Laurence S.; Garcia, Esperanza; Cain, Stuart M.; Thau, Elana M.; Tyson, John R.; Snutch, Terrance P.] Univ British Columbia, Michael Smith Labs, Vancouver, BC V5Z 1M9, Canada.
C3 University of British Columbia
RP Snutch, TP (corresponding author), Univ British Columbia, Michael Smith Labs, Vancouver, BC V5Z 1M9, Canada.
EM snutch@msl.ubc.ca
RI Snutch, Terrance/L-3464-2019
FU Canadian Institutes of Health Research; Canada Research Chair in
   Biotechnology and Genomics-Neurobiology; Heart and Stroke Foundation of
   Canada; Genome BC
FX The work was supported by operating grants from the Canadian Institutes
   of Health Research and Genome BC and a Canada Research Chair in
   Biotechnology and Genomics-Neurobiology (to Terrance P. Snutch).
   Laurence S. David was supported by a doctoral research award from the
   Heart and Stroke Foundation of Canada. We thank Dr. Edwin Moore for
   helpful comments and suggestions.
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NR 62
TC 43
Z9 43
U1 0
U2 3
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 1933-6950
EI 1933-6969
J9 CHANNELS
JI Channels
PD SEP-OCT
PY 2010
VL 4
IS 5
BP 375
EP 389
DI 10.4161/chan.4.5.12874
PG 15
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 663GB
UT WOS:000282870100006
PM 20699644
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Torrado, M
   Iglesias, R
   Nespereira, B
   Centeno, A
   López, E
   Mikhailov, AT
AF Torrado, Mario
   Iglesias, Raquel
   Nespereira, Beatriz
   Centeno, Alberto
   Lopez, Eduardo
   Mikhailov, Alexander T.
TI Intron retention generates ANKRD1 splice variants that are co-regulated
   with the main transcript in normal and failing myocardium
SO GENE
LA English
DT Article
DE ANKRD1/CARP; Alternative splicing; Intron retention; Myocardium; Gene
   delivery; Heart failure
ID ANKYRIN REPEAT PROTEIN; GENE-EXPRESSION; MESSENGER-RNA; HUMAN HEART;
   CARP; IDENTIFICATION; TITIN; STRESS; CELL; STIMULATION
AB The cardiac ankyrin repeat domain 1 protein (ANKRD1, also known as CARP) has been extensively characterized with regard to its proposed functions as a cardio-enriched transcriptional co-factor and stress-inducible myofibrillar protein. The present results show the occurrence of alternative splicing by intron retention events in the pig and human ankrd1 gene. In pig heart. ankrd1 is expressed as four alternatively spliced transcripts, three of which have non-excised introns: ankrd1-contained introns 6, 7 and 8 (i.e., ankrd1-i6,7,8), ankrd1-contained introns 7 and 8 (i.e., ankrd1-i7,8), and ankrd1 retained only intron 8 (i.e., ankrd1-i8). In the human heart, two orthologues of porcine intron-retaining ankrd1 variants (i.e., ankrd1-i8 and ankrd1-i7,8) are detected. We demonstrate that these newly-identified intron-retaining ankrd1 transcripts are functionally intact, efficiently translated into protein in vitro and exported to the cytoplasm in cardiomyocytes in vivo. In the piglet heart, both the intronless and intron-retaining ankrd1 mRNAs are co-expressed in a chamber-dependent manner being more abundant in the left as compared to the right myocardium. Our data further indicate co-upregulation of the ankrd1 spliced variants in myocardium in the porcine model of diastolic heart failure. Most significantly, we demonstrate that in vivo forced expression of recombinant intronless ankrd1 markedly increases the levels of intron-retaining ankrd1 variants (but not of the endogenous main transcript) in piglet myocardium, suggesting that ANKRD1 may positively regulate the expression of its own intron-containing RNAs in response to cardiac stress. Overall, our findings demonstrate that in cardiomyocytes ANKRD1 can exist in multiple isoforms which may contribute to the functional diversity of this factor in heart development and disease. (C) 2009 Elsevier B.V. All fights reserved.
C1 [Torrado, Mario; Iglesias, Raquel; Nespereira, Beatriz] Univ A Coruna, Dev Biol Grp, Inst Hlth Sci, La Coruna 15006, Spain.
   [Centeno, Alberto; Lopez, Eduardo] Univ Hosp Ctr La Coruna, Expt Surg Unit, La Coruna 15006, Spain.
C3 Universidade da Coruna; Complejo Hospitalario Universitario A Coruna
RP Mikhailov, AT (corresponding author), Univ A Coruna, Dev Biol Grp, Inst Hlth Sci, Campus Oza,Bldg El Fortin,As Xubias S-N, La Coruna 15006, Spain.
EM margot@udc.es
RI Mikhailov, Alexander/H-1897-2012; Iglesias, Raquel/D-3212-2019
OI Iglesias, Raquel/0000-0002-0212-3616; Torrado,
   Mario/0000-0001-9762-7018; Mikhailov, Alexander/0000-0002-1146-4113;
   Centeno Cortes, Alberto/0000-0002-9442-5733
FU Spanish Ministry of Science and Innovation [SAF2004-01462,
   SAF2008-00337]; Autonomic Government of Galicia [08CSA008161PR]; NIH,
   Bethesda, USA
FX This work was supported by grants (SAF2004-01462 and SAF2008-00337) from
   the Spanish Ministry of Science and Innovation and partially by a grant
   (08CSA008161PR) from the Autonomic Government of Galicia. HPLC-purified
   primers for RT-PCR-DD were a generous gift from Dr. Max Rothschild (Iowa
   State University, USA). We thank Drs. Marisa Crespo, Javier Muniz and
   Constancio Medrano (University Hospital Centre of La Coruna, Spain) for
   their help in sampling and characterization of human heart tissues, and
   Dr. Stanislav Tomarev (NIH, Bethesda, USA) for his support of cell-based
   assays.
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NR 57
TC 16
Z9 18
U1 0
U2 5
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0378-1119
EI 1879-0038
J9 GENE
JI Gene
PD JUL 1
PY 2009
VL 440
IS 1-2
BP 28
EP 41
DI 10.1016/j.gene.2009.03.017
PG 14
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 455GZ
UT WOS:000266747900005
PM 19341785
OA Green Submitted
DA 2025-04-10
ER

PT J
AU Moghaddam, MB
   Maleki, M
   Oveisee, M
   Moghaddam, MB
   Arabian, M
   Malakootian, M
AF Moghaddam, Maedeh Bagheri
   Maleki, Majid
   Oveisee, Maziar
   Moghaddam, Mahrokh Bagheri
   Arabian, Maedeh
   Malakootian, Mahshid
TI Circular RNAs: New Players in Cardiomyopathy
SO GENES
LA English
DT Review
DE circular RNAs; cardiomyopathy; non-coding RNAs; ceRNA
ID NONCODING RNA; REGULATES FORMATION; OXIDATIVE STRESS; HEART-FAILURE;
   EXPRESSION; GENE; DOXORUBICIN; CIRCRNA; CLASSIFICATION; FOXO3
AB Cardiomyopathies comprise a heterogeneous group of cardiac diseases identified by myocardium disorders and diminished cardiac function. They often lead to heart failure or heart transplantation and constitute one of the principal causes of morbidity and mortality worldwide. Circular RNAs (circRNAs) are a novel type of noncoding RNAs. They are covalently closed and single-stranded and derived from the exons and introns of genes by alternative splicing. This specific structure renders them resistant to exonuclease digestion. Many recent studies have demonstrated that circRNAs are highly abundant and conserved and can play central roles in biological functions such as microRNA (miRNA) sponging, splicing, and transcription regulation. Emerging evidence indicates that circRNAs can play significant roles in cardiovascular diseases, including cardiomyopathies. In this review, we briefly describe the current understanding regarding the classification, nomenclature, characteristics, and function of circRNAs and report recent significant findings concerning the roles of circRNAs in cardiomyopathies. Furthermore, we discuss the clinical application potential of circRNAs as the therapeutic targets and diagnostic biomarkers of cardiomyopathies.
C1 [Moghaddam, Maedeh Bagheri] Tarbiat Modares Univ, Fac Biol Sci, Mol Genet Dept, Tehran 141171311, Iran.
   [Moghaddam, Maedeh Bagheri; Maleki, Majid; Moghaddam, Mahrokh Bagheri; Arabian, Maedeh; Malakootian, Mahshid] Iran Univ Med Sci, Cardiogenet Res Ctr, Rajaie Cardiovasc Med & Res Ctr, Tehran 1995614331, Iran.
   [Oveisee, Maziar] Bam Univ Med Sci, Sch Med, Bam 7661771967, Iran.
C3 Tarbiat Modares University; Iran University of Medical Sciences
RP Malakootian, M (corresponding author), Iran Univ Med Sci, Cardiogenet Res Ctr, Rajaie Cardiovasc Med & Res Ctr, Tehran 1995614331, Iran.
EM malakootian@rhc.ac.ir
RI Malakootian, Mahshid/ABG-3790-2021; arabian, maedeh/AAZ-2614-2020;
   Oveisee, Maziar/HGA-4929-2022
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NR 145
TC 6
Z9 6
U1 0
U2 4
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2073-4425
J9 GENES-BASEL
JI Genes
PD SEP
PY 2022
VL 13
IS 9
AR 1537
DI 10.3390/genes13091537
PG 20
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 4T6ZR
UT WOS:000858263000001
PM 36140705
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Gang, HY
   Hai, Y
   Dhingra, R
   Gordon, JW
   Yurkova, N
   Aviv, Y
   Li, HZ
   Aguilar, F
   Marshall, A
   Leygue, E
   Kirshenbaum, LA
AF Gang, Hongying
   Hai, Yan
   Dhingra, Rimpy
   Gordon, Joseph W.
   Yurkova, Natalia
   Aviv, Yaron
   Li, Hongzhao
   Aguilar, Floribeth
   Marshall, Aaron
   Leygue, Etienne
   Kirshenbaum, Lorrie A.
TI A Novel Hypoxia-Inducible Spliced Variant of Mitochondrial Death Gene
   Bnip3 Promotes Survival of Ventricular Myocytes
SO CIRCULATION RESEARCH
LA English
DT Article
DE cardiac myocytes; cell death; heart failure; Bnip3; mitochondrion
ID BCL-2 FAMILY PROTEINS; NF-KAPPA-B; CELL-DEATH; MEDIATED APOPTOSIS;
   CANCER; NIX; EXPRESSION; STRESS
AB Rationale: Alternative splicing provides a versatile mechanism by which cells generate proteins with different or even antagonistic properties. Previously, we established hypoxia-inducible death factor Bnip3 as a critical component of the intrinsic death pathway.
   Objective: To investigate alternative splicing of Bnip3 pre-mRNA in postnatal ventricular myocytes during hypoxia.
   Methods and Results: We identify a novel previously unrecognized spliced variant of Bnip3 (Bnip3 Delta ex3) generated by alternative splicing of exon3 exclusively in cardiac myocytes subjected to hypoxia. Sequencing of Bnip3 Delta ex3 revealed a frame shift mutation that terminated transcription up-stream of exon5 and exon6 ablating translation of the BH3-like domain and critical carboxyl-terminal transmembrane domain crucial for mitochondrial localization and cell death. Notably, although the 26-kDa Bnip3 protein (Bnip3FL) encoded by full-length mRNA was localized to mitochondria and provoked cell death, the 8.2-kDa Bnip3 Delta ex3 protein encoded by the truncated spliced mRNA was defective for mitochondrial targeting but interacted with Bnip3FL resulting in less association of Bnip3FL with mitochondria and diminished apoptotic and necrotic cell death. Forced expression of Bnip3FL in cardiac myocytes or Bnip3(-/-) mouse embryonic fibroblasts triggered widespread cell death that was inhibited by coexpression of Bnip3 Delta ex3. Conversely, RNA interference targeted against sequences encompassing the unique exon2-exon4 junction of the Bnip3 Delta ex3 sensitized cardiac myocytes to mitochondrial perturbations and cell death induced by Bnip3FL.
   Conclusions: Given the otherwise lethal consequences of deregulated Bnip3FL expression in postmitotic cells, our findings reveal a novel intrinsic defense mechanism that opposes the mitochondrial defects and cell death of ventricular myocytes that is obligatorily linked and mutually dependent on alternative splicing of Bnip3FL during hypoxia or ischemic stress. (Circ Res. 2011;108:1084-1092.)
C1 [Gang, Hongying; Hai, Yan; Dhingra, Rimpy; Gordon, Joseph W.; Yurkova, Natalia; Aviv, Yaron; Aguilar, Floribeth; Kirshenbaum, Lorrie A.] Univ Manitoba, St Boniface Hosp, Res Ctr, Inst Cardiovasc Sci,Dept Physiol,Fac Med, Winnipeg, MB, Canada.
   [Li, Hongzhao; Marshall, Aaron] Univ Manitoba, Fac Med, Dept Immunol, Winnipeg, MB R3E 0W3, Canada.
   [Leygue, Etienne] Univ Manitoba, Fac Med, Dept Biochem & Med Genet, Winnipeg, MB R3E 0W3, Canada.
   [Kirshenbaum, Lorrie A.] Univ Manitoba, Fac Med, Dept Pharmacol & Therapeut, Winnipeg, MB R3E 0W3, Canada.
C3 University of Manitoba; Children's Hospital Research Institute of
   Manitoba; University of Manitoba; University of Manitoba; University of
   Manitoba
RP Kirshenbaum, LA (corresponding author), St Boniface Gen Hosp, Res Ctr, Inst Cardiovasc Sci, Rm 3016,351 Tache Ave, Winnipeg, MB R2H 2A6, Canada.
EM Lorrie@sbrc.ca
RI Li, Hongzhao/MFZ-6086-2025
OI Gordon, Joseph/0000-0002-0061-2168; Ryplanski,
   Kairee/0000-0002-3737-7181; Marshall, Aaron/0000-0002-1175-5498
FU Manitoba Health Research Council; Canadian Institutes of Health Research
FX R.D. holds a postdoctoral fellowship from the Manitoba Health Research
   Council; J.W.G. holds a postdoctoral Canadian Institutes of Health
   Research/IMPACT fellowship. This work was supported by grants to L.A.K.
   from the Canadian Institutes of Health Research. L.A.K. is a Canada
   Research Chair in Molecular Cardiology.
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NR 27
TC 41
Z9 50
U1 1
U2 9
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7330
EI 1524-4571
J9 CIRC RES
JI Circ.Res.
PD APR 29
PY 2011
VL 108
IS 9
BP 1084
EP 1092
DI 10.1161/CIRCRESAHA.110.238709
PG 9
WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Hematology
GA 756AL
UT WOS:000289983600008
PM 21415393
OA Bronze
DA 2025-04-10
ER

PT J
AU Lin, ZQ
   Guo, F
   Gregorich, ZR
   Sun, RX
   Zhang, H
   Hu, Y
   Shanmuganayagam, D
   Ge, Y
AF Lin, Ziqing
   Guo, Fang
   Gregorich, Zachery R.
   Sun, Ruixiang
   Zhang, Han
   Hu, Yang
   Shanmuganayagam, Dhanansayan
   Ge, Ying
TI Comprehensive Characterization of Swine Cardiac Troponin T Proteoforms
   by Top-Down Mass Spectrometry
SO JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
LA English
DT Article
DE Cardiac troponin; Heart disease; Proteoform; Top-down proteomics;
   Collisionally activated dissociation; Electron-transfer dissociation;
   Electron-capture dissociation
ID ELECTRON-CAPTURE DISSOCIATION; ACUTE MYOCARDIAL-INFARCTION;
   HEART-FAILURE; PROTEIN-PHOSPHORYLATION; PROTEOMICS REVEALS;
   SKELETAL-MUSCLE; ANIMAL-MODELS; MYOFILAMENT; DISEASE; DYSFUNCTION
AB Cardiac troponin T (cTnT) regulates the Ca2+-mediated interaction between myosin thick filaments and actin thin filaments during cardiac contraction and relaxation. cTnT is released into the blood following injury, and increased serum levels of the protein are used clinically as a biomarker for myocardial infarction. Moreover, mutations in cTnT are causative in a number of familial cardiomyopathies. With the increasing use of large animal (swine) model to recapitulate human diseases, it is essential to characterize species-dependent protein sequence variants, alternative RNA splicing, and post-translational modifications (PTMs), but challenges remain due to the incomplete database and lack of validation of the predicted splicing isoforms. Herein, we integrated top-down mass spectrometry (MS) with online liquid chromatography (LC) and immunoaffinity purification to comprehensively characterize miniature swine cTnT proteoforms, including those arising from alternative RNA splicing and PTMs. A total of seven alternative splicing isoforms of cTnT were identified by LC/MS from swine left ventricular tissue, with each isoform containing un-phosphorylated and mono-phosphorylated proteoforms. The phosphorylation site was localized to Ser1 for the mono-phosphorylated proteoforms of cTnT1, 3, 4, and 6 by online MS/MS combining collisionally activated dissociation (CAD) and electron transfer dissociation (ETD). Offline MS/MS on Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometer with CAD and electron capture dissociation (ECD) was then utilized to achieve deep sequencing of mono-phosphorylated cTnT1 (35.2 kDa) with a high sequence coverage of 87%. Taken together, this study demonstrated the unique advantage of top-down MS in the comprehensive characterization of protein alternative splicing isoforms together with PTMs.
C1 [Lin, Ziqing; Guo, Fang; Gregorich, Zachery R.; Sun, Ruixiang; Hu, Yang; Ge, Ying] Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53705 USA.
   [Lin, Ziqing; Ge, Ying] Univ Wisconsin, Human Prote Program, Madison, WI 53705 USA.
   [Guo, Fang] Shandong Prov Hosp, Dept Cardiol, Jinan 250021, Shandong, Peoples R China.
   [Sun, Ruixiang] Chinese Acad Sci, Inst Comp Technol, Beijing 100190, Peoples R China.
   [Zhang, Han; Ge, Ying] Univ Wisconsin, Dept Chem, 1101 Univ Ave, Madison, WI 53706 USA.
   [Shanmuganayagam, Dhanansayan] Univ Wisconsin, Dept Anim Sci, Madison, WI 53706 USA.
C3 University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison;
   Shandong First Medical University & Shandong Academy of Medical
   Sciences; Chinese Academy of Sciences; Institute of Computing
   Technology, CAS; University of Wisconsin System; University of Wisconsin
   Madison; University of Wisconsin System; University of Wisconsin Madison
RP Ge, Y (corresponding author), Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53705 USA.; Ge, Y (corresponding author), Univ Wisconsin, Human Prote Program, Madison, WI 53705 USA.; Ge, Y (corresponding author), Univ Wisconsin, Dept Chem, 1101 Univ Ave, Madison, WI 53706 USA.
EM ge2@wisc.edu
RI Sun, ruixiang/JVO-9216-2024
FU NIH [R01 HL109810, HL096971, R01 GM117058, S10 OD018475]
FX Financial support was kindly provided by NIH R01 HL109810 and HL096971
   (to Y.G.). Y. G. would like to acknowledge NIH R01 GM117058 and S10
   OD018475.
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NR 54
TC 14
Z9 20
U1 0
U2 16
PU SPRINGER
PI NEW YORK
PA 233 SPRING ST, NEW YORK, NY 10013 USA
SN 1044-0305
EI 1879-1123
J9 J AM SOC MASS SPECTR
JI J. Am. Soc. Mass Spectrom.
PD JUN
PY 2018
VL 29
IS 6
BP 1284
EP 1294
DI 10.1007/s13361-018-1925-y
PG 11
WC Biochemical Research Methods; Chemistry, Analytical; Chemistry,
   Physical; Spectroscopy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry; Spectroscopy
GA GJ7AZ
UT WOS:000435538300021
PM 29633223
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Zhou, YY
   Fan, J
   Zhu, HY
   Ji, L
   Fan, WY
   Kapoor, I
   Wang, Y
   Wang, Y
   Zhu, GQ
   Wang, JJ
AF Zhou, Yingying
   Fan, Jia
   Zhu, Huayuan
   Ji, Li
   Fan, Wenyong
   Kapoor, Isha
   Wang, Yue
   Wang, Yuan
   Zhu, Guoqing
   Wang, Juejin
TI Aberrant Splicing Induced by Dysregulated Rbfox2 Produces Enhanced
   Function of CaV1.2 Calcium Channel and Vascular Myogenic Tone
   in Hypertension
SO HYPERTENSION
LA English
DT Article
DE alternative splicing; calcium channels, L-type; electrophysiology;
   hypertension; myocytes, smooth muscle; vasoconstriction
ID SMOOTH-MUSCLE-CELLS; CARDIAC-HYPERTROPHY; REGULATOR RBFOX2;
   BLOOD-PRESSURE; HEART-FAILURE; CA2+ CHANNELS; ARTERIES; SUBUNIT;
   EXPRESSION; VARIANT
AB Calcium influx from activated voltage-gated calcium channel Ca(V)1.2 in vascular smooth muscle cells is indispensable for maintaining myogenic tone and blood pressure. The function of Ca(V)1.2 channel can be optimized by alternative splicing, one of post-transcriptional modification mechanisms. The splicing factor Rbfox2 is known to regulate the Ca(V)1.2 pre-mRNA alternative splicing events during neuronal development. However, Rbfox2's roles in modulating the key function of vascular Ca(V)1.2 channel and in the pathogenesis of hypertension remain elusive. Here, we report that the proportion of Ca(V)1.2 channels with alternative exon 9* is increased by 10.3%, whereas that with alternative exon 33 is decreased by 10.5% in hypertensive arteries. Surprisingly, the expression level of Rbfox2 is increased approximate to 3-folds, presumably because of the upregulation of a dominant-negative isoform of Rbfox2. In vascular smooth muscle cells, we find that knockdown of Rbfox2 dynamically increases alternative exon 9*, whereas decreases exon 33 inclusion of Ca(V)1.2 channels. By patch-clamp studies, we show that diminished Rbfox2-induced alternative splicing shifts the steady-state activation and inactivation curves of vascular Ca(V)1.2 calcium channel to hyperpolarization, which makes the window current potential to more negative. Moreover, siRNA-mediated knockdown of Rbfox2 increases the pressure-induced vascular myogenic tone of rat mesenteric artery. Taken together, our data indicate that Rbfox2 modulates the functions of vascular Ca(V)1.2 calcium channel by dynamically regulating the expressions of alternative exons 9* and 33, which in turn affects the vascular myogenic tone. Therefore, our work suggests a key role for Rbfox2 in hypertension, which provides a rational basis for designing antihypertensive therapies.
C1 [Zhou, Yingying; Fan, Jia; Ji, Li; Fan, Wenyong; Wang, Yue; Wang, Yuan; Zhu, Guoqing; Wang, Juejin] Nanjing Med Univ, Dept Physiol, Key Lab Cardiovasc Dis & Mol Intervent, 101 Longmian Ave, Nanjing 211166, Jiangsu, Peoples R China.
   [Zhu, Huayuan] Nanjing Med Univ, Affiliated Hosp 1, Dept Hematol, Nanjing, Jiangsu, Peoples R China.
   [Kapoor, Isha] Cleveland Clin, Dept Canc Biol, Lerner Res Inst, Cleveland, OH 44106 USA.
C3 Nanjing Medical University; Nanjing Medical University; Cleveland Clinic
   Foundation
RP Wang, JJ (corresponding author), Nanjing Med Univ, Dept Physiol, Key Lab Cardiovasc Dis & Mol Intervent, 101 Longmian Ave, Nanjing 211166, Jiangsu, Peoples R China.
EM juejinwang@njmu.edu.cn
RI Fan, Wenyong/MFH-2376-2025; Juejin, Wang/JAX-4081-2023
OI Zhu, Guo-Qing/0000-0002-3132-9592
FU National Natural Science Foundation of China [31371157, 81300193];
   Natural Science Foundation of Jiangsu Province [BK20171482]; Natural
   Science Foundation for Young Scholars of Jiangsu Province [BK20130887];
   Natural Science Foundation of the Higher Education Institutions of
   Jiangsu Province [13KJB310002]; Science and Technology Developmental
   Foundation of Nanjing Medical University [2012NJMU017]; Start-up
   Foundation of Nanjing Medical University; Priority Academic Program
   Development of Jiangsu Higher Education Institutions
FX This work was supported by the National Natural Science Foundation of
   China (31371157 and 81300193), the Natural Science Foundation of Jiangsu
   Province (BK20171482), the Natural Science Foundation for Young Scholars
   of Jiangsu Province (BK20130887), the Natural Science Foundation of the
   Higher Education Institutions of Jiangsu Province (13KJB310002), the
   Science and Technology Developmental Foundation of Nanjing Medical
   University (2012NJMU017), the Start-up Foundation of Nanjing Medical
   University (to J. Wang), and a project funded by the Priority Academic
   Program Development of Jiangsu Higher Education Institutions.
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NR 44
TC 28
Z9 29
U1 4
U2 16
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0194-911X
EI 1524-4563
J9 HYPERTENSION
JI Hypertension
PD DEC
PY 2017
VL 70
IS 6
BP 1183
EP 1192
DI 10.1161/HYPERTENSIONAHA.117.09301
PG 10
WC Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA FM3XD
UT WOS:000414943000020
PM 28993448
DA 2025-04-10
ER

PT J
AU Wang, YJ
   Li, ZX
   Yang, GH
   Cai, LL
   Yang, F
   Zhang, YQ
   Zeng, YT
   Ma, QW
   Zeng, FY
AF Wang, Yunjie
   Li, Zexu
   Yang, Guanheng
   Cai, Linlin
   Yang, Fan
   Zhang, Yaqiong
   Zeng, Yitao
   Ma, Qingwen
   Zeng, Fanyi
TI The Study of Alternative Splicing Events in Human Induced Pluripotent
   Stem Cells From a Down's Syndrome Patient
SO FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
LA English
DT Article
DE Down's syndrome; alternative splicing; iPSCs; gene regulation;
   differentially expressed genes
ID GENE; FIBROBLASTS
AB Down's syndrome (DS) is one of the most commonly known disorders with multiple congenital disabilities. Besides severe cognitive impairment and intellectual disability, individuals with DS also exhibit additional phenotypes of variable penetrance and severity, with one or more comorbid conditions, including Alzheimer's disease, congenital heart disease, or leukemia. Various vital genes and regulatory networks had been studied to reveal the pathogenesis of the disease. Nevertheless, very few studies have examined alternative splicing. Alternative splicing (AS) is a regulatory mechanism of gene expression when making one multi-exon protein-coding gene produce more than one unique mature mRNA. We employed the GeneChip Human Transcriptome Array 2.0 (HTA 2.0) for the global gene analysis with hiPSCs from DS and healthy individuals. Examining differentially expressed genes (DEGs) in these groups and focusing on specific transcripts with AS, 466 up-regulated and 722 down-regulated genes with AS events were identified. These genes were significantly enriched in biological processes, such as cell adhesion, cardiac muscle contraction, and immune response, through gene ontology (GO) analysis of DEGs. Candidate genes, such as FN1 were further explored for potentially playing a key role in DS. This study provides important insights into the potential role that AS plays in DS.
C1 [Wang, Yunjie; Li, Zexu; Yang, Guanheng; Cai, Linlin; Yang, Fan; Zhang, Yaqiong; Zeng, Yitao; Ma, Qingwen; Zeng, Fanyi] Shanghai Jiao Tong Univ, Shanghai Inst Med Genet, Shanghai Childrens Hosp, Shanghai, Peoples R China.
   [Wang, Yunjie; Li, Zexu; Yang, Guanheng; Cai, Linlin; Yang, Fan; Zhang, Yaqiong; Zeng, Yitao; Ma, Qingwen; Zeng, Fanyi] Natl Hlth Commiss, Shanghai Key Lab Embryo & Reprod Engn, Key Lab Embryo Mol Biol, Shanghai, Peoples R China.
   [Zeng, Fanyi] Shanghai Jiao Tong Univ, Sch Med, Dept Histoembryol Genet & Dev, Shanghai, Peoples R China.
C3 Shanghai Jiao Tong University; Shanghai Jiao Tong University
RP Ma, QW; Zeng, FY (corresponding author), Shanghai Jiao Tong Univ, Shanghai Inst Med Genet, Shanghai Childrens Hosp, Shanghai, Peoples R China.; Ma, QW; Zeng, FY (corresponding author), Natl Hlth Commiss, Shanghai Key Lab Embryo & Reprod Engn, Key Lab Embryo Mol Biol, Shanghai, Peoples R China.; Zeng, FY (corresponding author), Shanghai Jiao Tong Univ, Sch Med, Dept Histoembryol Genet & Dev, Shanghai, Peoples R China.
EM qwma1213@163.com; fzeng@VIP.163.com
RI Yang, Fan/HLX-3556-2023; Wang, Yunjie/AGT-2005-2022
FU National Key R&D Program of China [2016YFC1000503, 2019YFA0801402]; Key
   disciplines of top priority in Shanghai [2017ZZ02019]
FX Funding. The research was funded by National Key R&D Program of China
   (2016YFC1000503 and 2019YFA0801402) and Key disciplines of top priority
   in Shanghai (2017ZZ02019).
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NR 46
TC 4
Z9 6
U1 0
U2 7
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2296-634X
J9 FRONT CELL DEV BIOL
JI Front. Cell. Dev. Biol.
PD SEP 30
PY 2021
VL 9
AR 661381
DI 10.3389/fcell.2021.661381
PG 13
WC Cell Biology; Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Developmental Biology
GA WK2EZ
UT WOS:000709545400001
PM 34660567
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Pascual-Figal, DA
   Lax, A
   Perez-Martinez, MT
   Asensio-Lopez, MD
   Sanchez-Mas, J
AF Pascual-Figal, Domingo A.
   Lax, Antonio
   Teresa Perez-Martinez, Maria
   del Carmen Asensio-Lopez, Maria
   Sanchez-Mas, Jesus
CA GREAT Network
TI Clinical relevance of sST2 in cardiac diseases
SO CLINICAL CHEMISTRY AND LABORATORY MEDICINE
LA English
DT Review
DE biomarkers; coronary disease; heart failure; ST2
ID FAMILY-MEMBER ST2; DECOMPENSATED HEART-FAILURE; ACUTE
   MYOCARDIAL-INFARCTION; HIGH-SENSITIVITY ASSAY; LONG-TERM MORTALITY;
   SOLUBLE ST2; EMERGENCY-DEPARTMENT; NATRIURETIC PEPTIDE; IL-1 RECEPTOR;
   ACUTE DYSPNEA
AB ST2 has two main isoforms, ST2L and soluble isoform of ST2 (sST2), by alternative splicing. The interaction between interleukin (IL)-33 and the transmembrane isoform ST2L is up-regulated in response to myocardial stress and exerts cardio-protective actions in the myocardium by reducing fibrosis, hypertrophy and enhancing survival. The circulating isoform sST2, by sequestering IL-33, abrogates these favorable actions and will be elevated as a maladaptive response to cardiac diseases. Indeed, circulating sST2 concentrations correlate with a worse phenotype of disease including adverse remodeling and fibrosis, cardiac dysfunction, impaired hemodynamics and higher risk of progression. In patients with acute and chronic heart failure, sST2 concentrations are strongly predictive of death, regardless of the cause and left ventricle (LV) ejection fraction, and contribute relevant information in addition to other prognosticators and biomarkers, as natriuretic peptides or troponins. sST2 also retains prognostic information in the setting of acute myocardial infarction (AMI) and predicts cardiovascular death and risk of heart failure (HF) development in these patients. sST2 could also be a promising tool to stratify the risk of sudden cardiac death (SCD) in patients with depressed LV ejection fraction. Therefore, sST2 represents a clinically relevant biomarker reflecting pathophysiological processes and contributing predictive information in the setting of several cardiovascular diseases, and especially in patients with HF.
C1 [Pascual-Figal, Domingo A.] Univ Hosp Virgen de la Arrixaca, Heart Failure Unit, Dept Cardiol, Murcia 30120, Spain.
   [Lax, Antonio; Teresa Perez-Martinez, Maria; del Carmen Asensio-Lopez, Maria; Sanchez-Mas, Jesus] Univ Murcia, Sch Med, Univ Hosp Virgen de la Arrixaca, Murcia, Spain.
   [Lax, Antonio; Teresa Perez-Martinez, Maria; del Carmen Asensio-Lopez, Maria; Sanchez-Mas, Jesus] IMIB, Murcia, Spain.
C3 Hospital Clinico Universitario Virgen de la Arrixaca; University of
   Murcia; Hospital Clinico Universitario Virgen de la Arrixaca
RP Pascual-Figal, DA (corresponding author), Univ Hosp Virgen de la Arrixaca, Heart Failure Unit, Dept Cardiol, Ctra Madrid Cartagena S-N, Murcia 30120, Spain.
EM dpascual@um.es
RI Sanchez, Jesus/MBG-9320-2025; MARTINEZ, MARIA/ABF-8659-2020;
   Pascual-Figal, Domingo A./B-3794-2008; Asensio Lopez, Maria del
   Carmen/AAB-2895-2021; LAX PEREZ, ANTONIO MANUEL/Q-3177-2016
OI Pascual-Figal, Domingo A./0000-0002-4993-9540; Asensio Lopez, Maria del
   Carmen/0000-0002-8043-6925; LAX PEREZ, ANTONIO
   MANUEL/0000-0001-5452-8781
FU Instituto de Salud Carlos III [PI14/01637]
FX This work was supported by a grant from "Instituto de Salud Carlos III"
   PI14/01637.
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NR 38
TC 56
Z9 62
U1 1
U2 21
PU WALTER DE GRUYTER GMBH
PI BERLIN
PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY
SN 1434-6621
EI 1437-4331
J9 CLIN CHEM LAB MED
JI Clin. Chem. Lab. Med.
PD JAN
PY 2016
VL 54
IS 1
BP 29
EP 35
DI 10.1515/cclm-2015-0074
PG 7
WC Medical Laboratory Technology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Medical Laboratory Technology
GA DA5AK
UT WOS:000367814300012
PM 26544104
DA 2025-04-10
ER

PT J
AU Guo, W
   Zhu, CQ
   Yin, ZY
   Wang, QR
   Sun, MM
   Cao, HJ
   Greaser, ML
AF Guo, Wei
   Zhu, Chaoqun
   Yin, Zhiyong
   Wang, Qiurong
   Sun, Mingming
   Cao, Huojun
   Greaser, Marion L.
TI Splicing Factor RBM20 Regulates Transcriptional Network of Titin
   Associated and Calcium Handling Genes in The Heart
SO INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
LA English
DT Article
DE Titin; RBM20; Titin binding partners; Calcium handling; Intracellular
   calcium concentration
ID LIM DOMAIN PROTEIN-1; RYANODINE RECEPTOR; CARDIAC TITIN;
   VENTRICULAR-FUNCTION; CA2+ ACTIVATION; ALPHA-MYOSIN; C-PROTEIN; MUSCLE;
   EXPRESSION; SEQUENCE
AB RNA binding motif 20 (RBM20) regulates pre-mRNA splicing of over thirty genes, among which titin is a major target. With RBM20 expression, titin expresses a larger isoform at fetal stage to a smaller isoform at adult resulting from alternative splicing, while, without RBM20, titin expresses exclusively a larger isoform throughout all ages. In addition to splicing regulation, it is unknown whether RBM20 also regulates gene expression. In this study, we employed Rbm20 knockout rats to investigate gene expression profile using Affymetrix expression array. We compared wild type to Rbm20 knockout at day1, 20 and 49. Bioinformatics analysis showed RBM20 regulates fewer genes expression at younger age and more at older age and commonly expressed genes have the same trends. GSEA indicated up-regulated genes are associated with heart failure. We examined titin binding partners. All titin direct binding partners are up-regulated and their increased expression is associated with dilated cardiomyopathy. Particularly, we found that genes involving calcium handling and muscle contraction are changed by RBM20. Intracellular calcium level measurement with individual cardiomyocytes further confirmed that changes of these proteins impact calcium handling. Selected genes from titin binding partners and calcium handling were validated with QPCR and western blotting. These data demonstrate that RBM20 regulates gene splicing as well as gene expression. Altered gene expression by RBM20 influences protein-protein interaction, calcium releasing and thus muscle contraction. Our results first reported gene expression impacted by RBM20 with heart maturation, and provided new insights into the role of RBM20 in the progression of heart failure.
C1 [Guo, Wei; Zhu, Chaoqun; Yin, Zhiyong; Wang, Qiurong; Sun, Mingming] Univ Wyoming, Anim Sci, Laramie, WY 82071 USA.
   [Guo, Wei; Zhu, Chaoqun; Wang, Qiurong; Sun, Mingming] Univ Wyoming, Ctr Cardiovasc Res & Alternat Med, Laramie, WY 82071 USA.
   [Yin, Zhiyong] Fourth Mil Med Univ, Xi Jing Hosp, Dept Cardiol, Xian 710032, Shaanxi, Peoples R China.
   [Cao, Huojun] Univ Iowa, Coll Dent, Iowa Inst Oral Hlth Res, Iowa City, IA 52242 USA.
   [Cao, Huojun] Univ Iowa, Carver Coll Med, Craniofacial Anomalies Res Ctr, Iowa City, IA 52242 USA.
   [Greaser, Marion L.] Univ Wisconsin, Anim Sci, Madison, WI 53705 USA.
C3 University of Wyoming; University of Wyoming; Air Force Medical
   University; University of Iowa; University of Iowa; University of
   Wisconsin System; University of Wisconsin Madison
RP Guo, W (corresponding author), Univ Wyoming, Anim Sci, Laramie, WY 82071 USA.; Guo, W (corresponding author), Univ Wyoming, Ctr Cardiovasc Res & Alternat Med, Laramie, WY 82071 USA.
EM wguo3@uwyo.edu
RI cao, huojun/M-5431-2017; Greaser, Marion/C-6147-2012; Guo,
   Wei/KJM-4941-2024
OI Cao, Huojun/0000-0003-4428-8686; guo, wei/0000-0002-9158-8107; Wang,
   Qiurong/0000-0001-9654-9126
FU National Institute of Health/National Institute of General Medical
   Sciences [NIGMSP20GM103432]; BGIA from the American Heart Association
   [16BGIA790136]; USDA National Institute of Food and Agriculture
   [1009266]; National Institutes of Health [HL77196]
FX This work was supported by the National Institute of Health/National
   Institute of General Medical Sciences [NIGMSP20GM103432]; the BGIA from
   the American Heart Association [16BGIA790136 to WG]; the USDA National
   Institute of Food and Agriculture [Hatch project 1009266 to WG] and the
   National Institutes of Health [grant HL77196 to MLG]. The authors are
   grateful to Mark D. Hanna for his technical assistance, animal care and
   laboratory management.
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NR 81
TC 26
Z9 35
U1 0
U2 5
PU IVYSPRING INT PUBL
PI LAKE HAVEN
PA PO BOX 4546, LAKE HAVEN, NSW 2263, AUSTRALIA
SN 1449-2288
J9 INT J BIOL SCI
JI Int. J. Biol. Sci.
PY 2018
VL 14
IS 4
BP 369
EP +
DI 10.7150/ijbs.24117
PG 13
WC Biochemistry & Molecular Biology; Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other
   Topics
GA FY9QO
UT WOS:000427201500001
PM 29725258
OA Green Submitted, Green Published, gold
DA 2025-04-10
ER

PT J
AU de Angelis, CD
   Meddeb, M
   Chen, NL
   Fisher, SA
AF de Angelis, Celio Damacena
   Meddeb, Mariam
   Chen, Nelson
   Fisher, Steven A.
TI An antisense oligonucleotide efficiently suppresses splicing of an
   alternative exon in vascular smooth muscle in vivo
SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
LA English
DT Article
DE antisense oligonucleotides; alternative splicing; exon splicing;
   oligonucleotides; vascular smooth muscle
AB Targeting alternative exons for therapeutic gain has been achieved in a few instances and potentially could be applied more broadly. The myosin phosphatase (MP) enzyme is a critical hub upon which signals converge to regulate vessel tone. Alternative exon 24 of myosin phosphatase regulatory subunit (Mypt1 E24) is an ideal target as toggling between the two isoforms sets smooth muscle sensitivity to vasodilators such as nitric oxide (NO). This study aimed to develop a gene-based therapy to suppress splicing of Mypt1 E24 thereby switching MP enzyme to the NO-responsive isoform. CRISPR/Cas9 constructs were effective at editing of Mypt1 E24 in vitro; however, targeting of vascular smooth muscle in vivo with AAV9 was inefficient. In contrast, an octo-guanidine conjugated antisense oligonucleotide targeting the 5 ' splice site of Mypt1 E24 was highly efficient in vivo. It reduced the percent splicing inclusion of Mypt1 E24 from 80% to 10% in mesenteric arteries. The maximal and half-maximal effects occurred at 12.5 and 6.25 mg/kg, respectively. The effect persisted for at least 1 mo without toxicity. This highly effective splice-blocking antisense oligonucleotide could be developed as a novel therapy to reverse vascular dysfunction common to diseases such as hypertension and heart failure. NEW & NOTEWORTHY Alternative exon usage is a major driver of phenotypic diversity in all cell types including smooth muscle. However, the functional significance of most of the hundreds of thousands of alternative exons has not been defined, nor in most cases even tested. If their importance to vascular function were known these alternative exons could represent novel therapeutic targets. Here, we present injection of Vivo-morpholino splice-blocking antisense oligonucleotides as a simple, efficient, and cost-effective method for suppression of alternative exon usage in vascular smooth muscle in vivo.
C1 [de Angelis, Celio Damacena; Meddeb, Mariam; Fisher, Steven A.] Dept Med, Div Cardiol, Baltimore, MD 21201 USA.
   [Fisher, Steven A.] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA.
   [Fisher, Steven A.] Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA.
   [Chen, Nelson] Univ Maryland, Meyerhoff Scholars Program, Baltimore, MD USA.
C3 University System of Maryland; University of Maryland Baltimore; US
   Department of Veterans Affairs; Veterans Health Administration (VHA);
   Baltimore VA Medical Center; University System of Maryland; University
   of Maryland Baltimore
RP Fisher, SA (corresponding author), Dept Med, Div Cardiol, Baltimore, MD 21201 USA.; Fisher, SA (corresponding author), Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA.; Fisher, SA (corresponding author), Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA.
EM steven.fisher3@va.gov
OI fisher, steven/0000-0002-8785-2227; Meddeb, Mariam/0000-0002-6922-1587;
   Chen, Nelson/0000-0001-8537-4244
FU State of Maryland TEDCO Mil award
FX We thank Dr. Feng Zheng and Addgene for providing plasmids and AAV used
   in this study, and the Boston Children's Hospital viral vector core for
   the preparation of recombinant AAV.
CR Le BT, 2022, P NATL ACAD SCI USA, V119, DOI 10.1073/pnas.2207956119
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NR 5
TC 2
Z9 2
U1 0
U2 0
PU AMER PHYSIOLOGICAL SOC
PI Rockville
PA 6120 Executive Blvd, Suite 600, Rockville, MD, UNITED STATES
SN 0363-6135
EI 1522-1539
J9 AM J PHYSIOL-HEART C
JI Am. J. Physiol.-Heart Circul. Physiol.
PD MAR 26
PY 2024
VL 326
IS 3
BP H860
EP H869
DI 10.1152/ajpheart.00745.2023
PG 10
WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Physiology
GA KN0E9
UT WOS:001180519500001
PM 38276948
DA 2025-04-10
ER

PT J
AU Koelemen, J
   Gotthardt, M
   Steinmetz, LM
   Meder, B
AF Koelemen, Jan
   Gotthardt, Michael
   Steinmetz, Lars M.
   Meder, Benjamin
TI RBM20-Related Cardiomyopathy: Current Understanding and Future Options
SO JOURNAL OF CLINICAL MEDICINE
LA English
DT Review
DE dilated cardiomyopathy; RBM20; arrhythmia; heart failure; gene therapy;
   alternative splicing
ID DILATED CARDIOMYOPATHY; CLINICAL GENETICS; RBM20 MUTATION; MOUSE MODEL;
   TITIN; PROTEIN; HEART; IDENTIFICATION; EXPRESSION; PHENOTYPE
AB Splice regulators play an essential role in the transcriptomic diversity of all eukaryotic cell types and organ systems. Recent evidence suggests a contribution of splice-regulatory networks in many diseases, such as cardiomyopathies. Adaptive splice regulators, such as RNA-binding motif protein 20 (RBM20) determine the physiological mRNA landscape formation, and rare variants in the RBM20 gene explain up to 6% of genetic dilated cardiomyopathy (DCM) cases. With ample knowledge from RBM20-deficient mice, rats, swine and induced pluripotent stem cells (iPSCs), the downstream targets and quantitative effects on splicing are now well-defined and the prerequisites for corrective therapeutic approaches are set. This review article highlights some of the recent advances in the field, ranging from aspects of granule formation to 3D genome architectures underlying RBM20-related cardiomyopathy. Promising therapeutic strategies are presented and put into context with the pathophysiological characteristics of RBM20-related diseases.
C1 [Koelemen, Jan; Meder, Benjamin] Heidelberg Univ, Dept Internal Med 3, D-69120 Heidelberg, Germany.
   [Koelemen, Jan; Steinmetz, Lars M.; Meder, Benjamin] DZHK German Ctr Cardiovasc Res, Partner Site Heidelberg, D-69120 Heidelberg, Germany.
   [Gotthardt, Michael] DZHK German Ctr Cardiovasc Res, Partner Site Berlin, D-10117 Berlin, Germany.
   [Gotthardt, Michael] Max Delbruck Ctr Mol Med Helmholtz Assoc, Neuromuscular & Cardiovasc Cell Biol, D-13125 Berlin, Germany.
   [Gotthardt, Michael] Charite Univ Med Berlin, D-13353 Berlin, Germany.
   [Steinmetz, Lars M.; Meder, Benjamin] Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA.
   [Steinmetz, Lars M.; Meder, Benjamin] Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA.
   [Steinmetz, Lars M.] European Mol Biol Lab EMBL, Genome Biol Unit, D-69117 Heidelberg, Germany.
C3 Ruprecht Karls University Heidelberg; German Centre for Cardiovascular
   Research; German Centre for Cardiovascular Research; Helmholtz
   Association; Max Delbruck Center for Molecular Medicine; Berlin
   Institute of Health; Free University of Berlin; Humboldt University of
   Berlin; Charite Universitatsmedizin Berlin; Stanford University;
   Stanford University; European Molecular Biology Laboratory (EMBL)
RP Meder, B (corresponding author), Heidelberg Univ, Dept Internal Med 3, D-69120 Heidelberg, Germany.; Meder, B (corresponding author), DZHK German Ctr Cardiovasc Res, Partner Site Heidelberg, D-69120 Heidelberg, Germany.; Meder, B (corresponding author), Stanford Univ, Dept Genet, Palo Alto, CA 94304 USA.; Meder, B (corresponding author), Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA.
EM Jan.Koelemenoglu@med.uni-heidelberg.de; gotthardt@mdc-berlin.de;
   Lars.Steinmetz@stanford.edu; benjamin.meder@med.uni-heidelberg.de
RI Gotthardt, Michael/ABE-8274-2021
OI Koelemen, Jan/0000-0003-4760-7582; Steinmetz, Lars/0000-0002-3962-2865;
   Gotthardt, Michael/0000-0003-1788-3172
FU Leducq Foundation
FX This research was funded by the Leducq Foundation for funding the
   "Cardiac Splicing as a Therapeutic Target (CASTT)-Transatlantic Network
   of Excellence".
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NR 65
TC 29
Z9 32
U1 0
U2 5
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2077-0383
J9 J CLIN MED
JI J. Clin. Med.
PD SEP
PY 2021
VL 10
IS 18
AR 4101
DI 10.3390/jcm10184101
PG 15
WC Medicine, General & Internal
WE Science Citation Index Expanded (SCI-EXPANDED)
SC General & Internal Medicine
GA UX2RD
UT WOS:000700691800001
PM 34575212
OA Green Accepted, Green Published, gold
DA 2025-04-10
ER

PT J
AU Cao, T
   Rajasingh, S
   Samanta, S
   Dawn, B
   Bittel, DC
   Rajasingh, J
AF Cao, Thuy
   Rajasingh, Sheeja
   Samanta, Saheli
   Dawn, Buddhadeb
   Bittel, Douglas C.
   Rajasingh, Johnson
TI Biology and clinical relevance of noncoding sno/scaRNAs
SO TRENDS IN CARDIOVASCULAR MEDICINE
LA English
DT Article
DE Noncoding RNA; Small Cajal body-associated RNA; Spliceosomal RNA; Small
   nucleolar RNA; Alternative splicing
ID SMALL NUCLEOLAR RNAS; SPINAL MUSCULAR-ATROPHY; BOX C/D; RIBOSOMAL-RNA;
   CAJAL-BODY; PROSTATE-CANCER; CARDIOVASCULAR-DISEASE; HEART DEVELOPMENT;
   MULTIPLE-MYELOMA; COILIN
AB Small nucleolar RNAs (snoRNAs) are a group of noncoding RNAs that perform various biological functions, including biochemical modifications of other RNAs, precursors of miRNA, splicing, and telomerase activity. The small Cajal body-associated RNAs (scaRNAs) are a subset of the snoRNA family and collect in the Cajal body where they perform their canonical function to biochemically modify spliceosomal RNAs prior to maturation. Failure of sno/scaRNAs have been implicated in pathology such as congenital heart anomalies, neuromuscular disorders, and various malignancies. Thus, understanding of sno/scaRNAs demonstrates the clinical value.
C1 [Cao, Thuy; Rajasingh, Sheeja; Samanta, Saheli; Dawn, Buddhadeb; Rajasingh, Johnson] Cardiovasc Res Inst, Dept Internal Med, Div Cardiovasc Dis, Kansas City, KS USA.
   [Bittel, Douglas C.] Childrens Mercy Hosp, Kansas City, MO 64108 USA.
   [Rajasingh, Johnson] Univ Kansas, Med Ctr, Dept Biochem & Mol Biol, Kansas City, KS 66160 USA.
C3 Children's Mercy Hospital; University of Kansas; University of Kansas
   Medical Center
RP Rajasingh, J (corresponding author), Univ Kansas, Med Ctr, Dept Biochem & Mol Biol, Kansas City, KS 66160 USA.
EM rjohnson9@kumc.edu
RI Rajasingh, Johnson/AAT-1985-2021
FU American Heart Association, United States [16GRNT30950010]; National
   Institutes of Health COBRE, United States [P20GM104936]
FX This work was supported, in part, by American Heart Association, United
   States Grant-in-Aid 16GRNT30950010 and National Institutes of Health
   COBRE, United States grant P20GM104936 (to J.R.).
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NR 92
TC 28
Z9 32
U1 1
U2 12
PU ELSEVIER SCIENCE LONDON
PI LONDON
PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND
SN 1050-1738
J9 TRENDS CARDIOVAS MED
JI Trends Cardiovasc. Med.
PD FEB
PY 2018
VL 28
IS 2
BP 81
EP 90
DI 10.1016/j.tcm.2017.08.002
PG 10
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA FU7ZT
UT WOS:000424072300001
PM 28869095
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Yu, ST
   Sun, ZY
   Ju, TT
   Liu, YQ
   Mei, ZT
   Wang, CH
   Qu, ZZ
   Li, N
   Wu, F
   Liu, KW
   Lu, MX
   Huang, M
   Pang, XC
   Jia, YQ
   Li, Y
   Zhang, YZ
   Dou, SK
   Jiang, JH
   Dong, XH
   Huang, CH
   Li, WH
   Zhang, Y
   Yuan, Y
   Yang, BF
   Du, WJ
AF Yu, Shuting
   Sun, Zhiyong
   Ju, Tiantian
   Liu, Yingqi
   Mei, Zhongting
   Wang, Changhao
   Qu, Zhezhe
   Li, Na
   Wu, Fan
   Liu, Kuiwu
   Lu, Meixi
   Huang, Min
   Pang, Xiaochen
   Jia, Yingqiong
   Li, Ying
   Zhang, Yaozhi
   Dou, Shunkang
   Jiang, Jianhao
   Dong, Xianhui
   Huang, Chuanhao
   Li, Wanhong
   Zhang, Yi
   Yuan, Ye
   Yang, Baofeng
   Du, Weijie
TI The m7G Methyltransferase Mettl1 Drives Cardiac Hypertrophy by
   Regulating SRSF9-Mediated Splicing of NFATc4
SO ADVANCED SCIENCE
LA English
DT Article
DE alternative splicing; cardiac hypertrophy; m7G; Mettl1; NFATc4
ID MESSENGER-RNA; TUMORIGENESIS; PROTEINS
AB Cardiac hypertrophy is a key factor driving heart failure (HF), yet its pathogenesis remains incompletely elucidated. Mettl1-catalyzed RNA N7-methylguanosine (m7G) modification has been implicated in ischemic cardiac injury and fibrosis. This study aims to elucidate the role of Mettl1 and the mechanism underlying non-ischemic cardiac hypertrophy and HF. It is found that Mettl1 is upregulated in human failing hearts and hypertrophic murine hearts following transverse aortic constriction (TAC) and Angiotensin II (Ang II) infusion. YY1 acts as a transcriptional factor for Mettl1 during cardiac hypertrophy. Mettl1 knockout alleviates cardiac hypertrophy and dysfunction upon pressure overload from TAC or Ang II stimulation. Conversely, cardiac-specific overexpression of Mettl1 results in cardiac remodeling. Mechanically, Mettl1 increases SRSF9 expression by inducing m7G modification of SRSF9 mRNA, facilitating alternative splicing and stabilization of NFATc4, thereby promoting cardiac hypertrophy. Moreover, the knockdown of SRSF9 protects against TAC- or Mettl1-induced cardiac hypertrophic phenotypes in vivo and in vitro. The study identifies Mettl1 as a crucial regulator of cardiac hypertrophy, providing a novel therapeutic target for HF.
   This study elucidates a previously unknown role and the molecular mechanism by which Mettl1-mediated m7G modification contributes to cardiac hypertrophy. The findings indicate that Mettl1 enhances the stability of SRSF9 through m7G modification, resulting in the upregulation of NFACT4 expression and the promotion of cardiac hypertrophy and heart failure progression. The graphical abstract is created using BioRender. image
C1 [Yu, Shuting; Sun, Zhiyong; Ju, Tiantian; Liu, Yingqi; Mei, Zhongting; Wang, Changhao; Qu, Zhezhe; Li, Na; Wu, Fan; Liu, Kuiwu; Huang, Min; Pang, Xiaochen; Jia, Yingqiong; Li, Ying; Zhang, Yaozhi; Dou, Shunkang; Jiang, Jianhao; Dong, Xianhui; Huang, Chuanhao; Li, Wanhong; Zhang, Yi; Yang, Baofeng; Du, Weijie] Harbin Med Univ, Coll Pharm,Key Lab Cardiovasc Res,Minist Educ, Dept Pharmacol,State Prov Key Labs Biomed Pharmace, State Key Lab Frigid Zone Cardiovasc Dis SKLFZCD, Harbin 150081, Peoples R China.
   [Lu, Meixi] Beijing Univ Chinese Med, Tradit Chinese Med Sch, Beijing 100013, Peoples R China.
   [Yuan, Ye] Harbin Med Univ, Univ Key Lab Drug Res Heilongjiang Prov, Affiliated Hosp 2, Dept Pharm, Harbin 150086, Peoples R China.
   [Yang, Baofeng; Du, Weijie] Harbin Med Univ, Heilongjiang Acad Med Sci, Northern Translat Med Res & Cooperat Ctr, Harbin 150081, Peoples R China.
   [Yang, Baofeng; Du, Weijie] Chinese Acad Med Sci, Res Unit Noninfect Chron Dis Frigid Zone, 2019RU070, Harbin 150081, Peoples R China.
C3 Harbin Medical University; Beijing University of Chinese Medicine;
   Harbin Medical University; Harbin Medical University; Chinese Academy of
   Medical Sciences - Peking Union Medical College
RP Yang, BF; Du, WJ (corresponding author), Harbin Med Univ, Coll Pharm,Key Lab Cardiovasc Res,Minist Educ, Dept Pharmacol,State Prov Key Labs Biomed Pharmace, State Key Lab Frigid Zone Cardiovasc Dis SKLFZCD, Harbin 150081, Peoples R China.; Yuan, Y (corresponding author), Harbin Med Univ, Univ Key Lab Drug Res Heilongjiang Prov, Affiliated Hosp 2, Dept Pharm, Harbin 150086, Peoples R China.; Yang, BF; Du, WJ (corresponding author), Harbin Med Univ, Heilongjiang Acad Med Sci, Northern Translat Med Res & Cooperat Ctr, Harbin 150081, Peoples R China.; Yang, BF; Du, WJ (corresponding author), Chinese Acad Med Sci, Res Unit Noninfect Chron Dis Frigid Zone, 2019RU070, Harbin 150081, Peoples R China.
EM yuany@hrbmu.edu.cn; yangbf@ems.hrbmu.edu.cn; duweijie@hrbmu.edu.cn
RI Xie, Hui/ACL-9395-2022; ZHANG, YAOZHI/AAC-9115-2021; li,
   wanhong/GXN-0869-2022; wang, pengcheng/N-1680-2017
FU Natural Science Foundation of China; Outstanding Youth Project of
   Natural Science Foundation of Heilongjiang Province [YQ2020H010]; Youth
   Project of Scientific Research Institution of Heilongjiang Province
   [CZKYF2023-1-C047]; CAMS Innovation Fund for Medical Sciences (CIFMS)
   [2019-I2M-5-078];  [82273928];  [82330011];  [U21A20339]
FX This work was supported by grants from the Natural Science Foundation of
   China (82273928, 82330011, U21A20339); the Outstanding Youth Project of
   Natural Science Foundation of Heilongjiang Province (YQ2020H010); the
   Youth Project of Scientific Research Institution of Heilongjiang
   Province (CZKYF2023-1-C047); CAMS Innovation Fund for Medical Sciences
   (CIFMS) 2019-I2M-5-078.
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NR 45
TC 4
Z9 4
U1 9
U2 17
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
EI 2198-3844
J9 ADV SCI
JI Adv. Sci.
PD AUG
PY 2024
VL 11
IS 29
DI 10.1002/advs.202308769
EA MAY 2024
PG 18
WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials
   Science, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Chemistry; Science & Technology - Other Topics; Materials Science
GA C3F8G
UT WOS:001234206100001
PM 38810124
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Jordà, P
   Toro, R
   Diez, C
   Salazar-Mendiguchía, J
   Fernandez-Falgueras, A
   Perez-Serra, A
   Coll, M
   Puigmulé, M
   Arbelo, E
   García-Alvarez, A
   Sarquella-Brugada, G
   Cesar, S
   Tiron, C
   Iglesias, A
   Brugada, J
   Brugada, R
   Campuzano, O
AF Jorda, Paloma
   Toro, Rocio
   Diez, Carles
   Salazar-Mendiguchia, Joel
   Fernandez-Falgueras, Anna
   Perez-Serra, Alexandra
   Coll, Monica
   Puigmule, Marta
   Arbelo, Elena
   Garcia-Alvarez, Ana
   Sarquella-Brugada, Georgia
   Cesar, Sergi
   Tiron, Coloma
   Iglesias, Anna
   Brugada, Josep
   Brugada, Ramon
   Campuzano, Oscar
TI Malignant Arrhythmogenic Role Associated with RBM20: A
   Comprehensive Interpretation Focused on a Personalized Approach
SO JOURNAL OF PERSONALIZED MEDICINE
LA English
DT Review
DE sudden cardiac death; arrhythmia; dilated cardiomyopathy; genetics;
   RBM20
ID SUDDEN CARDIAC DEATH; FAMILIAL DILATED CARDIOMYOPATHY; COPY NUMBER
   VARIANTS; VENTRICULAR-ARRHYTHMIAS; POSITION STATEMENT; SEQUENCE
   VARIANTS; EUROPEAN-SOCIETY; HEART-FAILURE; WORKING GROUP; MUTATIONS
AB The RBM20 gene encodes the muscle-specific splicing factor RNA-binding motif 20, a regulator of heart-specific alternative splicing. Nearly 40 potentially deleterious variants in RBM20 have been reported in the last ten years, being found to be associated with highly arrhythmogenic events in familial dilated cardiomyopathy. Frequently, malignant arrhythmias can be a primary manifestation of disease. The early recognition of arrhythmic genotypes is crucial in avoiding lethal episodes, as it may have an impact on the adoption of personalized preventive measures. Our study performs a comprehensive update of data concerning rare variants in RBM20 that are associated with malignant arrhythmogenic phenotypes with a focus on personalized medicine.
C1 [Jorda, Paloma; Arbelo, Elena; Garcia-Alvarez, Ana; Brugada, Josep] Univ Barcelona, IDIBAPS, Hosp Clin, Dept Cardiol, Barcelona 08036, Spain.
   [Toro, Rocio] Univ Cadiz, Sch Med, Dept Med, Cadiz 11001, Spain.
   [Toro, Rocio] Biomed Res & Innovat Inst Cadiz INiBICA, Cadiz 11001, Spain.
   [Diez, Carles; Salazar-Mendiguchia, Joel] Bellvitge Biomed Res Inst IDIBELL, Cardiovasc Dis Res Grp, Barcelona 08001, Spain.
   [Diez, Carles] Bellvitge Univ Hosp, Dept Cardiol, Adv Heart Failure & Heart Transplant Unit, Barcelona 08001, Spain.
   [Fernandez-Falgueras, Anna; Perez-Serra, Alexandra; Coll, Monica; Puigmule, Marta; Iglesias, Anna; Brugada, Ramon; Campuzano, Oscar] Univ Girona, IDIBGI, Cardiovasc Genet Ctr, Girona 17001, Spain.
   [Perez-Serra, Alexandra; Arbelo, Elena; Brugada, Josep; Brugada, Ramon; Campuzano, Oscar] Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid 28029, Spain.
   Univ Barcelona, Hosp St Joan de Deu, Dept Cardiol, Pediat Arrhythmias,Inherited Cardiac Dis & Sudden, Barcelona 08950, Spain.
   [Sarquella-Brugada, Georgia; Cesar, Sergi] Univ Girona, Sch Med, Dept Med Sci, Girona 17001, Spain.
   [Sarquella-Brugada, Georgia; Tiron, Coloma; Brugada, Ramon; Campuzano, Oscar] Univ Girona, Hosp Josep Trueta, Serv Cardiol, Girona 17001, Spain.
C3 University of Barcelona; Hospital Clinic de Barcelona; IDIBAPS;
   Universidad de Cadiz; Institut d'Investigacio Biomedica de Bellvitge
   (IDIBELL); University of Barcelona; Institut d'Investigacio Biomedica de
   Bellvitge (IDIBELL); Bellvitge University Hospital; Universitat de
   Girona; Girona University Hospital Dr. Josep Trueta; Institut
   d'Investigacio Biomedica de Girona (IDIBGI); CIBER - Centro de
   Investigacion Biomedica en Red; CIBERCV; University of Barcelona;
   Universitat de Girona; Universitat de Girona; Girona University Hospital
   Dr. Josep Trueta
RP Brugada, R; Campuzano, O (corresponding author), Univ Girona, IDIBGI, Cardiovasc Genet Ctr, Girona 17001, Spain.; Brugada, R; Campuzano, O (corresponding author), Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid 28029, Spain.; Brugada, R; Campuzano, O (corresponding author), Univ Girona, Hosp Josep Trueta, Serv Cardiol, Girona 17001, Spain.
EM pjordab@clinic.cat; rociotorogreen@gmail.com;
   carles.diezlopez@gmail.com; jsalazarmg@gmail.com;
   afernandez@gencardio.com; aperez@idibgi.org; mcoll@gencardio.com;
   mpuigmule@gencardio.com; annai@brugada.org; ANAGARCI@clinic.cat;
   georgia@brugada.org; sergi.cesar@gmail.com; colomatiron@gmail.com;
   annai@brugada.org; josep@brugada.org; rbrugada@idibgi.org;
   oscar@brugada.org
RI Arbelo, Elena/GMX-0351-2022; Salazar, Joel/AAN-3422-2020; Toro,
   Rocio/AEU-8689-2022; García Alvarez, Ana/AAB-4999-2021;
   Fernandez-Falgueras, Anna/ACP-1966-2022; campuzano, oscar/J-1968-2014;
   CESAR, SERGI/ABH-4429-2020; Sarquella-Brugada, Georgia/W-9278-2018;
   Coll, Monica/H-3176-2015; TORO, ROCIO/M-5357-2014
OI Salazar-Mendiguchia, Joel/0000-0003-2171-8508; Diez-Lopez,
   Carles/0000-0002-3734-4777; CESAR, SERGI/0000-0002-2798-1756;
   Sarquella-Brugada, Georgia/0000-0002-6857-8904; Jorda,
   Paloma/0000-0002-9236-1713; Coll, Monica/0000-0003-1214-803X;
   Fernandez-Falgueras, Anna/0000-0002-3179-8372; TORO,
   ROCIO/0000-0003-3136-1776; ARBELO, ELENA/0000-0003-0424-6393;
   Garcia-Alvarez, Ana/0000-0002-1718-2424
FU Obra Social "La Caixa Foundation" [LCF/PR/GN16/50290001,
   LCF/PR/GN19/50320002]; Fondo Investigacion Sanitaria from Instituto
   Salud Carlos III (ISCIII) [FIS PI16/01203, FIS, PI17/01690]; Fundacio
   Privada Daniel Bravo Andreu
FX This work was supported by Obra Social "La Caixa Foundation"
   (LCF/PR/GN16/50290001 and LCF/PR/GN19/50320002), Fondo Investigacion
   Sanitaria (FIS PI16/01203 and FIS, PI17/01690) from Instituto Salud
   Carlos III (ISCIII), and "Fundacio Privada Daniel Bravo Andreu". CIBERCV
   is an initiative of the ISCIII, Spanish Ministry of Economy and
   Competitiveness.
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NR 74
TC 6
Z9 6
U1 0
U2 7
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2075-4426
J9 J PERS MED
JI J. Pers. Med.
PD FEB
PY 2021
VL 11
IS 2
AR 130
DI 10.3390/jpm11020130
PG 17
WC Health Care Sciences & Services; Medicine, General & Internal
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Health Care Sciences & Services; General & Internal Medicine
GA QN8GA
UT WOS:000622689500001
PM 33671899
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Zhou, N
   Chen, X
   Xi, J
   Ma, B
   Leimena, C
   Stoll, S
   Qin, GJ
   Wang, C
   Qiu, HY
AF Zhou, Ning
   Chen, Xin
   Xi, Jing
   Ma, Ben
   Leimena, Christiana
   Stoll, Shaunrick
   Qin, Gangjian
   Wang, Charles
   Qiu, Hongyu
TI Genomic characterization reveals novel mechanisms underlying the
   valosin-containing protein-mediated cardiac protection against heart
   failure
SO REDOX BIOLOGY
LA English
DT Article
DE Valosin-containing protein; Cardiac hypertrophy; Heart failure; Pressure
   overload; RNA sequencing
ID PRESSURE-OVERLOAD; MYOCARDIAL HYPERTROPHY; ENRICHMENT ANALYSIS;
   GENE-EXPRESSION; OVEREXPRESSION; PROGRESSION; TRANSITION; P97;
   CARDIOMYOPATHY; TRANSCRIPTION
AB Chronic hypertension is a key risk factor for heart failure. However, the underlying molecular mechanisms are not fully understood. Our previous studies found that the valosin-containing protein (VCP), an ATPase-associated protein, was significantly decreased in the hypertensive heart tissues. In this study, we tested the hypothesis that restoration of VCP protected the heart against pressure overload-induced heart failure. With a cardiac-specific transgenic (TG) mouse model, we showed that a moderate increase of VCP was able to attenuate chronic pressure overload-induced maladaptive cardiac hypertrophy and dysfunction. RNA sequencing and a comprehensive bioinformatic analysis further demonstrated that overexpression of VCP in the heart normalized the pressure overload-stimulated hypertrophic signals and repressed the stress-induced inflammatory response. In addition, VCP overexpression promoted cell survival by enhancing the mitochondria resistance to the oxidative stress via activating the Rictor-mediated-gene networks. VCP was also found to be involved in the regulation of the alternative splicing and differential isoform expression for some genes that are related to ATP production and protein synthesis by interacting with long no-coding RNAs and histone deacetylases, indicating a novel epigenetic regulation of VCP in integrating coding and noncoding genomic network in the stressed heart. In summary, our study demonstrated that the rescuing of a deficient VCP in the heart could prevent pressure overload-induced heart failure by rectifying cardiac hypertrophic and inflammatory signaling and enhancing the cardiac resistance to oxidative stress, which brought in novel insights into the understanding of the mechanism of VCP in protecting patients from hypertensive heart failure.
C1 [Zhou, Ning; Xi, Jing; Ma, Ben; Leimena, Christiana; Stoll, Shaunrick; Qiu, Hongyu] Loma Linda Univ, Sch Med, Dept Basic Sci, Div Physiol, Loma Linda, CA 92350 USA.
   [Zhou, Ning] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Internal Med,Div Cardiol, Wuhan 430000, Peoples R China.
   [Chen, Xin; Wang, Charles] Loma Linda Univ, Ctr Genom, Loma Linda, CA 92350 USA.
   [Chen, Xin; Wang, Charles] Loma Linda Univ, Dept Basic Sci, Sch Med, Loma Linda, CA 92350 USA.
   [Qin, Gangjian] Univ Alabama Birmingham, Sch Med & Sch Engn, Dept Biomed Engn, Birmingham, AL 35294 USA.
   [Ma, Ben; Qiu, Hongyu] Georgia State Univ, Ctr Mol & Translat Med, Inst Biomed Sci, Atlanta, GA 30303 USA.
C3 Loma Linda University; Huazhong University of Science & Technology; Loma
   Linda University; Loma Linda University; University of Alabama System;
   University of Alabama Birmingham; University System of Georgia; Georgia
   State University
RP Qiu, HY (corresponding author), Georgia State Univ, Ctr Mol & Translat Med, Inst Biomed Sci, Petit Res Ctr, Room 588,100 Piedmont Ave, Atlanta, GA 30303 USA.; Wang, C (corresponding author), Loma Linda Univ, Ctr Genom, Sch Med, Dept Basic Sci, 11021 Campus St,AH 120-104, Loma Linda, CA 92350 USA.
EM chwang@llu.edu; hqiu@gsu.edu
RI Chen, Xin/ABA-3794-2020; Ma, Ben/HMV-0820-2023
OI Xi, Jing/0000-0003-0881-2356
FU NIH [HL115195, HL137962, HL 142291]; Ardmore Institute of Health (AIH)
   [2150141]; National Natural Science Foundation of China [81570261]
FX This work is supported by NIH grants HL115195 (H.Q.), HL137962 (H.Q.),
   and HL 142291(H.Q. &. G.Q). We would also like to thank the partial
   support from the Ardmore Institute of Health (AIH) grant (2150141, CW),
   the National Natural Science Foundation of China 81570261 (N.Z.) and Dr.
   Charles A. Sims' gift to Loma Linda University (LLU) Center for
   Genomics.
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NR 80
TC 14
Z9 14
U1 0
U2 14
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 2213-2317
J9 REDOX BIOL
JI Redox Biol.
PD SEP
PY 2020
VL 36
AR 101662
DI 10.1016/j.redox.2020.101662
PG 12
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA NS3KU
UT WOS:000572165200001
PM 32795937
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Oakley, RH
   Campen, MJ
   Paffett, ML
   Chen, X
   Wang, ZJ
   Parry, TL
   Hillhouse, C
   Cidlowski, JA
   Willis, MS
AF Oakley, Robert H.
   Campen, Matthew J.
   Paffett, Michael L.
   Chen, Xin
   Wang, Zhongjing
   Parry, Traci L.
   Hillhouse, Carolyn
   Cidlowski, John A.
   Willis, Monte S.
TI Muscle-specific regulation of right ventricular transcriptional
   responses to chronic hypoxia-induced hypertrophy by the muscle ring
   finger-1 (MuRF1) ubiquitin ligase in mice
SO BMC MEDICAL GENETICS
LA English
DT Article
DE MuRF1; Hypoxia; Right heart failure; Gene expression; Microarray
ID LARGE GENE LISTS; CARDIAC-HYPERTROPHY; IN-VIVO; STEM-CELLS;
   HEART-FAILURE; ALPHA; METABOLISM; KINASE; ASSOCIATION; EXPRESSION
AB Background: We recently identified a role for the muscle-specific ubiquitin ligase MuRF1 in right-sided heart failure secondary to pulmonary hypertension induced by chronic hypoxia (CH). MuRF1-/-mice exposed to CH are resistant to right ventricular (RV) dysfunction whereas MuRF1 Tg + mice exhibit impaired function indicative of heart failure. The present study was undertaken to understand the underlying transcriptional alterations in the RV of MuRF1-/- and MuRF1 Tg + mice.
   Methods: Microarray analysis was performed on RNA isolated from the RV of MuRF1-/-, MuRF1 Tg+, and wild-type control mice exposed to CH.
   Results: MuRF1-/-RV differentially expressed 590 genes in response to CH. Analysis of the top 66 genes (> 2-fold or < -2-fold) revealed significant associations with oxidoreductase, transcription regulation, and transmembrane component annotations. The significant genes had promoters enriched for HOXD12, HOXC13, and RREB-1 protein transcription factor binding sites. MuRF1 Tg + RV differentially expressed 150 genes in response to CH. Analysis of the top 45 genes (> 3-fold or < -3-fold) revealed significant associations with oxidoreductase-metabolic, glycoprotein-transmembrane- integral proteins, and alternative splicing/splice variant annotations. The significant genes were enriched for promoters with ZIC1 protein transcription factor binding sites.
   Conclusions: The differentially expressed genes in MuRF1-/-and MuRF1 Tg + RV after CH have common functional annotations related to oxidoreductase (including antioxidant) and transmembrane component functions. Moreover, the functionally-enhanced MuRF1-/-hearts regulate genes related to transcription, homeobox proteins, and kinases/phosphorylation. These studies also reveal potential indirect effects of MuRF1 through regulating Rreb-1, and they reveal mechanisms by which MuRF1 may transcriptionally regulate anti-oxidant systems in the face of right heart failure.
C1 [Oakley, Robert H.; Cidlowski, John A.] NIEHS, Dept Hlth & Human Serv, Signal Transduct Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA.
   [Campen, Matthew J.; Paffett, Michael L.] Univ New Mexico, Coll Pharm, Dept Pharmaceut Sci, Hlth Sci Ctr, Albuquerque, NM 87131 USA.
   [Chen, Xin; Parry, Traci L.; Hillhouse, Carolyn; Willis, Monte S.] Univ N Carolina, McAllister Heart Inst, Chapel Hill, NC 27515 USA.
   [Wang, Zhongjing] Univ N Carolina, Dept Surg, Chapel Hill, NC 27515 USA.
   [Willis, Monte S.] Indiana Univ Sch Med, Dept Pathol & Lab Med, 635 Barnhill Dr,Van Nuys MS 5067, Indianapolis, IN 46202 USA.
   [Willis, Monte S.] Indiana Univ Sch Med, Krannert Inst Cardiol, Indianapolis, IN 46202 USA.
   [Willis, Monte S.] Indiana Univ Sch Med, Div Cardiol, Dept Internal Med, Indianapolis, IN 46202 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Institute of
   Environmental Health Sciences (NIEHS); University of New Mexico;
   University of New Mexico's Health Sciences Center; University of North
   Carolina; University of North Carolina Chapel Hill; University of North
   Carolina; University of North Carolina Chapel Hill; Indiana University
   System; Indiana University Bloomington; Indiana University System;
   Indiana University Bloomington; Indiana University System; Indiana
   University Bloomington
RP Willis, MS (corresponding author), Univ N Carolina, McAllister Heart Inst, Chapel Hill, NC 27515 USA.; Willis, MS (corresponding author), Indiana Univ Sch Med, Dept Pathol & Lab Med, 635 Barnhill Dr,Van Nuys MS 5067, Indianapolis, IN 46202 USA.; Willis, MS (corresponding author), Indiana Univ Sch Med, Krannert Inst Cardiol, Indianapolis, IN 46202 USA.; Willis, MS (corresponding author), Indiana Univ Sch Med, Div Cardiol, Dept Internal Med, Indianapolis, IN 46202 USA.
EM willisms@iu.edu
RI Wang, Zhongjing/G-3315-2012; Willis, Monte/J-9994-2015; Cidlowski,
   John/G-2548-2019
OI Cidlowski, John/0000-0003-1420-0516; /0000-0002-0769-5816
FU National Institutes of Health [NIH R01ES014639, R01HL104129];
   Jefferson-Pilot Corporation; Leducq Foundation Transatlantic Networks of
   Excellence; National Institutes of Health (NIEHS)
FX This work is supported by the National Institutes of Health (NIEHS to
   R.H.O. and J.A.C., NIH R01ES014639 to M.J.C. and R01HL104129 to M.S.W.),
   the Jefferson-Pilot Corporation (Fellowship to M.S.W.), and the Leducq
   Foundation Transatlantic Networks of Excellence (to M.W.).
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NR 68
TC 0
Z9 1
U1 0
U2 2
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1471-2350
J9 BMC MED GENET
JI BMC Med. Genet.
PD SEP 21
PY 2018
VL 19
AR 175
DI 10.1186/s12881-018-0670-1
PG 17
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA GU3RU
UT WOS:000445198000002
PM 30241514
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Hua, YY
   Qian, JA
   Cao, J
   Wang, X
   Zhang, W
   Zhang, JJ
AF Hua, Yuyun
   Qian, Jianan
   Cao, Ji
   Wang, Xue
   Zhang, Wei
   Zhang, Jingjing
TI Ca<SUP>2+</SUP>/Calmodulin-Dependent Protein Kinase II Regulation by
   Inhibitor of Receptor Interacting Protein Kinase 3 Alleviates
   Necroptosis in Glycation End Products-Induced Cardiomyocytes Injury
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Article
DE advanced glycation end products; cardiomyocytes; necroptosis; receptor
   interacting protein kinase 3; calcium; calmodulin-dependent protein
   kinase II; oxidative stress
ID CELL-DEATH; INSULIN-RESISTANCE; DIABETIC CARDIOMYOPATHY; DELTA-B;
   CAMKII; RIP3; RESTRICTION; MECHANISMS; APOPTOSIS; IMPROVES
AB Necroptosisis a regulatory programmed form of necrosis. Receptor interacting protein kinase 3 (RIPK3) is a robust indicator of necroptosis. RIPK3 mediates myocardial necroptosis through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in cardiac ischemia-reperfusion (I/R) injury and heart failure. However, the exact mechanism of RIPK3 in advanced glycation end products (AGEs)-induced cardiomyocytes necroptosis is not clear. In this study, cardiomyocytes were subjected to AGEs stimulation for 24 h. RIPK3 expression, CaMKII expression, and necroptosis were determined in cardiomyocytes after AGEs stimulation. Then, cardiomyocytes were transfected with RIPK3 siRNA to downregulate RIPK3 followed by AGEs stimulation for 24 h. CaMKII delta alternative splicing, CaMKII activity, oxidative stress, necroptosis, and cell damage were detected again. Next, cardiomyocytes were pretreated with GSK ' 872, a specific RIPK3 inhibitor to assess whether it could protect cardiomyocytes against AGEs stimulation. We found that AGEs increased the expression of RIPK3, aggravated the disorder of CaMKII delta alternative splicing, promoted CaMKII activation, enhanced oxidative stress, induced necroptosis, and damaged cardiomyocytes. RIPK3 downregulation or RIPK3 inhibitor GSK ' 872 corrected CaMKII delta alternative splicing disorder, inhibited CaMKII activation, reduced oxidative stress, attenuated necroptosis, and improved cell damage in cardiomyocytes.
C1 [Hua, Yuyun; Qian, Jianan; Cao, Ji; Wang, Xue; Zhang, Wei; Zhang, Jingjing] Nantong Univ, Sch Pharm, Nantong 226001, Peoples R China.
   [Zhang, Wei; Zhang, Jingjing] Nantong Univ, Sch Med, Nantong 226001, Peoples R China.
C3 Nantong University; Nantong University
RP Zhang, W; Zhang, JJ (corresponding author), Nantong Univ, Sch Pharm, Nantong 226001, Peoples R China.; Zhang, W; Zhang, JJ (corresponding author), Nantong Univ, Sch Med, Nantong 226001, Peoples R China.
EM huayuyun@outlook.com; qjn29103@163.com; caojie@stmail.ntu.edu.cn;
   w18862936086@163.com; zhangw@ntu.edu.cn; zhangjingjing@stmail.ntu.edu.cn
RI Zhang, Wei/JKI-3565-2023
FU National Natural Science Foundation of China [81873470, 82070418]
FX This work was funded by grants (81873470 and 82070418) from the National
   Natural Science Foundation of China.
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NR 53
TC 6
Z9 6
U1 0
U2 10
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD JUL
PY 2022
VL 23
IS 13
AR 6988
DI 10.3390/ijms23136988
PG 19
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA 2Y1EO
UT WOS:000825635800001
PM 35805993
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Morisaki, H
   Morisaki, T
   Kariko, K
   Genetta, T
   Holmes, EW
AF Morisaki, H
   Morisaki, T
   Kariko, K
   Genetta, T
   Holmes, EW
TI Positive and negative elements mediate control of alternative splicing
   in the AMPD1 gene
SO GENE
LA English
DT Article
DE AMP deaminase; cis-element; processing; RNA
ID MOLECULAR-BASIS; RNA; SITE; DEAMINASE; EXON; TRANSCRIPTS; RECOGNITION;
   DEFICIENCY; EXPRESSION; SELECTION
AB The second exon of the AMP deaminase (AMPD) 1 gene is alternatively spliced in response to stage-specific signals elaborated during myocyte differentiation. Since inheritance of the mutation in exon 2 of the AMPD1 gene has been recently shown to be associated with a better prognosis of congestive heart failure and the alternative splicing of exon 2 modulates the residual activity of AMPD1 in individuals with this mutant allele, the regulatory mechanism of alternative splicing in the AMPD1 gene is clinically intriguing. Retention or exclusion of exon 2 results from the interplay between negative and positive elements in the primary transcript. Exon 2 is intrinsically defective and difficult to recognize. Herein, we show that this property of exon 2 is the consequence of three defects; a suboptimal 3' splice acceptor site, a suboptimal 5' splice donor site and the small size of the exon. An improvement in any one of these defects relieves the masking of this exon. Further, this defective exon can only be identified in the presence of the adjacent downstream intron. (C) 2000 Elsevier Science B.V. All rights reserved.
C1 Univ Penn, Dept Med, Philadelphia, PA 19104 USA.
   Univ Penn, Dept Genet, Philadelphia, PA 19104 USA.
   Natl Cardiovasc Ctr, Inst Res, Dept Biosci, Suita, Osaka, Japan.
C3 University of Pennsylvania; University of Pennsylvania; National
   Cerebral & Cardiovascular Center - Japan
RP Holmes, EW (corresponding author), Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA.
RI Holmes, Edward/GVR-9499-2022
FU NIDDK NIH HHS [DK12314] Funding Source: Medline
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NR 33
TC 3
Z9 3
U1 0
U2 1
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0378-1119
J9 GENE
JI Gene
PD APR 4
PY 2000
VL 246
IS 1-2
BP 365
EP 372
DI 10.1016/S0378-1119(00)00078-0
PG 8
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 304NP
UT WOS:000086490600038
PM 10767559
OA hybrid
DA 2025-04-10
ER

PT J
AU Biesiadecki, BJ
   Elder, BD
   Yu, ZB
   Jin, JP
AF Biesiadecki, BJ
   Elder, BD
   Yu, ZB
   Jin, JP
TI Cardiac troponin T variants produced by aberrant splicing of multiple
   exons in animals with high instances of dilated cardiomyopathy
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID ADULT ISOFORMS; HYPERTROPHIC CARDIOMYOPATHY; CONFORMATIONAL MODULATION;
   MOLECULAR-BASIS; HEART; EXPRESSION; BINDING; DISEASE; MODEL; GENE
AB Adult cardiac muscle normally expresses a single cardiac troponin T (cTnT). As a potential pathogenic mechanism for turkey dilated cardiomyopathy, the splice-out of a normally constitutive exon generates an additional low molecular weight cTnT with altered conformation and function. We further found that aberrant splicing of cTnT also occurs in several mammals correlating to dilated cardiomyopathy. Skipping of the same exon as that in the turkey was found in the canine cTnT. Splice-out of the adjacent exon 6 occurred in the guinea pig cTnT. Retention of the embryonic exon 5 was found in the cTnT of cat, dog, and guinea pig. These aberrant splicing variants significantly altered the structure of cTnT to sustain functional effects as that in the myopathic turkey cTnT. The genomic sequence of canine cTnT gene shows no specific alterations. However, the alternative splicing patterns of canine cTnT are different in developing cardiac and skeletal muscles, suggesting abnormality of trans-regulatory factors. Transgenic expression of the aberrant cTnT variants resulted in contractile changes in mouse cardiomyocytes. The findings support the hypothesis that thin filament heterogeneity due to the co-expression of alternatively spliced cTnT variants may desynchronize myocardial contraction and contribute to the pathogenesis and pathophysiology of cardiomyopathy and heart failure.
C1 Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA.
C3 University System of Ohio; Case Western Reserve University
RP Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, 10900 Euclid Ave, Cleveland, OH 44106 USA.
EM jxj12@po.cwru.edu
RI Jin, Jian-Ping/AAD-1149-2020
OI Jin, JP/0000-0001-9932-1063
FU NHLBI NIH HHS [T32-HL07887] Funding Source: Medline
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NR 48
TC 62
Z9 74
U1 0
U2 3
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI ROCKVILLE
PA 11200 ROCKVILLE PIKE, SUITE 302, ROCKVILLE, MD, UNITED STATES
SN 0021-9258
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD DEC 27
PY 2002
VL 277
IS 52
BP 50275
EP 50285
DI 10.1074/jbc.M206369200
PG 11
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 631QD
UT WOS:000180177700010
PM 12377784
OA hybrid
DA 2025-04-10
ER

PT J
AU Tian, XL
   Paul, M
AF Tian, XL
   Paul, M
TI Species-specific splicing and expression of angiotensin converting
   enzyme
SO BIOCHEMICAL PHARMACOLOGY
LA English
DT Article
DE ACE isoforms; RNA splicing; cloning; male maturation; cardiac
   hypertrophy
ID HEART-FAILURE; MOLECULAR-CLONING; MALE-FERTILITY; MICE; HYPERTENSION;
   GENE; SOLUBILIZATION; ACTIVATION; ISOZYME; ACE
AB Angiotensin converting enzyme (ACE) is a critical determinant in the pathogenesis of various cardiovascular diseases and in the control of male fertility. Multiple isoforms of ACE protein are present in body fluids and tissues, but their formation and functions in vivo remain to be investigated. To determine whether alternative splicing contributes to the formation of ACE isoforms, this study was designed to clone all possible spliced transcripts in rat. We found that the splicing of intron 13 in testicular ACE was species-dependent. Compared with human and mouse testicular ACE, rat testicular-ACE (rtACE) retained intron 13 in its mature transcripts. The insertion of the intron 13 did not change or shift the reading frame. Cloning and characterization of the rtACE showed that, in addition to testicular tissue, it was wildly expressed in somatic tissues, such as lung, kidney, cardiac ventricle, and skeletal muscle from both genders. Furthermore, we demonstrated that the expression of rtACE was developmentally up-regulated in testicular tissue and increased during cardiac hypertrophy. Our data suggests that the inclusion of intron 13 produces a novel ACE isoform. This isoform likely participates in local angiotensin II formation in both somatic and germinal tissues, and associates with certain physiological or pathophysiological events. (C) 2003 Elsevier Inc. All rights reserved.
C1 Free Univ Berlin, Benjamin Franklin Med Ctr, Inst Clin Pharmacol, Dept Toxicol, D-14195 Berlin, Germany.
   Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany.
C3 Berlin Institute of Health; Free University of Berlin; Humboldt
   University of Berlin; Charite Universitatsmedizin Berlin; Helmholtz
   Association; Max Delbruck Center for Molecular Medicine
RP Tian, XL (corresponding author), Cleveland Clin Fdn, Lerner Res Inst, Dept Mol Cardiol, ND4-67, Cleveland, OH 44195 USA.
RI Tian, Xiaoli/MIP-5310-2025; Paul, Martin/K-5425-2015
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NR 31
TC 10
Z9 12
U1 0
U2 2
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 0006-2952
J9 BIOCHEM PHARMACOL
JI Biochem. Pharmacol.
PD SEP 15
PY 2003
VL 66
IS 6
BP 1037
EP 1044
DI 10.1016/S0006-2952(03)00457-X
PG 8
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA 724RU
UT WOS:000185501200018
PM 12963491
DA 2025-04-10
ER

PT J
AU Bull, M
   Methawasin, M
   Strom, J
   Nair, P
   Hutchinson, K
   Granzier, H
AF Bull, Mathew
   Methawasin, Mei
   Strom, Joshua
   Nair, Pooja
   Hutchinson, Kirk
   Granzier, Henk
TI Alternative Splicing of Titin Restores Diastolic Function in an
   HFpEF-Like Genetic Murine Model (Ttn<SUP>IAjxn</SUP>)
SO CIRCULATION RESEARCH
LA English
DT Article
DE compliance; diastole; diastolic heart failure; hypertrophy; myocardium
ID PRESERVED EJECTION FRACTION; HEART-FAILURE; CARDIAC TITIN;
   SKELETAL-MUSCLE; MECHANISM; STRESS; PHOSPHORYLATION; DYSFUNCTION;
   PREVALENCE; EXPRESSION
AB Rationale: Patients with heart failure with preserved ejection fraction (HFpEF) experience elevated filling pressures and reduced ventricular compliance. The splicing factor RNA-binding motif 20 (RBM20) regulates the contour length of titin's spring region and thereby determines the passive stiffness of cardiomyocytes. Inhibition of RBM20 leads to super compliant titin isoforms (N2BAsc) that reduce passive stiffness.
   Objective: To determine the therapeutic potential of upregulating compliant titin isoforms in an HFpEF-like state in the mouse.
   Methods and Results: Constitutive and inducible cardiomyocyte-specific RBM20-inhibited mice were produced on a Ttn(IAjxn) background to assess the effect of upregulating compliant titin at the cellular and organ levels. Genetic deletion of the I-band-A-band junction (IAjxn) in titin increases strain on the spring region and causes a HFpEF-like syndrome in the mouse without pharmacological or surgical intervention. The increased strain represents a mechanical analog of deranged post-translational modification of titin that results in increased passive myocardial stiffness in patients with HFpEF. On inhibition of RBM20 in Ttn(IAjxn) mice, compliant titin isoforms were expressed, diastolic function was normalized, exercise performance was improved, and pathological hypertrophy was attenuated.
   Conclusions: We report for the first time a benefit from upregulating compliant titin isoforms in a murine model with HFpEF-like symptoms. Constitutive and inducible RBM20 inhibition improves diastolic function resulting in greater tolerance to exercise. No effective therapies exists for treating this pervasive syndrome; therefore, our data on RBM20 inhibition are clinically significant.
C1 [Bull, Mathew; Methawasin, Mei; Strom, Joshua; Nair, Pooja; Hutchinson, Kirk; Granzier, Henk] Univ Arizona, Dept Cellular & Mol Med, Med Res Bldg MRB 325,1656 E Mabel St, Tucson, AZ 85724 USA.
   [Bull, Mathew; Methawasin, Mei; Strom, Joshua; Nair, Pooja; Hutchinson, Kirk; Granzier, Henk] Univ Arizona, Sarver Mol Cardiovasc Res Program, Tucson, AZ 85724 USA.
C3 University of Arizona; University of Arizona
RP Granzier, H (corresponding author), Univ Arizona, Dept Cellular & Mol Med, Med Res Bldg MRB 325,1656 E Mabel St, Tucson, AZ 85724 USA.; Granzier, H (corresponding author), Univ Arizona, Sarver Mol Cardiovasc Res Program, Tucson, AZ 85724 USA.
EM granzier@email.arizona.edu
OI Strom, Joshua/0000-0003-1236-1877; Methawasin, Mei/0000-0002-2509-1936
FU Van Denburgh ARCS; National Institutes of Health [HL062881, HL118524];
   Foundation Leducq [TNE-13CVD04];  [T32HL007249]
FX This work was supported by training grant T32HL007249 and Van Denburgh
   ARCS award to (M. Bull), National Institutes of Health grants HL062881
   and HL118524, and Foundation Leducq TNE-13CVD04 (H. Granzier).
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NR 39
TC 29
Z9 31
U1 0
U2 8
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7330
EI 1524-4571
J9 CIRC RES
JI Circ.Res.
PD SEP 2
PY 2016
VL 119
IS 6
BP 764
EP 772
DI 10.1161/CIRCRESAHA.116.308904
PG 9
WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Hematology
GA DW0JT
UT WOS:000383327400016
PM 27470639
OA Bronze, Green Accepted
DA 2025-04-10
ER

PT J
AU Dasgupta, T
   Stillwagon, SJ
   Ladd, AN
AF Dasgupta, Twishasri
   Stillwagon, Samantha J.
   Ladd, Andrea N.
TI Gene Expression Analyses Implicate an Alternative Splicing Program in
   Regulating Contractile Gene Expression and Serum Response Factor
   Activity in Mice
SO PLOS ONE
LA English
DT Article
ID RNA-BINDING PROTEINS; CARDIAC-HYPERTROPHY; ANKYRIN-B; TRANSGENIC MICE;
   HOMEOBOX GENE; CELF; CARDIOMYOCYTES; CARDIOMYOPATHY; HEART;
   OVEREXPRESSION
AB Members of the CUG-BP, Elav-like family (CELF) regulate alternative splicing in the heart. In MHC-CELF Delta transgenic mice, CELF splicing activity is inhibited postnatally in heart muscle via expression of a nuclear dominant negative CELF protein under an alpha-myosin heavy chain promoter. MHC-CELF Delta mice develop dilated cardiomyopathy characterized by alternative splicing defects, enlarged hearts, and severe contractile dysfunction. In this study, gene expression profiles in the hearts of wild type, high- and low-expressing lines of MHC-CELF Delta mice were compared using microarrays. Gene ontology and pathway analyses identified contraction and calcium signaling as the most affected processes. Network analysis revealed that the serum response factor (SRF) network is highly affected. Downstream targets of SRF were up-regulated in MHC-CELF Delta mice compared to the wild type, suggesting an increase in SRF activity. Although SRF levels remained unchanged, known inhibitors of SRF activity were down-regulated. Conversely, we found that these inhibitors are up-regulated and downstream SRF targets are down-regulated in the hearts of MCKCUG-BP1 mice, which mildly over-express CELF1 in heart and skeletal muscle. This suggests that changes in SRF activity are a consequence of changes in CELF-mediated regulation rather than a secondary result of compensatory pathways in heart failure. In MHC-CELF Delta males, where the phenotype is only partially penetrant, both alternative splicing changes and down-regulation of inhibitors of SRF correlate with the development of cardiomyopathy. Together, these results strongly support a role for CELF-mediated alternative splicing in the regulation of contractile gene expression, achieved in part through modulating the activity of SRF, a key cardiac transcription factor.
C1 [Dasgupta, Twishasri; Stillwagon, Samantha J.; Ladd, Andrea N.] Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44106 USA.
C3 Cleveland Clinic Foundation
RP Ladd, AN (corresponding author), Cleveland Clin, Lerner Res Inst, Dept Cellular & Mol Med, Cleveland, OH 44106 USA.
EM ladda@ccf.org
OI Ladd, Andrea/0000-0003-4725-5644; Auboeuf, Didier/0000-0002-3757-0002
FU National Heart, Lung, and Blood Institute of the National Institutes of
   Health [R01HL089376]
FX This work was supported by a grant to ANL from the National Heart, Lung,
   and Blood Institute of the National Institutes of Health (R01HL089376).
   The funders had no role in study design, data collection and analysis,
   decision to publish, or preparation of the manuscript.
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NR 40
TC 11
Z9 13
U1 0
U2 6
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD FEB 20
PY 2013
VL 8
IS 2
AR e56590
DI 10.1371/journal.pone.0056590
PG 13
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 093IE
UT WOS:000315184200117
PM 23437181
OA gold, Green Published, Green Submitted
DA 2025-04-10
ER

PT J
AU Ortiz-Sánchez, P
   Villalba-Orero, M
   López-Olañeta, MM
   Larrasa-Alonso, J
   Sánchez-Cabo, F
   Martí-Gómez, C
   Camafeita, E
   Gómez-Salinero, JM
   Ramos-Hernández, L
   Nielsen, PJ
   Vázquez, J
   Müller-McNicoll, M
   García-Pavía, P
   Lara-Pezzi, E
AF Ortiz-Sanchez, Paula
   Villalba-Orero, Maria
   Lopez-Olaneta, Marina M.
   Larrasa-Alonso, Javier
   Sanchez-Cabo, Fatima
   Marti-Gomez, Carlos
   Camafeita, Emilio
   Gomez-Salinero, Jesus M.
   Ramos-Hernandez, Laura
   Nielsen, Peter J.
   Vazquez, Jesus
   Mueller-McNicoll, Michaela
   Garcia-Pavia, Pablo
   Lara-Pezzi, Enrique
TI Loss of SRSF3 in Cardiomyocytes Leads to Decapping of
   Contraction-Related mRNAs and Severe Systolic Dysfunction
SO CIRCULATION RESEARCH
LA English
DT Article
DE alternative splicing; mRNA decapping; myocardial contraction; myocardial
   infarction; phosphorylation
ID SPLICING FACTOR SRSF3; SR PROTEINS; SRP20; GENE; PHOSPHORYLATION;
   QUANTIFICATION; CARDIOMYOPATHY; HYPERTROPHY; TRANSLATION; METABOLISM
AB Rationale: RBPs (RNA binding proteins) play critical roles in the cell by regulating mRNA transport, splicing, editing, and stability. The RBP SRSF3 (serine/arginine-rich splicing factor 3) is essential for blastocyst formation and for proper liver development and function. However, its role in the heart has not been explored. Objective: To investigate the role of SRSF3 in cardiac function. Methods and Results: Cardiac SRSF3 expression was high at mid gestation and decreased during late embryonic development. Mice lacking SRSF3 in the embryonic heart showed impaired cardiomyocyte proliferation and died in utero. In the adult heart, SRSF3 expression was reduced after myocardial infarction, suggesting a possible role in cardiac homeostasis. To determine the role of this RBP in the adult heart, we used an inducible, cardiomyocyte-specific SRSF3 knockout mouse model. After SRSF3 depletion in cardiomyocytes, mice developed severe systolic dysfunction that resulted in death within 8 days. RNA-Seq analysis revealed downregulation of mRNAs encoding sarcomeric and calcium handling proteins. Cardiomyocyte-specific SRSF3 knockout mice also showed evidence of alternative splicing of mTOR (mammalian target of rapamycin) mRNA, generating a shorter protein isoform lacking catalytic activity. This was associated with decreased phosphorylation of 4E-BP1 (eIF4E-binding protein 1), a protein that binds to eIF4E (eukaryotic translation initiation factor 4E) and prevents mRNA decapping. Consequently, we found increased decapping of mRNAs encoding proteins involved in cardiac contraction. Decapping was partially reversed by mTOR activation. Conclusions: We show that cardiomyocyte-specific loss of SRSF3 expression results in decapping of critical mRNAs involved in cardiac contraction. The molecular mechanism underlying this effect likely involves the generation of a short mTOR isoform by alternative splicing, resulting in reduced 4E-BP1 phosphorylation. The identification of mRNA decapping as a mechanism of systolic heart failure may open the way to the development of urgently needed therapeutic tools.
C1 [Ortiz-Sanchez, Paula; Villalba-Orero, Maria; Lopez-Olaneta, Marina M.; Larrasa-Alonso, Javier; Sanchez-Cabo, Fatima; Marti-Gomez, Carlos; Camafeita, Emilio; Gomez-Salinero, Jesus M.; Ramos-Hernandez, Laura; Vazquez, Jesus; Lara-Pezzi, Enrique] CNIC, Madrid, Spain.
   [Ortiz-Sanchez, Paula; Garcia-Pavia, Pablo] Hosp Univ Puerta Hierro, Dept Cardiol, Heart Failure & Inherited Cardiac Dis Unit, Madrid, Spain.
   [Nielsen, Peter J.] Max Planck Inst Immunobiol & Epigenet, Freiburg, Germany.
   [Vazquez, Jesus; Garcia-Pavia, Pablo; Lara-Pezzi, Enrique] Ctr Invest Biomed Red Cardiovasc CIBERCV, Madrid, Spain.
   [Mueller-McNicoll, Michaela] Goethe Univ Frankfurt, Inst Cell Biol & Neurosci, Frankfurt, Germany.
   [Garcia-Pavia, Pablo] UFV, Fac Ciencias Salud, Madrid, Spain.
   [Lara-Pezzi, Enrique] Imperial Coll London, Natl Heart & Lung Inst, London, England.
C3 Centro Nacional de Investigaciones Cardiovasculares (CNIC); Hospital
   Puerta de Hierro-Majadahonda; Max Planck Society; CIBER - Centro de
   Investigacion Biomedica en Red; CIBERCV; Goethe University Frankfurt;
   Imperial College London
RP Lara-Pezzi, E (corresponding author), Ctr Nacl Invest Cardiovasc Carlos III, Myocardial Pathophysiol Area, Melchor Fernandez Almagro 3, Madrid 28029, Spain.
EM elara@cnic.es
RI Sanchez-Cabo, Fatima/IZD-8966-2023; Müller-McNicoll,
   Michaela/AAC-6125-2019; Garcia-Pavia, Pablo/T-9100-2019; Villalba-Orero,
   María/P-1331-2019; Marti Gomez-Aldaravi, Carlos/W-4936-2018; Vazquez,
   Jesus/B-7697-2015; Lara-Pezzi, Enrique/E-2350-2015; Sanchez-Cabo,
   Fatima/N-5030-2014; Villalba Orero, Maria/B-6765-2016
OI Garcia-Pavia, Pablo/0000-0002-5470-2257; Marti Gomez-Aldaravi,
   Carlos/0000-0002-2042-843X; Ares, Manny/0000-0002-2552-9168; Vazquez,
   Jesus/0000-0003-1461-5092; Lara-Pezzi, Enrique/0000-0002-2743-1033;
   Sanchez-Cabo, Fatima/0000-0003-1881-1664; Ramos hernandez,
   Laura/0000-0002-1454-0388; Muller-McNicoll,
   Michaela/0000-0002-7174-8310; Villalba Orero, Maria/0000-0002-7680-3980
FU European Union [CardioNeT-ITN-289600, CardioNext-ITN-608027]; Spanish
   Ministerio de Economia y Competitividad [RTI2018-096961-B-I00,
   SAF2015-65722-R, SAF2012-31451, BIO2015-67580-P, PGC2018-097019-B-I00];
   Spanish Carlos III Institute of Health [CPII14/00027, RD12/0042/066,
   RD12/0042/0056, PRB2-IPT13/0001-ISCIII-SGEFI/FEDER]; Madrid Regional
   Government [2010-BMD-2321]; Plan Estatal de I+D+I 2013-2016-European
   Regional Development Fund (ERDF) A way of making Europe, Spain;
   Ministerio de Ciencia, Innovacion y Universidades (MCNU); Pro CNIC
   Foundation
FX This study was supported by grants from the European Union
   (CardioNeT-ITN-289600 and CardioNext-ITN-608027 to E. Lara-Pezzi), from
   the Spanish Ministerio de Economia y Competitividad
   (RTI2018-096961-B-I00, SAF2015-65722-R, and SAF2012-31451 to E.
   Lara-Pezzi; BIO2015-67580-P and PGC2018-097019-B-I00 to J. Vazquez), the
   Spanish Carlos III Institute of Health (CPII14/00027 to E. Lara-Pezzi,
   RD12/0042/066 to P. Garcia-Pavia and E. Lara-Pezzi, and RD12/0042/0056,
   PRB2-IPT13/0001-ISCIII-SGEFI/FEDER, ProteoRed to J. Vazquez), the Madrid
   Regional Government (2010-BMD-2321 Fibroteam to E. Lara-Pezzi). This
   study was also supported by the Plan Estatal de I+D+I 2013-2016-European
   Regional Development Fund (ERDF) A way of making Europe, Spain. The CNIC
   is supported by the Ministerio de Ciencia, Innovacion y Universidades
   (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of
   Excellence (SEV-2015-0505).
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NR 50
TC 98
Z9 102
U1 1
U2 15
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7330
EI 1524-4571
J9 CIRC RES
JI Circ.Res.
PD JUL 5
PY 2019
VL 125
IS 2
BP 170
EP 183
DI 10.1161/CIRCRESAHA.118.314515
PG 14
WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Hematology
GA IG9XM
UT WOS:000474146200005
PM 31145021
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Kiczak, L
   Walecka-Zacharska, E
   Bania, J
   Sambor, I
   Stefaniak, T
   Dziegiel, P
   Zacharski, M
   Tomaszek, A
   Rybinska, I
   Paslawska, U
AF Kiczak, L.
   Walecka-Zacharska, E.
   Bania, J.
   Sambor, I.
   Stefaniak, T.
   Dziegiel, Piotr
   Zacharski, M.
   Tomaszek, A.
   Rybinska, I.
   Paslawska, U.
TI Anti-inflammatory properties and expression in selected organs of canine
   interleukin-1β splice variant 1
SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY
LA English
DT Article
DE Dog; Interleukin-1 beta; Alternative splicing; Liver; Lung; Inflamation
ID HEART-FAILURE; IL-33; TRANSCRIPTION; IL-1-BETA; MONOCYTES
AB The IL-1 beta gene can be also be spliced with the intron 4 retention; the result is a IL-1 beta splice variant 1 (IL-1 beta sv1), which was significantly up-regulated in failing myocardium of dogs suffering from chronic degenerative valvular disease (CDVD). Expression of IL-1 beta sv1 was assessed, at both RNA and protein levels, in organs affected by heart failure, namely, kidneys, liver, and lungs from 35 dogs suffering chronic degenerative valvular disease (CDVD) and in 20 disease free control dogs. IL-1 beta sv1 RNA was detected in the dogs from both groups. In the CDVD group, the highest RNA and protein IL-1 beta sv1 levels were observed in lungs, followed, in that order, by the liver and kidneys. IL-1 beta sv1 protein was found in the cytoplasm of hepatocytes and IL-1 beta sv1-overexpressing DH82 cells. In lungs, IL-1 beta sv1 was localized in the cytoplasm and in the nuclei of bronchiolar epithelial and smooth-muscle cells. Cytoplasmic and nuclear IL-1 beta sv1 expression was observed in macrophages, and a strong nuclear signal was detected in epithelial cells of the alveolar sacs. Following lipopolysaccharide (LPS) stimulation, overexpression of IL-1 beta sv1 in DH82 cells decreased the pro-inflammatory response. Our results indicate that IL-1 beta sv1 is constitutively expressed in both normal tissues and in tissues from cases of heart failure. The presence of IL-1 beta sv1 in tissues exposed to invading agents and its anti-inflammatory activity in DH82 cells may point to its immunomodulatory role in vivo. (C) 2015 Elsevier B.V. All rights reserved.
C1 [Kiczak, L.; Sambor, I.; Zacharski, M.] Wroclaw Univ Environm & Life Sci, Dept Biochem Pharmacol & Toxicol, Fac Vet Med, Norwida 31, PL-50375 Wroclaw, Poland.
   [Walecka-Zacharska, E.; Bania, J.] Wroclaw Univ Environm & Life Sci, Dept Food Hyg & Consumer Protect, Fac Vet Med, PL-50375 Wroclaw, Poland.
   [Stefaniak, T.] Wroclaw Univ Environm & Life Sci, Dept Immunol, Fac Vet Med, PL-50375 Wroclaw, Poland.
   [Dziegiel, Piotr] Wroclaw Med Univ, Dept Histol & Embryol, Wroclaw, Poland.
   [Tomaszek, A.; Rybinska, I.] Wroclaw Med Univ, Dept Heart Dis, Wroclaw, Poland.
   [Tomaszek, A.; Paslawska, U.] Wroclaw Univ Environm & Life Sci, Dept Internal Dis Clin Horses Dogs & Cats, Fac Vet Med, PL-50375 Wroclaw, Poland.
C3 Wroclaw University of Environmental & Life Sciences; Wroclaw University
   of Environmental & Life Sciences; Wroclaw University of Environmental &
   Life Sciences; Wroclaw Medical University; Wroclaw Medical University;
   Wroclaw University of Environmental & Life Sciences
RP Kiczak, L (corresponding author), Wroclaw Univ Environm & Life Sci, Dept Biochem Pharmacol & Toxicol, Fac Vet Med, Norwida 31, PL-50375 Wroclaw, Poland.
EM liliana.kiczak@up.wroc.pl
RI Stefaniak, Tadeusz/A-1897-2017; Rybinska, Ilona/AAN-8041-2020;
   Zacharski, Maciej/K-7138-2018; Paslawska, Urszula/S-7691-2016; Bania,
   Jacek/S-5633-2016; Stefaniak, Tadeusz/M-8386-2018; Rybinska,
   Ilona/J-7084-2017
OI Stefaniak, Tadeusz/0000-0002-8982-211X; Dziegiel,
   Piotr/0000-0002-8292-1385; Rybinska, Ilona/0000-0003-4871-9922;
   Zacharski, Maciej/0000-0002-9947-4980
FU Polish Ministry of Science and Higher Education [N N 308 3037 33]
FX This study was supported by the Polish Ministry of Science and Higher
   Education Project No. N N 308 3037 33. We are grateful to Dr Michal
   Majkowski (University of Wroclaw) for his help with confocal microscopy.
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NR 33
TC 0
Z9 0
U1 0
U2 9
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0165-2427
EI 1873-2534
J9 VET IMMUNOL IMMUNOP
JI Vet. Immunol. Immunopathol.
PD OCT 15
PY 2015
VL 167
IS 3-4
BP 91
EP 95
DI 10.1016/j.vetimm.2015.07.007
PG 5
WC Immunology; Veterinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Immunology; Veterinary Sciences
GA CT8OX
UT WOS:000363077000001
PM 26239893
DA 2025-04-10
ER

PT J
AU Lara-Pezzi, E
   Gómez-Salinero, J
   Gatto, A
   García-Pavía, P
AF Lara-Pezzi, Enrique
   Gomez-Salinero, Jesus
   Gatto, Alberto
   Garcia-Pavia, Pablo
TI The Alternative Heart: Impact of Alternative Splicing in Heart Disease
SO JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
LA English
DT Article
DE Alternative splicing; Molecular cardiology; Sarcomere; Cell signalling;
   Ion channels; Antisense oligonucleotides
ID CARDIAC TROPONIN-T; PRE-MESSENGER-RNA; UNFOLDED PROTEIN RESPONSE;
   BINDING-PROTEIN; DILATED CARDIOMYOPATHY; HYPERTROPHIC CARDIOMYOPATHY;
   MYOTONIC-DYSTROPHY; PASSIVE STIFFNESS; ALPHA-TROPOMYOSIN; CHLORIDE
   CHANNEL
AB Alternative splicing is the main driver of protein diversity and allows the production of different proteins from each gene in the genome. Changes in exon exclusion, intron retention or the use of alternative splice sites can alter protein structure, localisation, regulation and function. In the heart, alternative splicing of sarcomeric genes, ion channels and cell signalling proteins can lead to cardiomyopathies, arrhythmias and other pathologies. Also, a number of inherited conditions and heart-related diseases develop as a result of mutations affecting splicing. Here, we review the impact that changes in alternative splicing have on individual genes and on whole biological processes associated with heart disease. We also discuss promising therapeutic tools based on the manipulation of alternative splicing.
C1 [Lara-Pezzi, Enrique; Gomez-Salinero, Jesus; Gatto, Alberto] Ctr Nacl Invest Cardiovasc, Cardiovasc Dev & Repair Dept, Madrid 28029, Spain.
   [Garcia-Pavia, Pablo] Hosp Univ Puerta Hierro Majadahonda, Dept Cardiol, Madrid, Spain.
C3 Centro Nacional de Investigaciones Cardiovasculares (CNIC); Hospital
   Puerta de Hierro-Majadahonda
RP Lara-Pezzi, E (corresponding author), Ctr Nacl Invest Cardiovasc, Cardiovasc Dev & Repair Dept, Melchor Fernandez Almagro 3, Madrid 28029, Spain.
EM elara@cnic.es
RI Gatto, Alberto/GQI-4247-2022; Garcia-Pavia, Pablo/T-9100-2019;
   Lara-Pezzi, Enrique/E-2350-2015
OI Garcia-Pavia, Pablo/0000-0002-5470-2257; Lara-Pezzi,
   Enrique/0000-0002-2743-1033; Gatto, Alberto/0000-0002-8378-0131
FU European Union [ITN-289600]; Spanish Ministry of Economy
   [SAF2012-31451]; Madrid Regional Government [S2010/BMD-2321]; Instituto
   de Salud Carlos III (Red Enfermedades Cardiovasculares) [RD12/0042/0002]
FX E.L-P. is supported by grants from the European Union's FP7 ("CardioNeT"
   ITN-289600), the Spanish Ministry of Economy (SAF2012-31451) and from
   the Madrid Regional Government ("Fibroteam", S2010/BMD-2321). P.G-P. and
   E.L-P. are supported by the Instituto de Salud Carlos III (Red
   Enfermedades Cardiovasculares RD12/0042/0002).
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NR 113
TC 68
Z9 76
U1 0
U2 15
PU SPRINGER
PI NEW YORK
PA 233 SPRING ST, NEW YORK, NY 10013 USA
SN 1937-5387
EI 1937-5395
J9 J CARDIOVASC TRANSL
JI J. Cardiovasc. Transl. Res.
PD DEC
PY 2013
VL 6
IS 6
SI SI
BP 945
EP 955
DI 10.1007/s12265-013-9482-z
PG 11
WC Cardiac & Cardiovascular Systems; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Research & Experimental Medicine
GA 258KW
UT WOS:000327459200007
PM 23775418
DA 2025-04-10
ER

PT J
AU Hartmann, M
   Skryabin, BV
   Müller, T
   Gazinski, A
   Schröter, J
   Gassner, B
   Nikolaev, VO
   Bünemann, M
   Kuhn, M
AF Hartmann, Michael
   Skryabin, Boris V.
   Mueller, Thomas
   Gazinski, Alexandra
   Schroeter, Juliane
   Gassner, Birgit
   Nikolaev, Viacheslav O.
   Buenemann, Moritz
   Kuhn, Michaela
TI Alternative splicing of the guanylyl cyclase-A receptor modulates atrial
   natriuretic peptide signaling
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID ESSENTIAL-HYPERTENSION; DOWN-REGULATION; BINDING DOMAIN; HEART-FAILURE;
   SPLIT GENES; NPR-B; PROTEIN; MICE; IDENTIFICATION; POLYMORPHISMS
AB Atrial (ANP) and B-type natriuretic peptides (BNP) modulate blood pressure and volume through the stimulation of cyclic GMP production by their guanylyl cyclase-A (GC-A) receptor. A novel isoform of GC-A has been identified that is the result of differential splicing of exon 4. The deletion of a 51-bp sequence is predicted to delete 17 amino acids (Lys(314)-Gln(330)) in the membrane-distal part of the extracellular domain. Reverse transcription-PCR analyses demonstrated low messenger RNA expression levels of spliced GC-A in all tissues. Homology modeling suggested that the alterations in the protein structure could interfere with ANP binding or signaling. Indeed, functional studies in transfected HEK 293 cells demonstrated that binding of ANP and ANP-induced cyclic GMP formation by GC-A Delta(Lys314-Gln330) were totally abolished. Furthermore, cotransfection studies showed that this GC-A variant forms heterodimers with the wild type receptor and inhibits ligand-inducible cGMP generation. Finally, treatment of mice with angiotensin II (300 ng/kg/min during 7 days) resulted in enhanced pulmonary mRNA expression of spliced GC-A, which was concomitant to diminished GC-A/cGMP responses to ANP. We conclude that alternative splicing can regulate endogenous ANP/GC-A signaling. Angiotensin II-induced alternative splicing of GC-A may represent a novel mechanism for reducing the sensitivity to ANP.
C1 [Hartmann, Michael; Gazinski, Alexandra; Schroeter, Juliane; Gassner, Birgit; Kuhn, Michaela] Univ Wurzburg, Inst Physiol, D-97070 Wurzburg, Germany.
   [Skryabin, Boris V.] Univ Hosp Munster, Inst Expt Pathol, D-48149 Munster, Germany.
   [Mueller, Thomas] Univ Wurzburg, Dept Mol Plant Physiol & Biophys, Julius von Sachs Inst, Bioctr, D-97070 Wurzburg, Germany.
   [Nikolaev, Viacheslav O.; Buenemann, Moritz] Univ Wurzburg, Inst Pharmacol & Toxicol, D-97070 Wurzburg, Germany.
C3 University of Wurzburg; University of Munster; University of Wurzburg;
   University of Wurzburg
RP Kuhn, M (corresponding author), Univ Wurzburg, Inst Physiol, Rontgenring 9, D-97070 Wurzburg, Germany.
EM michaela.kuhn@mail.uni-wuerzburg.de
RI Nikolaev, Vyacheslav/AAT-7746-2020; Skryabin, Boris/AAL-3100-2020;
   Müller, Timo/AAZ-4445-2020; Buenemann, Moritz/ADE-7767-2022
OI Skryabin, Boris/0000-0002-4392-185X; Mueller,
   Thomas/0000-0003-1862-7357; Buenemann, Moritz/0000-0002-2259-4378
FU Deutsche Forschungsgemeinschaft Sonderforschungsbereich 487;
   Sonderforschungsbereich 688
FX This work was supported by Deutsche Forschungsgemeinschaft
   Sonderforschungsbereich 487 (to T. M., M. B., and M. K.) and
   Sonderforschungsbereich 688 (to M. K.). The costs of publication of this
   article were defrayed in part by the payment of page charges. This
   article must therefore be hereby marked "advertisement" in accordance
   with 18 U.S.C. Section 1734 solely to indicate this fact.
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NR 37
TC 10
Z9 12
U1 0
U2 2
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD OCT 17
PY 2008
VL 283
IS 42
BP 28313
EP 28320
DI 10.1074/jbc.M805521200
PG 8
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 359EN
UT WOS:000259969300033
PM 18713751
OA Green Published
DA 2025-04-10
ER

PT J
AU Feng, L
   Guo, M
   Jin, CR
AF Feng, Li
   Guo, Min
   Jin, Chunrong
TI Identification of alternative splicing and RNA-binding proteins involved
   in myocardial ischemia-reperfusion injury
SO GENOME
LA English
DT Article
DE myocardial ischemia-reperfusion injury (MIRI); RNA-seq; regulated
   alternative splicing events (RASEs); RNA-binding proteins (RBPs)
ID CARDIAC-FUNCTION; APOPTOSIS; ANNEXINS
AB Alternative splicing (AS) and RNA-binding proteins (RBPs) have been implicated in various cardiovascular diseases. Yet, a comprehensive understanding of their role in myocardial ischemia-reperfusion injury (MIRI) remains elusive. We aimed to identify potential therapeutic targets for MIRI by studying genome-wide changes in AS events and RBPs. We analyzed RNA-seq data from ischemia-reperfusion mouse models and the control group from the GSE130217 data set using Splicing Site Usage Variation Analysis software. We identified 28 regulated alternative splicing events (RASEs) and 47 differentially expressed RBP (DE-RBP) genes in MIRI. Most variable splicing events were involved in cassette exon, alternative 5' splice, alternative 3' splice, and retained intron types. Gene Ontology and Kyoto Encyclopedia of Genes (KOBAS 2.0 server) and Genomes pathway enrich-ment analyses showed that the differentially expressed variable splicing and RBP genes were mainly enriched in pathways related to myocardial function. The RBP-RASE network demonstrated a common variance relationship between DE-RBPs and RASEs, indicating that RBPs regulate variable shear events in MIRI. This study systematically identified important alterations in RASEs and RBPs in MIRI, expanding our understanding of the underlying pathogenesis of MIRI.
C1 [Feng, Li; Guo, Min; Jin, Chunrong] Shanxi Med Univ, Hosp 1, Dept Cardiol, Taiyuan 030001, Shanxi, Peoples R China.
C3 Shanxi Medical University
RP Jin, CR (corresponding author), Shanxi Med Univ, Hosp 1, Dept Cardiol, Taiyuan 030001, Shanxi, Peoples R China.
EM chunrong_jin@163.com
OI , Chunrong Jin/0000-0002-1414-7914
FU Key Ramp;D Project of Shanxi Province [201903D321181]
FX Funding information This research was supported by the Key R&D Project
   of Shanxi Province (201903D321181) .
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NR 40
TC 4
Z9 4
U1 0
U2 6
PU CANADIAN SCIENCE PUBLISHING
PI OTTAWA
PA 123 Slater Street, Suite 610, OTTAWA, ON K1P 5H2, CANADA
SN 0831-2796
EI 1480-3321
J9 GENOME
JI Genome
PD OCT
PY 2023
VL 66
IS 10
BP 261
EP 268
DI 10.1139/gen-2022-0102
EA JUL 2023
PG 8
WC Biotechnology & Applied Microbiology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Genetics & Heredity
GA T3SK1
UT WOS:001034481000001
PM 37466303
DA 2025-04-10
ER

PT J
AU Chen, ZL
   Song, JP
   Chen, L
   Zhu, CQ
   Cai, HF
   Sun, MM
   Stern, A
   Mozdziak, P
   Ge, Y
   Means, WJ
   Guo, W
AF Chen, Zhilong
   Song, Jiangping
   Chen, Liang
   Zhu, Chaoqun
   Cai, Hanfang
   Sun, Mingming
   Stern, Allysa
   Mozdziak, Paul
   Ge, Ying
   Means, Warrie J.
   Guo, Wei
TI Characterization of TTN Novex Splicing Variants across Species and the
   Role of RBM20 in Novex-Specific Exon Splicing
SO GENES
LA English
DT Article
DE TTN; RBM20; Novex isoforms; cardiomyopathy; alternative splicing
ID TITIN ISOFORM EXPRESSION; CARDIAC TITIN; DILATED CARDIOMYOPATHY;
   HEART-FAILURE; DIASTOLIC DYSFUNCTION; Z-LINE; STIFFNESS; MYOCARDIUM;
   SEQUENCE; DISEASE
AB Titin (TTN) is a major disease-causing gene in cardiac muscle. Titin (TTN) contains 363 exons in human encoding various sizes of TTN protein due to alternative splicing regulated mainly by RNA binding motif 20 (RBM20). Three isoforms of TTN protein are produced by mutually exclusive exons 45 (Novex 1), 46 (Novex 2), and 48 (Novex 3). Alternatively splicing in Novex isoforms across species and whether Novex isoforms are associated with heart disease remains completely unknown. Cross-species exon comparison with the mVISTA online tool revealed that exon 45 is more highly conserved across all species than exons 46 and 48. Importantly, a conserved region between exons 47 and 48 across species was revealed for the first time. Reverse transcript polymerase chain reaction (RT-PCR) and DNA sequencing confirmed a new exon named as 48 in Novex 3. In addition, with primer pairs for Novex 1, a new truncated form preserving introns 44 and 45 was discovered. We discovered that Novex 2 is not expressed in the pig, mouse, and rat with Novex 2 primer pairs. Unexpectedly, three truncated forms were identified. One TTN variant with intron 46 retention is mainly expressed in the human and frog heart, another variant with co-expression of exons 45 and 46 exists predominantly in chicken and frog heart, and a third with retention of introns 45 and 46 is mainly expressed in pig, mouse, rat, and chicken. Using Rbm20 knockout rat heart, we revealed that RBM20 is not a splicing regulator of Novex variants. Furthermore, the expression levels of Novex variants in human hearts with cardiomyopathies suggested that Novexes 2 and 3 could be associated with dilated cardiomyopathy (DCM) and/or arrhythmogenic right ventricular cardiomyopathy (ARVC). Taken together, our study reveals that splicing diversity of Novex exons across species and Novex variants might play a role in cardiomyopathy.
C1 [Chen, Zhilong; Cai, Hanfang] Northwest A&F Univ, Coll Anim Sci & Technol, Yangling 712100, Peoples R China.
   [Chen, Zhilong; Zhu, Chaoqun; Cai, Hanfang; Sun, Mingming; Means, Warrie J.; Guo, Wei] Univ Wyoming, Anim Sci, Laramie, WY 82071 USA.
   [Song, Jiangping; Chen, Liang] Chinese Acad Med Sci, Fuwai Hosp, Natl Ctr Cardiovasc Dis, Dept Cardiac Surg,State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China.
   [Song, Jiangping; Chen, Liang] Peking Union Med Coll, Beijing 100730, Peoples R China.
   [Stern, Allysa; Mozdziak, Paul] North Carolina State Univ, Prestage Dept Poultry Sci, Raleigh, NC 27695 USA.
   [Ge, Ying] Univ Wisconsin, Dept Chem, Dept Cell & Regenerat Biol, Human Prote Program, Madison, WI 53705 USA.
C3 Northwest A&F University - China; University of Wyoming; Chinese Academy
   of Medical Sciences - Peking Union Medical College; Fu Wai Hospital -
   CAMS; Chinese Academy of Medical Sciences - Peking Union Medical
   College; Peking Union Medical College; North Carolina State University;
   University of Wisconsin System; University of Wisconsin Madison
RP Guo, W (corresponding author), Univ Wyoming, Anim Sci, Laramie, WY 82071 USA.
EM zhilongchen@sina.com; fwsongjiangping@126.com; chenliang_2012@126.com;
   czhu1@uwyo.edu; hcai@uwyo.edu; msun2@uwyo.edu; rastern@ncsu.edu;
   pemozdzi@ncsu.edu; ying.ge@wisc.edu; means@uwyo.edu; wguo3@uwyo.edu
RI Jiangping, Song/JBJ-3345-2023; Guo, Wei/KJM-4941-2024
OI guo, wei/0000-0002-9158-8107; Stern, Rachel/0000-0001-9503-1931;
   mozdziak, paul/0000-0002-1575-3123; Chen, Liang/0000-0001-6374-112X
FU National Institute of Health/National Institute of General Medical
   Sciences [NIGMSP20GM103432]; BGIA from the American Heart Association
   [16BGIA27790136]; USDA National Institute of Food and Agriculture
   [1009266]; Chinese Scholarship Council (CSC, Beijing, China); NIH [R01
   HL109810, HL096971]; American Heart Association (AHA) [16BGIA27790136]
   Funding Source: American Heart Association (AHA)
FX This work was supported by the National Institute of Health/National
   Institute of General Medical Sciences [NIGMSP20GM103432]; the BGIA from
   the American Heart Association [16BGIA27790136 to WG]; the USDA National
   Institute of Food and Agriculture [Hatch project 1009266 to WG]. We
   gratefully thank Dan Levy at the University of Wyoming to provide frog
   heart tissues and Kelcey Christensen at Meat Science lab of University
   of Wyoming to collect pig tissues for us. Zhilong Chen was supported by
   the Chinese Scholarship Council (CSC, Beijing, China). We would like to
   thank Peter W. Nathanielsz for proofreading the manuscript. Ying Ge
   would like to acknowledge NIH R01 HL109810 and HL096971.
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NR 50
TC 8
Z9 9
U1 0
U2 12
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 2073-4425
J9 GENES-BASEL
JI Genes
PD FEB
PY 2018
VL 9
IS 2
AR 86
DI 10.3390/genes9020086
PG 14
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA FZ3VM
UT WOS:000427518700032
PM 29438341
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU van Stuijvenberg, L
   Yildirim, C
   Kok, BGJM
   van Veen, TAB
   Varró, A
   Winckels, SKG
   Vos, MA
   Bierhuizen, MFA
AF van Stuijvenberg, Leonie
   Yildirim, Cansu
   Kok, Bart G. J. M.
   van Veen, Toon A. B.
   Varro, Andras
   Winckels, Stephan K. G.
   Vos, Marc A.
   Bierhuizen, Marti F. A.
TI Alternative Promoter Usage and Splicing of the Human SCN5A Gene
   Contribute to Transcript Heterogeneity
SO DNA AND CELL BIOLOGY
LA English
DT Article
ID CARDIAC SODIUM-CHANNEL; UNTRANSLATED REGIONS; HEART-FAILURE; NA+
   CHANNELS; EXPRESSION; MECHANISMS; NA(V)1.5; MOUSE; ORGANIZATION;
   VARIANTS
AB The sodium channel isoform Na(v)1.5 mediates sodium current, excitability, and electrical conduction in the human heart. Recent studies have indicated alternative splicing within the protein-coding portion of its gene, SCN5A, as a mechanism to generate diversity in Na(v)1.5 protein structure and function. In the present study we identified several novel SCN5A transcripts in human heart, displaying distinct 5'-untranslated regions but identical protein-coding sequences. These transcripts originated from the splicing of alternative exons 1 (designated 1A, 1B, 1C, and 1D) to the translational start codon-containing exon 2, and were preferentially expressed in the heart as compared to other tissues. Comparison of their expression level between adult and fetal heart demonstrated that exon 1C- and 1D-derived sequences were more prominent in adult than in fetal heart. Two new promoters (designated P2 and P3) for the SCN5A gene were identified and functionally characterized in myocardial-and nonmyocardial-derived cell lines. Translation of the transcript containing exon 1D-derived sequences proved to be significantly impaired in these cell lines, which could be restored by mutation of an upstream translational start codon. These results implicate the usage of alternative promoters and 5'-untranslated regions as new mechanisms in the regulation of human Na(v)1.5 expression.
C1 [van Stuijvenberg, Leonie; Yildirim, Cansu; Kok, Bart G. J. M.; van Veen, Toon A. B.; Winckels, Stephan K. G.; Vos, Marc A.; Bierhuizen, Marti F. A.] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Med Physiol, NL-3584 CM Utrecht, Netherlands.
   [Varro, Andras] Univ Szeged, Dept Pharmacol & Pharmacotherapy, Szeged, Hungary.
C3 Utrecht University; Utrecht University Medical Center; Szeged University
RP Bierhuizen, MFA (corresponding author), Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Med Physiol, A Numan Bldg,Room 04-36-00,Yalelaan 50, NL-3584 CM Utrecht, Netherlands.
EM M.F.A.Bierhuizen@umcutrecht.nl
RI Varro, Andras/M-2647-2016; YILDIRIM, CANSU/ABB-8045-2021
OI YILDIRIM, CANSU/0000-0002-9015-6636
FU Netherlands Heart Foundation [M96.001]
FX The authors are grateful to Dr. Dan M. Roden (Vanderbilt University
   School of Medicine, Nashville, TN, USA) for providing us with the
   pGL3-SCN5A (-454, +764) (P1) and pGL3-SCN5A (-261, +140) (P1 basal)
   constructs. This study was supported by the Netherlands Heart Foundation
   (grant number M96.001).
CR Bierhuizen MFA, 2008, J MOL CELL CARDIOL, V45, P373, DOI 10.1016/j.yjmcc.2008.06.011
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NR 27
TC 8
Z9 9
U1 0
U2 2
PU MARY ANN LIEBERT INC
PI NEW ROCHELLE
PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA
SN 1044-5498
J9 DNA CELL BIOL
JI DNA Cell Biol.
PD OCT
PY 2010
VL 29
IS 10
BP 577
EP 587
DI 10.1089/dna.2009.0999
PG 11
WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity
GA 658BS
UT WOS:000282464400002
PM 20618077
DA 2025-04-10
ER

PT J
AU Ni, L
   Lin, BW
   Hu, LJ
   Zhang, RY
   Fu, FM
   Shen, MT
   Yang, J
   Shi, D
AF Ni, Le
   Lin, Bowen
   Hu, Lingjie
   Zhang, Ruoyu
   Fu, Fengmei
   Shen, Meiting
   Yang, Jian
   Shi, Dan
TI Pyruvate Kinase M2 Protects Heart from Pressure Overload-Induced Heart
   Failure by Phosphorylating RAC1
SO JOURNAL OF THE AMERICAN HEART ASSOCIATION
LA English
DT Article
DE heart failure; protein kinase; pyruvate kinase M2; rho family; small GTP
   binding protein
ID CELL-MIGRATION; MYOCYTES
AB Background Heart failure, caused by sustained pressure overload, remains a major public health problem. PKM (pyruvate kinase M) acts as a rate-limiting enzyme of glycolysis. PKM2 (pyruvate kinase M2), an alternative splicing product of PKM, plays complex roles in various biological processes and diseases. However, the role of PKM2 in the development of heart failure remains unknown. Methods and Results Cardiomyocyte-specific Pkm2 knockout mice were generated by crossing the floxed Pkm2 mice with alpha-MHC (myosin heavy chain)-Cre transgenic mice, and cardiac specific Pkm2 overexpression mice were established by injecting adeno-associated virus serotype 9 system. The results showed that cardiomyocyte-specific Pkm2 deletion resulted in significant deterioration of cardiac functions under pressure overload, whereas Pkm2 overexpression mitigated transverse aortic constriction-induced cardiac hypertrophy and improved heart functions. Mechanistically, we demonstrated that PKM2 acted as a protein kinase rather than a pyruvate kinase, which inhibited the activation of RAC1 (rho family, small GTP binding protein)-MAPK (mitogen-activated protein kinase) signaling pathway by phosphorylating RAC1 in the progress of heart failure. In addition, blockade of RAC1 through NSC23766, a specific RAC1 inhibitor, attenuated pathological cardiac remodeling in Pkm2 deficiency mice subjected to transverse aortic constriction. Conclusions This study revealed that PKM2 attenuated overload-induced pathological cardiac hypertrophy and heart failure, which provides an attractive target for the prevention and treatment of cardiomyopathies.
C1 [Ni, Le; Lin, Bowen; Hu, Lingjie; Shen, Meiting; Yang, Jian; Shi, Dan] Tongji Univ, Sch Med, Shanghai East Hosp, Dept Cardiol, Shanghai, Peoples R China.
   [Ni, Le; Lin, Bowen; Hu, Lingjie; Shen, Meiting; Yang, Jian; Shi, Dan] Tongji Univ, Sch Med, Shanghai East Hosp, Key Lab Arrhythmias,Minist Educ China, Shanghai, Peoples R China.
   [Yang, Jian] Tongji Univ, Sch Med, Dept Cell Biol, Shanghai, Peoples R China.
   [Zhang, Ruoyu; Fu, Fengmei] Jinzhou Med Univ, Jinzhou, Liaoning, Peoples R China.
   [Yang, Jian] Tongji Univ, Inst Med Genet, Shanghai, Peoples R China.
C3 Tongji University; Tongji University; Tongji University; Jinzhou Medical
   University; Tongji University
RP Yang, J; Shi, D (corresponding author), Tongji Univ, Sch Med, 160 Jimo Rd, Shanghai 200136, Peoples R China.
EM jy279@tongji.edu.cn; shidan@tongji.edu.cn
RI Lin, Bowen/IQU-3812-2023; Ye, Jun/I-3222-2019; Yang, Yi/B-8285-2009
OI Yang, Jian/0000-0002-1964-7061
FU Programs of National Natural Science Foundation of China [82000377,
   31871491]
FX This work was funded by the Programs of National Natural Science
   Foundation of China (82000377 to Dan Shi; 31871491 to Jian Yang).
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NR 41
TC 16
Z9 16
U1 4
U2 17
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
EI 2047-9980
J9 J AM HEART ASSOC
JI J. Am. Heart Assoc.
PD JUN 7
PY 2022
VL 11
IS 11
AR e024854
DI 10.1161/JAHA.121.024854
PG 47
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 1W8MG
UT WOS:000807022400023
PM 35656980
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Davis, FJ
   Gupta, M
   Pogwizd, SM
   Bacha, E
   Jeevanandam, V
   Gupta, MP
AF Davis, FJ
   Gupta, M
   Pogwizd, SM
   Bacha, E
   Jeevanandam, V
   Gupta, MP
TI Increased expression of alternatively spliced dominant-negative isoform
   of SRF in human failing hearts
SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
LA English
DT Article
DE serum response factor; cardiac hypertrophy; cardiac gene regulation;
   alternative gene splicing
ID SERUM RESPONSE FACTOR; ACTIN GENE-TRANSCRIPTION; MYOGENIC
   DIFFERENTIATION; MUSCLE DIFFERENTIATION; PHOSPHORYLATION SITES;
   UP-REGULATION; FACTOR PLAYS; FAILURE; TRANSACTIVATION; PROTEINS
AB Serum response factor (SRF) has been shown to play a key role in cardiac cell growth and muscle gene regulation. To understand the role of SRF in heart failure, we compared its expression pattern between control and failing human heart samples. Western blot analysis of control samples showed expression of four different isoforms of SRF, with similar to67-kDa full-length SRF being the predominant isoform. Interestingly, in failing hearts we found robust expression of a low-molecular- mass (similar to52 kDa) SRF isoform, accompanied by decreased expression of full-length SRF. By RT-PCR and Southern blot analyses, we characterized this similar to52-kDa SRF isoform as being encoded by an alternatively spliced form of SRF lacking exons 4 and 5 of the SRF primary RNA transcript (SRF-Delta4,5 isoform). We cloned SRF-Delta4,5 cDNA and showed that overexpression of this isoform into cells inhibits SRF-dependent activation of cardiac muscle genes. These results suggest that expression of SRF-Delta4,5 in failing hearts may in part contribute to impaired cardiac gene expression and consequently to the pathogenesis of heart failure.
C1 Univ Chicago, Dept Surg Cardiac & Thorac, Chicago, IL 60637 USA.
   Hope Childrens Hosp, Heart Inst Children, Oak Lawn, IL 60453 USA.
   Univ Illinois, Dept Physiol & Biophys, Chicago, IL 60612 USA.
   Univ Illinois, Dept Med Cardiol, Chicago, IL 60612 USA.
C3 University of Chicago; University of Illinois System; University of
   Illinois Chicago; University of Illinois Chicago Hospital; University of
   Illinois System; University of Illinois Chicago; University of Illinois
   Chicago Hospital
RP Gupta, MP (corresponding author), Univ Chicago, Dept Surg Cardiac & Thorac, MC 5040,5841 S Maryland Ave, Chicago, IL 60637 USA.
FU NHLBI NIH HHS [R0-1 HL-46929, R0-1 HL-68083] Funding Source: Medline
CR [Anonymous], LANCET S
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NR 44
TC 58
Z9 64
U1 0
U2 2
PU AMER PHYSIOLOGICAL SOC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0363-6135
J9 AM J PHYSIOL-HEART C
JI Am. J. Physiol.-Heart Circul. Physiol.
PD APR
PY 2002
VL 282
IS 4
BP H1521
EP H1533
DI 10.1152/ajpheart.00844.2001
PG 13
WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Physiology
GA 530NV
UT WOS:000174365800042
PM 11893590
DA 2025-04-10
ER

PT J
AU Gazzara, MR
   Mallory, MJ
   Roytenberg, R
   Lindberg, JP
   Jha, A
   Lynch, KW
   Barashl, Y
AF Gazzara, Matthew R.
   Mallory, Michael J.
   Roytenberg, Renat
   Lindberg, John P.
   Jha, Anupama
   Lynch, Kristen W.
   Barashl, Yoseph
TI Ancient antagonism between CELF and RBFOX families tunes mRNA splicing
   outcomes
SO GENOME RESEARCH
LA English
DT Article
ID REGULATOR RBFOX2; PROTEIN-BINDING; EXPRESSION; REPRESSION; SEQUENCE;
   NETWORK; FOX-1; CARDIOMYOCYTES; IDENTIFICATION; TRANSCRIPTION
AB Over 95% of human multi-exon genes undergo alternative splicing, a process important in normal development and often dysregulated in disease. We sought to analyze the global splicing regulatory network of CELF2 in human T cells, a well-studied splicing regulator critical to T cell development and function. By integrating high-throughput sequencing data for binding and splicing quantification with sequence features and probabilistic splicing code models, we find evidence of splicing antagonism between CELF2 and the RBFOX family of splicing factors. We validate this functional antagonism through knockdown and overexpression experiments in human cells and find CELF2 represses RBFOX2 mRNA and protein levels. Because both families of proteins have been implicated in the development and maintenance of neuronal, muscle, and heart tissues, we analyzed publicly available data in these systems. Our analysis suggests global, antagonistic coregulation of splicing by the CELF and RBFOX proteins in mouse muscle and heart in several physiologically relevant targets, including proteins involved in calcium signaling and members of the MEF2 family of transcription factors. Importantly, a number of these coregulated events are aberrantly spliced in mouse models and human patients with diseases that affect these tissues, including heart failure, diabetes, or myotonic dystrophy. Finally, analysis of exons regulated by ancient CELF family homologs in chicken, Drosophila, and Caenorhabditis elegans suggests this antagonism is conserved throughout evolution.
C1 [Gazzara, Matthew R.; Lynch, Kristen W.; Barashl, Yoseph] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA.
   [Gazzara, Matthew R.; Mallory, Michael J.; Roytenberg, Renat; Lindberg, John P.; Lynch, Kristen W.] Univ Penn, Perelman Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA.
   [Jha, Anupama; Barashl, Yoseph] Univ Penn, Dept Comp & Informat Sci, Sch Engn & Appl Sci, Philadelphia, PA 19104 USA.
C3 University of Pennsylvania; University of Pennsylvania; University of
   Pennsylvania
RP Lynch, KW; Barashl, Y (corresponding author), Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA.; Lynch, KW (corresponding author), Univ Penn, Perelman Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA.; Barashl, Y (corresponding author), Univ Penn, Dept Comp & Informat Sci, Sch Engn & Appl Sci, Philadelphia, PA 19104 USA.
EM klync@mail.med.upenn.edu; yosephb@upenn.edu
RI Lynch, Kristen/JPY-3750-2023; Jha, Anupama/P-2249-2019
OI Roytenberg, Renat/0000-0001-6167-8278; Gazzara,
   Matthew/0000-0001-7710-4551; Jha, Anupama/0000-0003-3029-2086
FU NIH grant from the National Institute on Aging [R01 AG046544]; NIH grant
   from the National Institute of General Medical Sciences [R35 GM118048]
FX We thank all the members of the Barash and Lynch laboratories for
   helpful discussions and advice, particularly Caleb Radens and Jorge
   Vaquero-Garcia. We also thank the Genomics Division of the Iowa
   Institute of Human Genetics for their assistance with the RNA-seq. This
   work was funded by NIH grants from the National Institute on Aging, R01
   AG046544 (Y.B.) and from the National Institute of General Medical
   Sciences, R35 GM118048 (K.W.L.).
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TC 38
Z9 48
U1 2
U2 6
PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
PI COLD SPRING HARBOR
PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA
SN 1088-9051
EI 1549-5469
J9 GENOME RES
JI Genome Res.
PD AUG
PY 2017
VL 27
IS 8
BP 1360
EP 1370
DI 10.1101/gr.220517.117
PG 11
WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology;
   Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology;
   Genetics & Heredity
GA FB7XW
UT WOS:000406354300007
PM 28512194
OA Green Published, Green Submitted, hybrid
DA 2025-04-10
ER

PT J
AU Lin, LZ
   Chu, JM
   An, SQ
   Liu, XL
   Tan, RX
AF Lin, Lizhu
   Chu, Jiemei
   An, Sanqi
   Liu, Xinli
   Tan, Runxian
TI The Biological Mechanisms and Clinical Roles of RNA-Binding Proteins in
   Cardiovascular Diseases
SO BIOMOLECULES
LA English
DT Review
DE RNA-binding proteins (RBPs); cardiovascular diseases (CVDs); myocardial
   injury; RNA alternative splicing; therapeutic targets; biomarkers
ID MESSENGER-RNA; NETWORKS; RBFOX2; ATHEROSCLEROSIS; CARDIOTOXICITY;
   ACTIVATION; EXPRESSION; PROTEOME; QUAKING
AB RNA-binding proteins (RBPs) have pivotal roles in cardiovascular biology, influencing various molecular mechanisms underlying cardiovascular diseases (CVDs). This review explores the significant roles of RBPs, focusing on their regulation of RNA alternative splicing, polyadenylation, and RNA editing, and their impact on CVD pathogenesis. For instance, RBPs are crucial in myocardial injury, contributing to disease progression and repair mechanisms. This review systematically analyzes the roles of RBPs in myocardial injury, arrhythmias, myocardial infarction, and heart failure, revealing intricate interactions that influence disease outcomes. Furthermore, the potential of RBPs as therapeutic targets for cardiovascular dysfunction is explored, highlighting the advances in drug development and clinical research. This review also discusses the emerging role of RBPs as biomarkers for cardiovascular diseases, offering insights into their diagnostic and prognostic potential. Despite significant progress, current research faces several limitations, which are critically examined. Finally, this review identifies the major challenges and outlines future research directions to advance the understanding and application of RBPs in cardiovascular medicine.
C1 [Lin, Lizhu] Guangxi Med Univ, Peoples Hosp Qinzhou 1, Affiliated Hosp 10, Dept Anaesthesiol, Qinzhou 535000, Peoples R China.
   [Chu, Jiemei; An, Sanqi; Liu, Xinli] Guangxi Med Univ, Life Sci Inst, Nanning 530021, Peoples R China.
   [Tan, Runxian] Guangxi Med Univ, Peoples Hosp Qinzhou 1, Affiliated Hosp 10, Dept Lab Med, Qinzhou 535000, Peoples R China.
C3 Guangxi Medical University; Guangxi Medical University; Guangxi Medical
   University
RP Liu, XL (corresponding author), Guangxi Med Univ, Life Sci Inst, Nanning 530021, Peoples R China.; Tan, RX (corresponding author), Guangxi Med Univ, Peoples Hosp Qinzhou 1, Affiliated Hosp 10, Dept Lab Med, Qinzhou 535000, Peoples R China.
EM lizhulin529@gmail.com; jmchu@gxmu.edu.cn; ansq@mail2.sysu.edu.cn;
   219756@sr.gxmu.edu.cn; tanrunxian@163.com
RI lin, lizhu/MVV-5348-2025; liu, xinli/MHQ-8850-2025; An,
   Sanqi/JDD-2195-2023
OI An, Sanqi/0000-0002-3177-213X
FU Self-Funded Scientific Research Project of the Guangxi Zhuang Autonomous
   Region Health Committee; First People's Hospital of Qinzhou, Guangxi; 
   [Z20200172]
FX This work was financially supported by the Self-Funded Scientific
   Research Project of the Guangxi Zhuang Autonomous Region Health
   Committee (Z20200172), and by the First People's Hospital of Qinzhou,
   Guangxi.
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NR 108
TC 0
Z9 0
U1 6
U2 6
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2218-273X
J9 BIOMOLECULES
JI Biomolecules
PD SEP
PY 2024
VL 14
IS 9
AR 1056
DI 10.3390/biom14091056
PG 24
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA H4Z2Q
UT WOS:001323533100001
PM 39334823
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Ruknudin, A
   He, SW
   Lederer, WJ
   Schulze, DH
AF Ruknudin, A
   He, SW
   Lederer, WJ
   Schulze, DH
TI Functional differences between cardiac and renal isoforms of the rat
   Na<SUP>+</SUP>-Ca<SUP>2+</SUP> exchanger NCX1 expressed in
   Xenopus oocytes
SO JOURNAL OF PHYSIOLOGY-LONDON
LA English
DT Article
ID SODIUM-CALCIUM EXCHANGE; HUMAN VENTRICULAR MYOCYTES; TISSUE-SPECIFIC
   EXPRESSION; CONVOLUTED TUBULE CELLS; PROTEIN-KINASE-C; NA+/CA2+
   EXCHANGER; SARCOPLASMIC-RETICULUM; VOLTAGE-DEPENDENCE; DYNAMIC
   PROPERTIES; HEART-FAILURE
AB 1. The transcript of the Na+-Ca2+ exchanger gene NC;SII undergoes alternative splicing to produce tissue-specific isoforms. The cloned NCX1 isoforms were expressed in Xenopus oocytes and studied using a two-electrode voltage clamp method to measure Na+-Ca2+ exchanger activity.
   2. The cardiac isoform (NCX1.1) expressed in oocytes was less sensitive to depolarizing voltages and to activation by [Ca2+](i) than the renal isoform (NCX1.3).
   3. The cardiac isoform of NCX1 is more sensitive to activation by protein kinase A (PKA) than the renal isoform which may be explained by preferential phosphorylation. The cardiac isoform of NCX1 is phosphorylated to a greater extent than the renal isoform.
   4. The action of PKA phosphorylation which increases the activity of the cardiac isoform of the Na+-Ca2+ exchanger in oocytes was confirmed in adult rat ventricular cardiomyocytes by measuring Na+-dependent Ca2+ flux.
   5. We conclude that alternative splicing of NCX1 confers distinct functional characteristics to tissue-specific isoforms of the Na+-Ca2+ exchanger.
C1 Univ Maryland, Dept Microbiol & Immunol, Sch Med, UMBI, Baltimore, MD 21201 USA.
   Univ Maryland, Dept Physiol, Sch Med, UMBI, Baltimore, MD 21201 USA.
   Univ Maryland, Ctr Med Biotechnol, Sch Med, UMBI, Baltimore, MD 21201 USA.
C3 University System of Maryland; University of Maryland Baltimore;
   University System of Maryland; University of Maryland Baltimore;
   University System of Maryland; University of Maryland Baltimore
RP Univ Maryland, Dept Microbiol & Immunol, Sch Med, UMBI, 655 W Baltimore St, Baltimore, MD 21201 USA.
EM aruknudi@umaryland.edu
RI Lederer, William/B-1285-2010
FU NHLBI NIH HHS [R01 HL036974, R01 HL025675, R37 HL036974, HL25675,
   HL36974] Funding Source: Medline; NIA NIH HHS [AG08191] Funding Source:
   Medline
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NR 47
TC 63
Z9 66
U1 0
U2 1
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0022-3751
EI 1469-7793
J9 J PHYSIOL-LONDON
JI J. Physiol.-London
PD DEC 15
PY 2000
VL 529
IS 3
BP 599
EP 610
DI 10.1111/j.1469-7793.2000.00599.x
PG 12
WC Neurosciences; Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology; Physiology
GA 390QC
UT WOS:000166307000008
PM 11118492
OA Green Published
DA 2025-04-10
ER

PT J
AU Nutter, CA
   Jaworski, EA
   Verma, SK
   Deshmukh, V
   Wang, QL
   Botvinnik, OB
   Lozano, MJ
   Abass, IJ
   Ijaz, T
   Brasier, AR
   Garg, NJ
   Wehrens, XHT
   Yeo, GW
   Kuyumcu-Martinez, MN
AF Nutter, Curtis A.
   Jaworski, Elizabeth A.
   Verma, Sunil K.
   Deshmukh, Vaibhav
   Wang, Qiongling
   Botvinnik, Olga B.
   Lozano, Mario J.
   Abass, Ismail J.
   Ijaz, Talha
   Brasier, Allan R.
   Garg, Nisha J.
   Wehrens, Xander H. T.
   Yeo, Gene W.
   Kuyumcu-Martinez, Muge N.
TI Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of
   Diabetes
SO CELL REPORTS
LA English
DT Article
ID SPLICING REGULATOR RBFOX2; CORONARY-ARTERY-DISEASE; STRIATED-MUSCLE;
   MESSENGER-RNA; HEART-FAILURE; PKC-BETA; CARDIOMYOPATHY; MEF2A;
   RUBOXISTAURIN; EXPRESSION
AB Alternative splicing (AS) defects that adversely affect gene expression and function have been identified in diabetic hearts; however, the mechanisms responsible are largely unknown. Here, we show that the RNA-binding protein RBFOX2 contributes to transcriptome changes under diabetic conditions. RBFOX2 controls AS of genes with important roles in heart function relevant to diabetic cardiomyopathy. RBFOX2 protein levels are elevated in diabetic hearts despite low RBFOX2 AS activity. A dominant-negative (DN) isoform of RBFOX2 that blocks RBFOX2-mediated AS is generated in diabetic hearts. DN RBFOX2 interacts with wild-type (WT) RBFOX2, and ectopic expression of DN RBFOX2 inhibits AS of RBFOX2 targets. Notably, DN RBFOX2 expression is specific to diabetes and occurs at early stages before cardiomyopathy symptoms appear. Importantly, DN RBFOX2 expression impairs intracellular calcium release in cardiomyocytes. Our results demonstrate that RBFOX2 dysregulation by DN RBFOX2 is an early pathogenic event in diabetic hearts.
C1 [Nutter, Curtis A.; Jaworski, Elizabeth A.; Verma, Sunil K.; Ijaz, Talha; Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA.
   [Deshmukh, Vaibhav; Wang, Qiongling; Wehrens, Xander H. T.] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA.
   [Wang, Qiongling; Wehrens, Xander H. T.] Baylor Coll Med, Cardiovasc Res Inst, Houston, TX 77030 USA.
   [Botvinnik, Olga B.; Yeo, Gene W.] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92037 USA.
   [Lozano, Mario J.] Univ Texas Dallas, Dept Biol Sci, Richardson, TX 75080 USA.
   [Abass, Ismail J.; Brasier, Allan R.] Univ Texas Med Branch, Dept Internal Med, Galveston, TX 77555 USA.
   [Brasier, Allan R.; Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Inst Translat Sci, Galveston, TX 77555 USA.
   [Garg, Nisha J.] Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA.
   [Garg, Nisha J.] Univ Texas Med Branch, Dept Pathol, Galveston, TX 77555 USA.
   [Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Dept Neurosci & Cell Biol, Galveston, TX 77555 USA.
   [Garg, Nisha J.] Univ Texas Med Branch, Inst Human Infect & Immun, Galveston, TX 77555 USA.
   [Wehrens, Xander H. T.] Baylor Coll Med, Dept Med Cardiol, Houston, TX 77030 USA.
   [Wehrens, Xander H. T.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA.
   [Yeo, Gene W.] Univ Calif San Diego, Inst Genom Med, La Jolla, CA 92037 USA.
C3 University of Texas System; University of Texas Medical Branch
   Galveston; Baylor College of Medicine; Baylor College of Medicine;
   University of California System; University of California San Diego;
   University of Texas System; University of Texas Dallas; University of
   Texas System; University of Texas Medical Branch Galveston; University
   of Texas System; University of Texas Medical Branch Galveston;
   University of Texas System; University of Texas Medical Branch
   Galveston; University of Texas System; University of Texas Medical
   Branch Galveston; University of Texas System; University of Texas
   Medical Branch Galveston; University of Texas System; University of
   Texas Medical Branch Galveston; Baylor College of Medicine; Baylor
   College of Medicine; University of California System; University of
   California San Diego
RP Kuyumcu-Martinez, MN (corresponding author), Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA.; Kuyumcu-Martinez, MN (corresponding author), Univ Texas Med Branch, Inst Translat Sci, Galveston, TX 77555 USA.; Kuyumcu-Martinez, MN (corresponding author), Univ Texas Med Branch, Dept Neurosci & Cell Biol, Galveston, TX 77555 USA.
EM nmmartin@utmb.edu
RI Verma, Sunil/J-8838-2019; Ijaz, Talha/HNR-4391-2023; Brasier,
   allan/LSI-6520-2024; Deshmukh, Vaibhav/HPG-7012-2023; Yeo,
   Gene/AAE-7676-2019; Wehrens, Xander/AAQ-9574-2020
OI Brasier, Allan/0000-0002-5012-4090; Verma, Sunil/0000-0001-9443-2493;
   Yeo, Eugene/0000-0002-0799-6037; Wehrens, Xander/0000-0001-5044-672X
FU March of Dimes Starter Basil O'Connor Starter Scholar Award [5FY12-21];
   American Heart Association Grant [15GRNT22830010]; UTMB Institute for
   Human Infections and Immunity Mini Center Pilot Award; UTMB pilot grant;
   NIH/National Institute of Allergy and Infectious Diseases
   [2RO1AI05478-08]; NIH/National Heart, Blood and Lung Institute
   [5R25HL09636305]; NIH [HG0046590, NS075449, R01-HL089598, R01-HL091947,
   R01-HL117641, R41-HL129570, UL1TR000071 UTMB CTSA, NIEHS P30 ES006676];
   Ruth L. Kirschstein National Research Service Award from the National
   Heart Lung Blood Institute [F30HL128036]; American Heart Association
   [13EIA14560061]; American Heart Association (AHA) [15GRNT22830010]
   Funding Source: American Heart Association (AHA)
FX We thank Hong Sun, Yareli Perez, and Rosario Espejo for technical
   support; Dr. David Konkel for editing the manuscript; Dr. Douglas Black
   for providing the WT and DN RBFOX2 plasmid DNA constructs; and Dr. Corey
   Reynolds for his help in quantification of echocardiography data. This
   work was supported, in part, by a March of Dimes Starter Basil O'Connor
   Starter Scholar Award (5FY12-21), an American Heart Association Grant
   (15GRNT22830010), an UTMB Institute for Human Infections and Immunity
   Mini Center Pilot Award, UTMB pilot grant, and startup funds to
   M.N.K.-M. This work was supported, in part, by a grant from the
   NIH/National Institute of Allergy and Infectious Diseases
   (2RO1AI05478-08) and UTMB Institute for Human Infections and Immunity
   Mini Center Pilot Award to N.J.G., NIH (UL1TR000071 UTMB CTSA and NIEHS
   P30 ES006676) grants to A.R.B., a NIH/National Heart, Blood and Lung
   Institute grant to I.J.A. (5R25HL09636305), and NIH grants (HG0046590
   and NS075449) to G.W.Y. G.W.Y. is an Alfred P. Sloan Research Fellow.
   O.B.B. is a National Defense Science and Engineering Graduate Fellow and
   NumFOCUS John Hunter Technical Fellow. T.I. was supported by a Ruth L.
   Kirschstein National Research Service Award from the National Heart Lung
   Blood Institute (F30HL128036). X.H.T.W. was supported by NIH grants
   R01-HL089598, R01-HL091947, R01-HL117641, and R41-HL129570 and American
   Heart Association grant 13EIA14560061.
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NR 46
TC 61
Z9 71
U1 0
U2 6
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 2211-1247
J9 CELL REP
JI Cell Reports
PD JUN 7
PY 2016
VL 15
IS 10
BP 2200
EP 2213
DI 10.1016/j.celrep.2016.05.002
PG 14
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA DO4TF
UT WOS:000377776300011
PM 27239029
OA Green Accepted, gold
DA 2025-04-10
ER

PT J
AU Warnecke, C
   Sürder, D
   Curth, R
   Fleck, E
   Regitz-Zagrosek, V
AF Warnecke, C
   Sürder, D
   Curth, R
   Fleck, E
   Regitz-Zagrosek, V
TI Analysis and functional characterization of alternatively spliced
   angiotensin II type 1 and 2 receptor transcripts in the human heart
SO JOURNAL OF MOLECULAR MEDICINE-JMM
LA English
DT Article
DE angiotensin II receptor; splicing; heart failure; messenger RNA
   translation; 5 ' untranslated region
ID MESSENGER-RNA; MYOCARDIAL-INFARCTION; GENOMIC ORGANIZATION;
   GENE-EXPRESSION; DOWN-REGULATION; SUBTYPES; FAILURE; AT(1)-RECEPTOR;
   TRANSLATION
AB Expression levels of angiotensin II type 1 and type 2 receptors (AT1, AT2) vary at different cardiac localizations and are regulated in cardiac diseases. Differential splicing of the 5' untranslated exons of the primary AT1 mRNA transcripts may modulate translational efficiency and thus receptor expression. We therefore searched for ATI and AT1 mRNA splice patterns specific to chamber localization or to cardiac performance and analyzed their effect on protein expression in transfection experiments. The exon composition of the BT1 and AT2 mRNA transcripts in normal and diseased human hearts were analyzed using a reverse transcription polymerase chain reaction Followed by HPLC quantitation of the amplificates. We compared atrial (n=18) and ventricular (n=28) samples and endomyocardial biopsies (n=10) from patients with normal and severely impaired cardiac function and one donor heart, which was not used for transplantation. ATI transcripts with the exon composition 1/2/5 and 1/5 represented about 93-98% of all ATI mRNAs; transcript 1/2/3/5 represented 8% in the atria and 2% in ventricles. Since exon 2 reduces translational efficiency in vitro, the ratios of transcripts with and without exon 2, (1/2/5+1/2/3/5) to (1/5), were compared. These were 1.24+/-0.07 in normal atria, 0.96+/-0.09 in atria 1 from failing hearts (P<0.05), 0.68 in the left ventricle of the donor heart, and 0.58+/-0.03 in failing left ventricles. Endomyocardial biopsy specimens showed significant differences between controls and heart failure (controls 0.63+/-0.04 vs. heart failure 0.52+/-0.02, P<0.05). Of the two identified AT2 transcripts, mRNA 1/2/3 was the most abundant in the human heart (92%). Luciferase reporter gene assays were performed to test the effect of the various 5' untranslated regions (5' UTRs) on protein expression. Among the constructs which contained the ATI promoter/AT1 5' UTRs the plasmid Ex 1/2/5 exhibited 27% lower luciferase activity than Ex 1/5 (n=24%, P<0.001), and Ex 1/2/3/5 expressed only 35.9% of Ex 1/5 activity (P<0.001). Among the reporter gene plasmids with the AT2 promoter/AT2 5' UTRs the construct Ex 1/2/3 expressed a 31% lower luciferase activity than Ex 1/3 (n=20, P<0.001). In conclusion, alternative splicing may represent a mechanism of ATR regulation in vivo. In the human heart, ATI splice patterns differ distinctly between atria and ventricles and to a lesser degree between controls and failing hearts. This may lead to differences in ATI mRNA translation into protein in the various cardiac areas and under different pathophysiological conditions.
C1 Humboldt Univ, Med Clin Cardiol, D-13353 Berlin, Germany.
   Deutsch Herzzentrum Berlin, D-13353 Berlin, Germany.
C3 Humboldt University of Berlin; German Heart Center Berlin
RP Warnecke, C (corresponding author), Humboldt Univ, Med Clin Cardiol, Campus Virchow Clin,Augustenburger Pl 1, D-13353 Berlin, Germany.
RI Sürder, Daniel/ABH-9163-2020
OI Regitz-Zagrosek, Vera/0000-0002-3566-3467
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NR 25
TC 20
Z9 23
U1 0
U2 0
PU SPRINGER VERLAG
PI NEW YORK
PA 175 FIFTH AVE, NEW YORK, NY 10010 USA
SN 0946-2716
J9 J MOL MED-JMM
JI J. Mol. Med.
PD OCT
PY 1999
VL 77
IS 10
BP 718
EP 727
DI 10.1007/s001099900049
PG 10
WC Genetics & Heredity; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity; Research & Experimental Medicine
GA 258UH
UT WOS:000083857200005
PM 10606207
DA 2025-04-10
ER

PT J
AU Philipson, KD
   Nicoll, DA
AF Philipson, KD
   Nicoll, DA
TI Sodium-calcium exchange: A molecular perspective
SO ANNUAL REVIEW OF PHYSIOLOGY
LA English
DT Review
DE sodium transport; calcium transport; antiporter; excitation-contraction
   coupling; calcium signaling
ID CARDIAC NA+-CA2+ EXCHANGER; NA-CA EXCHANGE; ALTERNATIVELY SPLICED
   ISOFORMS; PIG VENTRICULAR MYOCYTES; INDUCED HEART-FAILURE;
   PROTEIN-KINASE-C; NA+/CA2+ EXCHANGER; SARCOPLASMIC-RETICULUM; FUNCTIONAL
   EXPRESSION; DEPENDENT REGULATION
AB Plasma membrane Na+-Ca2+ exchange is an essential component of Ca2+ signaling pathways in several tissues. Activity is especially high in the heart where the exchanger is an important regulator of contractility. An expanding exchanger superfamily includes three mammalian Na+-Ca2+ exchanger genes and a number of alternative splicing products. New information indicates that the exchanger protein has nine transmembrane segments. The exchanger, which transports Naf and Ca2+, is also regulated by these substrates. Some molecular information is available on regulation by Na+ and Ca2+ and by PIP2 and phosphorylation. Altered expression of the exchanger in pathophysiological states may contribute to various cardiac phenotypes. Use of transgenic approaches is beginning to improve our knowledge of exchanger function.
C1 Univ Calif Los Angeles, Sch Med, Dept Physiol, Los Angeles, CA 90095 USA.
   Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90095 USA.
   Univ Calif Los Angeles, Sch Med, Cardiovasc Res Labs, Los Angeles, CA 90095 USA.
C3 University of California System; University of California Los Angeles;
   University of California Los Angeles Medical Center; David Geffen School
   of Medicine at UCLA; University of California System; University of
   California Los Angeles; University of California Los Angeles Medical
   Center; David Geffen School of Medicine at UCLA; University of
   California System; University of California Los Angeles; University of
   California Los Angeles Medical Center; David Geffen School of Medicine
   at UCLA
RP Philipson, KD (corresponding author), Univ Calif Los Angeles, Sch Med, Dept Physiol, Los Angeles, CA 90095 USA.
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NR 111
TC 443
Z9 485
U1 0
U2 21
PU ANNUAL REVIEWS
PI PALO ALTO
PA 4139 EL CAMINO WAY, PO BOX 10139, PALO ALTO, CA 94303-0139 USA
SN 0066-4278
J9 ANNU REV PHYSIOL
JI Annu. Rev. Physiol.
PY 2000
VL 62
BP 111
EP 133
DI 10.1146/annurev.physiol.62.1.111
PG 25
WC Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Physiology
GA 341KF
UT WOS:000088589000006
PM 10845086
DA 2025-04-10
ER

PT J
AU Williams, AL
   Walton, CB
   Pinell, B
   Khadka, VS
   Dunn, B
   Lee, K
   Anagaran, MCT
   Avelar, A
   Shohet, RV
AF Williams, Allison Lesher
   Walton, Chad B.
   Pinell, Blake
   Khadka, Vedbar S.
   Dunn, Brandyn
   Lee, Katie
   Anagaran, M. C. Therese
   Avelar, Abigail
   Shohet, Ralph V.
TI Ischemic heart injury leads to HIF1-dependent differential splicing of
   CaMK2γ
SO SCIENTIFIC REPORTS
LA English
DT Article
ID PROTEIN-KINASE-II; GENOME-WIDE ASSOCIATION; CAM KINASE;
   CARDIAC-HYPERTROPHY; DELTA-ISOFORMS; EXPRESSION; MUSCLE; IDENTIFICATION;
   TRANSCRIPTS; ACTIVATION
AB Ischemic heart disease is a leading cause of heart failure and hypoxia inducible factor 1 (HIF1) is a key transcription factor in the response to hypoxic injury. Our lab has developed a mouse model in which a mutated, oxygen-stable form of HIF1 alpha (HIF-PPN) can be inducibly expressed in cardiomyocytes. We observed rapid cardiac dilation and loss of contractility in these mice due to lower expression of excitation-contraction coupling genes and reduced calcium flux. As alternative splicing plays an underappreciated role in transcriptional regulation, we used RNA sequencing to search for splicing changes in calcium-handling genes of HIF-PPN hearts and compared them to previous sequencing data from a model of myocardial infarction (MI) to select for transcripts that are modified in a pathological setting. We found overlap between genes differentially expressed in HIF-PPN and post-MI mice (54/131 genes upregulated in HIF-PPN hearts at 1 day and/or 3 days post-MI, and 45/78 downregulated), as well as changes in alternative splicing. Interestingly, calcium/calmodulin dependent protein kinase II, gamma (CAMK2G) was alternatively spliced in both settings, with variant 1 (v1) substantially decreased compared to variants 2 (v2) and 3 (v3). These findings were also replicated in vitro when cells were transfected with HIF-PPN or exposed to hypoxia. Further analysis of CAMK2 gamma protein abundance revealed only v1 was detectable and substantially decreased up to 7 days post-MI. Rbfox1, a splicing factor of CAMK2G, was also decreased in HIF-PPN and post-MI hearts. Subcellular fractionation showed CAMK2 gamma v1 was found in the nuclear and cytoplasmic fractions, and abundance decreased in both fractions post-MI. Chromatin immunoprecipitation analysis of HIF1 in post-MI hearts also demonstrated direct HIF1 binding to CAMK2G. CaMK2 is a key transducer of calcium signals in both physiological and pathological settings. The predominantly expressed isoform in the heart, CaMK2 delta, has been extensively studied in cardiac injury, but the specific role of CaMK2 gamma is not well defined. Our data suggest that loss of CaMK2 gamma after MI is HIF1-dependent and may play an important role in the heart's calcium signaling and transcriptional response to hypoxia.
C1 [Williams, Allison Lesher; Walton, Chad B.; Pinell, Blake; Dunn, Brandyn; Lee, Katie; Anagaran, M. C. Therese; Avelar, Abigail; Shohet, Ralph V.] Univ Hawaii, John A Burns Sch Med, Ctr Cardiovasc Res, 651 Ilalo St BSB 311, Honolulu, HI 96813 USA.
   [Khadka, Vedbar S.] Univ Hawaii, John A Burns Sch Med, Bioinformat Core, Honolulu, HI 96822 USA.
C3 University of Hawaii System; University of Hawaii System
RP Shohet, RV (corresponding author), Univ Hawaii, John A Burns Sch Med, Ctr Cardiovasc Res, 651 Ilalo St BSB 311, Honolulu, HI 96813 USA.
EM shohet@hawaii.edu
RI Williams, Allison/AAG-1481-2019; Khadka, Vedbar/O-4156-2018
OI Williams, Allison/0000-0002-2920-1733; Khadka,
   Vedbar/0000-0002-8652-2904
FU National Institutes of Health [R01 HL080532, P20 RR016453, P30 GM103341,
   T32 HL115505, P30 CA071789, 5G12 MD007601, P20 GM103466, U54 MD007601,
   5P30 GM114737]; American Heart Association [16POST29960013]; Jean Estes
   Epstein Foundation; American Heart Association (AHA) [16POST29960013]
   Funding Source: American Heart Association (AHA)
FX This work was supported by the following grants from the National
   Institutes of Health: R01 HL080532, P20 RR016453 and P30 GM103341 to
   R.V.S., T32 HL115505 to A.L.W. and K.L., P30 CA071789 and 5G12 MD007601
   to the Microscopy and Imaging Core, P20 GM103466, U54 MD007601 and 5P30
   GM114737 to the Bioinformatics Core. This work was also supported by the
   American Heart Association (Medical Student Scholarship to B.D. and
   16POST29960013 to A.L.W.) and the Jean Estes Epstein Foundation.
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NR 52
TC 18
Z9 19
U1 1
U2 6
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD JUN 23
PY 2021
VL 11
IS 1
AR 13116
DI 10.1038/s41598-021-92426-2
PG 14
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA TE4QJ
UT WOS:000669995600003
PM 34162925
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Mohan, N
   Kumar, V
   Kandala, DT
   Kartha, CC
   Laishram, RS
AF Mohan, Nimmy
   Kumar, Vikas
   Kandala, Divya T.
   Kartha, Chandrasekharan C.
   Laishram, Rakesh S.
TI A Splicing-Independent Function of RBM10 Controls Specific 3′ UTR
   Processing to Regulate Cardiac Hypertrophy
SO CELL REPORTS
LA English
DT Article
ID STAR-PAP; GENE-EXPRESSION; PIPKI-ALPHA; POLYMERASE; IDENTIFICATION;
   POLYADENYLATION; MECHANISM; PROTEIN; CLONING
AB RNA binding motif protein 10 (RBM10) is a regulator of alternative splicing in apoptosis and inflammation. We discovered a splicing-independent function of RBM10 critical for the regulation of heart failure (HF). RBM10 is enriched in the heart and associates with Star-PAP (TUT1) to control the expression and 3' zend processing of cardiac mRNAs. The RBM10 RRM2 domain binds the Star-PAP catalytic domain, which directs Star-PAP activity toward polyadenylation. RBM10 binds the pre-mRNA UTR, assembles the Star-PAP complex, and guides this complex specifically to mRNAs encoding anti-hypertrophy regulators. Accordingly, we tested cellular hypertrophy in rat cardiomyoblasts and cardiac hypertrophy (CH) and the subsequent progression to HF in Wistar rat hearts. We demonstrated downregulation of RBM10 during CH and HF. Ectopic re-expression of RBM10 rescued cardiomyocyte hypertrophy. RBM10 depletion evoked a hypertrophic response in H9c2 cells. Our results establish an anti-hypertrophy-mechanism mediated by RBM10 in the heart that is directly linked to HF.
C1 [Mohan, Nimmy; Kumar, Vikas; Kandala, Divya T.; Kartha, Chandrasekharan C.; Laishram, Rakesh S.] Rajiv Gandhi Ctr Biotechnol, Cardiovasc Dis & Diabet Biol Grp, Trivandrum 695014, Kerala, India.
   [Mohan, Nimmy; Kumar, Vikas] Manipal Acad Higher Educ, Manipal 576104, Karnataka, India.
   [Kandala, Divya T.] Immagina BioTechnol, I-38123 Trento, Italy.
C3 Department of Biotechnology (DBT) India; Rajiv Gandhi Centre for
   Biotechnology (RGCB); Manipal Academy of Higher Education (MAHE)
RP Laishram, RS (corresponding author), Rajiv Gandhi Ctr Biotechnol, Cardiovasc Dis & Diabet Biol Grp, Trivandrum 695014, Kerala, India.
EM laishram@rgcb.res.in
RI Kumar, Vikas/AEI-2617-2022
OI Kartha, CC/0000-0002-6782-4456; Kumar, Vikas/0000-0001-5826-4680; MOHAN,
   NIMMY/0000-0003-0950-9076
FU Wellcome Trust-DBT India Alliance grant [IA/I/12/1/500508]; Science and
   Engineering Research Board (SERB), Ministry of Science and Technology
   [EMR/2015/000747]; Council of Scientific and Industrial Research
FX We thank G. Ajitkumar for assisting with animal surgery and sacrifice
   and Fiona P. Ukken (UW-Madison, USA) and the R.S.L. lab members for
   carefully reading the manuscript. This work was supported by Wellcome
   Trust-DBT India Alliance grant IA/I/12/1/500508 and Science and
   Engineering Research Board (SERB), Ministry of Science and Technology
   grant EMR/2015/000747 (to R.S.L.) and an SRF fellowship from the Council
   of Scientific and Industrial Research (to N.M.).
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NR 44
TC 37
Z9 38
U1 0
U2 5
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
SN 2211-1247
J9 CELL REP
JI Cell Reports
PD SEP 25
PY 2018
VL 24
IS 13
BP 3539
EP 3553
DI 10.1016/j.celrep.2018.08.077
PG 15
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA GU7SC
UT WOS:000445524700017
PM 30257214
OA gold
DA 2025-04-10
ER

PT J
AU Kong, W
   Po, S
   Yamagishi, T
   Ashen, MD
   Stetten, G
   Tomaselli, GF
AF Kong, W
   Po, S
   Yamagishi, T
   Ashen, MD
   Stetten, G
   Tomaselli, GF
TI Isolation and characterization of the human gene encoding
   Ito:: further diversity by alternative mRNA splicing
SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
LA English
DT Article
DE potassium channel; Kv4.2; Kv4.3; Xenopus oocytes; heterologous
   expression; fluorescence in situ hybridization; chromosome 1
ID TRANSIENT OUTWARD CURRENT; RAT VENTRICULAR MYOCYTES; CARDIAC
   PURKINJE-FIBERS; TERMINAL HEART-FAILURE; HUMAN ATRIAL MYOCYTES; KV4.3 K+
   CHANNEL; REGIONAL DIFFERENCES; POTASSIUM CHANNELS; THYROID-HORMONE;
   CURRENT-DENSITY
AB The transient outward K+ current (I-to) in the heart is responsible for the initial phase of repolarization and for setting the plateau voltage of the ventricular action potential. Recently, Kv4.3 has emerged as the leading candidate alpha-subunit gene that underlies I-to in larger mammals such as dogs and humans. we have cloned the human Kv4.3 homolog and describe a carboxyl-terminal splice variant that inserts 19 amino acids with a consensus protein kinase C (PKC) phosphorylation site into the protein after the last membrane-spanning segment. The coding region of Kv4.3 is comprised of at least five exons and is located on chromosome 1p13.3. In the basal state the basic biophysical properties of bath of the splice variants are identical.
C1 Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol,Sect Mol & Cellular Cardiol, Baltimore, MD 21205 USA.
   Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD 21205 USA.
C3 Johns Hopkins University; Johns Hopkins University
RP Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol,Sect Mol & Cellular Cardiol, Ross 844,720 N Rutland Ave, Baltimore, MD 21205 USA.
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NR 44
TC 69
Z9 80
U1 0
U2 2
PU AMER PHYSIOLOGICAL SOC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0363-6135
EI 1522-1539
J9 AM J PHYSIOL-HEART C
JI Am. J. Physiol.-Heart Circul. Physiol.
PD DEC
PY 1998
VL 275
IS 6
BP H1963
EP H1970
DI 10.1152/ajpheart.1998.275.6.H1963
PG 8
WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Physiology
GA 151XA
UT WOS:000077744900007
DA 2025-04-10
ER

PT J
AU Yuan, J
   Wang, JM
   Li, ZW
   Zhang, CS
   Cheng, B
   Yang, SH
   Liu, BT
   Zhu, LJ
   Cai, DJ
   Yu, SG
AF Yuan, Jing
   Wang, Jun-Meng
   Li, Zhi-Wei
   Zhang, Cheng-Shun
   Cheng, Bin
   Yang, Su-Hao
   Liu, Bai-Tong
   Zhu, Li-Juan
   Cai, Ding-Jun
   Yu, Shu-Guang
TI Full-length transcriptome analysis reveals the mechanism of acupuncture
   at PC6 improves cardiac function in myocardial ischemia model
SO CHINESE MEDICINE
LA English
DT Article
DE Acupuncture; Myocardial ischemia; Full-length transcriptome;
   Differential expression genes; Alternative splicing; New genes
ID PROTECTS CARDIOMYOCYTES; HEART-FAILURE; INFARCTION; PRETREATMENT;
   REPERFUSION; INVOLVEMENT; EXPRESSION; GENES
AB Background The pathological process of myocardial ischemia (MI) is very complicated. Acupuncture at PC6 has been proved to be effective against MI injury, but the mechanism remains unclear. This study investigated the mechanism that underlies the effect of acupuncture on MI through full-length transcriptome. Methods Adult male C57/BL6 mice were randomly divided into control, MI, and PC6 groups. Mice in MI and PC6 group generated MI model by ligating the left anterior descending (LAD) coronary artery. The samples were collected 5 days after acupuncture treatment. Results The results showed that treatment by acupuncture improved cardiac function, decreased myocardial infraction area, and reduced the levels of cTnT and cTnI. Based on full-length transcriptome sequencing, 5083 differential expression genes (DEGs) and 324 DEGs were identified in the MI group and PC6 group, respectively. These genes regulated by acupuncture were mainly enriched in the inflammatory response pathway. Alternative splicing (AS) is a post-transcriptional action that contributes to the diversity of protein. In all samples, 8237 AS events associated with 1994 genes were found. Some differential AS-involved genes were enriched in the pathway related to heart disease. We also identified 602 new genes, 4 of which may the novel targets of acupuncture in MI. Conclusions Our findings suggest that the effect of acupuncture on MI may be based on the multi-level regulation of the transcriptome.
C1 [Yuan, Jing; Wang, Jun-Meng; Li, Zhi-Wei; Zhang, Cheng-Shun; Cheng, Bin; Yang, Su-Hao; Liu, Bai-Tong; Zhu, Li-Juan; Cai, Ding-Jun; Yu, Shu-Guang] Chengdu Univ Tradit Chinese Med, Teaching Hosp 3, Acupuncture & Tuina Sch, Chengdu 610075, Sichuan, Peoples R China.
C3 Chengdu University of Traditional Chinese Medicine
RP Cai, DJ; Yu, SG (corresponding author), Chengdu Univ Tradit Chinese Med, Teaching Hosp 3, Acupuncture & Tuina Sch, Chengdu 610075, Sichuan, Peoples R China.
EM djcai@cdutcm.cn; ysg@cdutcm.edu.cn
OI Wang, Jun-meng/0000-0003-3771-4026
FU National Key R&D Program of China [2019YFC1709001]; National Natural
   Science Foundation of China [81704187, 81774434]; Department of Science
   and Technology of Sichuan Province [2018JY0482, 2019YJ0587]
FX This study was supported by the National Key R&D Program of China (No.
   2019YFC1709001), the National Natural Science Foundation of China (No.
   81774434), the National Natural Science Foundation of China (No.
   81704187), the Department of Science and Technology of Sichuan Province
   (No. 2019YJ0587), the Department of Science and Technology of Sichuan
   Province (No. 2018JY0482).
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NR 49
TC 4
Z9 5
U1 2
U2 25
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1749-8546
J9 CHIN MED-UK
JI Chin. Med.
PD JUL 8
PY 2021
VL 16
IS 1
AR 55
DI 10.1186/s13020-021-00465-8
PG 14
WC Integrative & Complementary Medicine; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Integrative & Complementary Medicine; Pharmacology & Pharmacy
GA TH8YW
UT WOS:000672370500001
PM 34238326
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Weeland, CJ
   van den Hoogenhof, MM
   Beqqali, A
   Creemers, EE
AF Weeland, Cornelis J.
   van den Hoogenhof, Maarten M.
   Beqqali, Abdelaziz
   Creemers, Esther E.
TI Insights into alternative splicing of sarcomeric genes in the heart
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Review
DE Sarcomere; RBM20; RBM24; Alternative splicing; Titin
ID TROPONIN-T ISOFORMS; RNA-BINDING PROTEIN; TITIN ISOFORM; DILATED
   CARDIOMYOPATHY; M-BAND; PASSIVE STIFFNESS; FORCE DEVELOPMENT; RESTORING
   FORCE; Z-LINE; EXPRESSION
AB Driven by rapidly evolving technologies in next-generation sequencing, alternative splicing has emerged as a crucial layer in gene expression, greatly expanding protein diversity and governing complex biological processes in the cardiomyocyte. At the core of cardiac contraction, the physical properties of the sarcomere are carefully orchestrated through alternative splicing to fit the varying demands on the heart. By the recent discovery of RBM20 and RBM24, two major heart and skeletal muscle-restricted splicing factors, it became evident that alternative splicing events in the heart occur in regulated networks rather than in isolated events. Analysis of knockout mice of these splice factors has shed light on the importance of these fundamental processes in the heart. In this review, we discuss recent advances in our understanding of the role and regulation of alternative splicing in the developing and diseased heart, specifically within the sarcomere. Through various examples (titin, myomesin, troponin T, tropomyosin and LDB3) we illustrate how alternative splicing regulates the functional properties of the sarcomere. Finally, we evaluate opportunities and obstacles to modulate alternative splicing in therapeutic approaches for cardiac disease. (C) 2015 Elsevier Ltd. All rights reserved.
C1 [Weeland, Cornelis J.; van den Hoogenhof, Maarten M.; Beqqali, Abdelaziz; Creemers, Esther E.] Acad Med Ctr, Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands.
C3 University of Amsterdam; Academic Medical Center Amsterdam
RP Creemers, EE (corresponding author), Acad Med Ctr, Expt Cardiol, Room L2-108-3,Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands.
EM e.e.creemers@amc.uva.nl
RI ; Beqqali, Abdelaziz/F-8568-2013
OI Weeland, Cees/0000-0003-1238-3769; Creemers, Esther/0000-0002-9001-3854;
   Beqqali, Abdelaziz/0000-0003-1390-5821; van den Hoogenhof,
   Maarten/0000-0003-2768-3457
FU Netherlands Organisation for Scientific Research (NWO) [825.13.007,
   836.12.002]; Netherlands Cardiovascular Research Initiative [CVON
   2011-11]
FX This work was supported by grants from the Netherlands Organisation for
   Scientific Research (NWO) [grant numbers 825.13.007 and 836.12.002] and
   the Netherlands Cardiovascular Research Initiative [grant number CVON
   2011-11].
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NR 81
TC 50
Z9 54
U1 0
U2 17
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD APR
PY 2015
VL 81
BP 107
EP 113
DI 10.1016/j.yjmcc.2015.02.008
PG 7
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA CG2BF
UT WOS:000353079200016
PM 25683494
DA 2025-04-10
ER

PT J
AU Briganti, F
   Wang, ZL
AF Briganti, Francesca
   Wang, Zilu
TI Alternative Splicing in the Heart: The Therapeutic Potential of
   Regulating the Regulators
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Review
DE splicing; cardiac differentiation; RBM20
ID RNA-BINDING PROTEIN; PRE-MESSENGER-RNA; TITIN ISOFORMS; PASSIVE
   STIFFNESS; STRUCTURAL BASIS; EXPRESSION; POLYADENYLATION;
   CARDIOMYOPATHY; RBM24; PATTERNS
AB Alternative splicing allows a single gene to produce a variety of protein isoforms. Changes in splicing isoform usage characterize virtually every stage of the differentiation process and define the physiological differences between cardiomyocytes with different function, at different stages of development, and pathological function. Recent identification of cardiac splicing factors provided insights into the mechanisms underlying alternative splicing and revealed how these splicing factors impact functional properties of the heart. Alterations of the splicing of sarcomeric genes, cell signaling proteins, and ion channels have been associated with the development of pathological conditions such as cardiomyopathy and arrhythmia. RBM20, RBM24, PTBP1, RBFOX, and QKI play key roles in cardiac development and pathology. A better understanding of their regulation will yield insights into healthy cardiac development and inform the development of molecular therapeutics.
C1 [Briganti, Francesca; Wang, Zilu] Univ Calif San Diego, Dept Pediat, Div Genet, La Jolla, CA 92093 USA.
   [Briganti, Francesca] UNIV CALIF SAN DIEGO, Dept Pediat, Div Cardiol, LA JOLLA, CA 92093 USA.
C3 University of California System; University of California San Diego;
   University of California System; University of California San Diego
RP Briganti, F (corresponding author), Univ Calif San Diego, Dept Pediat, Div Genet, La Jolla, CA 92093 USA.; Briganti, F (corresponding author), UNIV CALIF SAN DIEGO, Dept Pediat, Div Cardiol, LA JOLLA, CA 92093 USA.
EM fbriganti@health.ucsd.edu
RI Briganti, Francesca/KFS-7672-2024; wang, zilu/W-5209-2019
OI Briganti, Francesca/0000-0001-5738-2642
FU National Institute of Health;  [K99HL165099];  [R00HL165099]
FX This study was supported by the National Institute of Health grants
   K99HL165099 and R00HL165099.
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NR 109
TC 1
Z9 1
U1 3
U2 3
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD DEC
PY 2024
VL 25
IS 23
AR 13023
DI 10.3390/ijms252313023
PG 16
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA P2O1S
UT WOS:001376359700001
PM 39684734
OA gold
DA 2025-04-10
ER

PT J
AU Peng, Y
   Ayaz-Guner, S
   Yu, DY
   Ge, Y
AF Peng, Ying
   Ayaz-Guner, Serife
   Yu, Deyang
   Ge, Ying
TI Top-down mass spectrometry of cardiac myofilament proteins in health and
   disease
SO PROTEOMICS CLINICAL APPLICATIONS
LA English
DT Review
DE Electron capture dissociation; Heart failure; Myofilaments;
   Phosphorylation; Top-down mass spectrometry; Troponin
ID TROPONIN-I PHOSPHORYLATION; ELECTRON-CAPTURE DISSOCIATION;
   MULTIPLY-CHARGED IONS; HEART-FAILURE; HYPERTROPHIC CARDIOMYOPATHY;
   TROPOMYOSIN ISOFORM; C PHOSPHORYLATION; ALPHA-TROPOMYOSIN;
   POSTTRANSLATIONAL MODIFICATIONS; MYOCARDIAL-INFARCTION
AB Myofilaments are composed of thin and thick filaments that coordinate with each other to regulate muscle contraction and relaxation. PTMs together with genetic variations and alternative splicing of the myofilament proteins play essential roles in regulating cardiac contractility in health and disease. Therefore, a comprehensive characterization of the myofilament proteins in physiological and pathological conditions is essential for better understanding the molecular basis of cardiac function and dysfunction. Due to the vast complexity and dynamic nature of proteins, it is challenging to obtain a holistic view of myofilament protein modifications. In recent years, top-down MS has emerged as a powerful approach to study isoform composition and PTMs of proteins owing to its advantage of complete sequence coverage and its ability to identify PTMs and sequence variants without a priori knowledge. In this review, we will discuss the application of top-down MS to the study of cardiac myofilaments and highlight the insights it provides into the understanding of molecular mechanisms in contractile dysfunction of heart failure. Particularly, recent results of cardiac troponin and tropomyosin modifications will be elaborated. The limitations and perspectives on the use of top-down MS for myofilament protein characterization will also be briefly discussed.
C1 [Peng, Ying; Ayaz-Guner, Serife; Yu, Deyang; Ge, Ying] Univ Wisconsin, Sch Med & Publ Hlth, Dept Cell & Regenerat Biol, Madison, WI 53706 USA.
   [Yu, Deyang] Univ Wisconsin, Mol & Environm Toxicol Program, Madison, WI 53706 USA.
   [Ge, Ying] Univ Wisconsin, Dept Chem, Madison, WI 53706 USA.
   [Ge, Ying] Univ Wisconsin, Sch Med & Publ Hlth, Human Prote Program, Madison, WI 53706 USA.
C3 University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison
RP Peng, Y (corresponding author), Univ Wisconsin, 1300 Univ Ave,SMI 130, Madison, WI 53706 USA.
EM ge2@wisc.edu
RI Ayaz-Guner, Serife/K-4139-2019
OI AYAZ GUNER, SERIFE/0000-0002-1052-0961
FU National Institute of Health [R01HL096971, R01HL109810]
FX We acknowledge the financial support by National Institute of Health
   R01HL096971 and R01HL109810 (to YG).
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NR 143
TC 23
Z9 36
U1 3
U2 19
PU WILEY-V C H VERLAG GMBH
PI WEINHEIM
PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY
SN 1862-8346
EI 1862-8354
J9 PROTEOM CLIN APPL
JI Proteom. Clin. Appl.
PD AUG
PY 2014
VL 8
IS 7-8
SI SI
BP 554
EP 568
DI 10.1002/prca.201400043
PG 15
WC Biochemical Research Methods; Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA AN4YJ
UT WOS:000340595600010
PM 24945106
OA Bronze, Green Accepted
DA 2025-04-10
ER

PT J
AU Shaji, F
   Mohanan, NK
   Shahzad, S
   Gowri, VP
   Prabhashankar, AB
   Sundaresan, NR
   Laishram, RS
AF Shaji, Feba
   Mohanan, Neeraja K.
   Shahzad, Sumayya
   Gowri, V. P.
   Prabhashankar, Arathi Bangalore
   Sundaresan, Nagalingam R.
   Laishram, Rakesh S.
TI Proto-oncogene cSrc-mediated RBM10 phosphorylation arbitrates
   anti-hypertrophy gene program in the heart and controls cardiac
   hypertrophy
SO LIFE SCIENCES
LA English
DT Article
DE RBM10; mRNA 3'-end processing; untranslated RNA; cardiac hypertrophy;
   heart failure; phosphorylation; Star-PAP
ID RNA-BINDING PROTEIN; PRESSURE-OVERLOAD; MASS-SPECTROMETRY; PIPKI-ALPHA;
   SRC; IDENTIFICATION; SPECIFICITY; RECOGNITION; ACTIVATION; EXPRESSION
AB Aims: RBM10 is a well-known RNA binding protein that regulates alternative splicing in various disease states. We have shown a splicing-independent function of RBM10 that regulates heart failure. This study aims to unravel a new biological function of RBM10 phosphorylation by proto-oncogene cSrc that enables anti-hypertrophy gene program and controls cardiac hypertrophy. Materials and methods: We employ in vitro and in vivo approaches to characterise RBM10 phosphorylation at three-tyrosine residues (Y81, Y500, and Y971) by cSrc and target mRNA regulation. We also use isoproterenol induced rat heart and cellular hypertrophy model to determine role of cSrc-mediated RBM10 phosphorylation. Key findings: We show that RBM10 phosphorylation is induced in cellular and animal heart model of cardiac hypertrophy and regulates target mRNA expression and 3 '-end formation. Inhibition of cSrc kinase or mutation of the three-tyrosine phosphorylation sites to phenylalanine accentuates myocyte hypertrophy, and results in advancement and an early attainment of hypertrophy in the heart. RBM10 is down regulated in the hypertrophic myocyte and that its re-expression reverses cellular and molecular changes in the myocyte. However, in the absence of phosphorylation (cSrc inhibition or phospho-deficient mutation), restoration of endogenous RBM10 level in the hypertrophic heart or ectopic re-expression in vitro failed to reverse cardiomyocyte hypertrophy. Mechanistically, loss of RBM10 phosphorylation inhibits nuclear localisation and interaction with Star-PAP compromising anti-hypertrophy gene expression. Significance: Our study establishes that cSrc-mediated RBM10 phosphorylation arbitrates anti-hypertrophy gene program. We also report a new functional regulation of RBM10 by phosphorylation that is poised to control heart failure.
C1 [Shaji, Feba; Mohanan, Neeraja K.; Shahzad, Sumayya; Gowri, V. P.; Laishram, Rakesh S.] Rajiv Gandhi Ctr Biotechnol, Cardiovasc Dis & Diabet Biol Grp, Thiruvananthapuram 695014, India.
   [Mohanan, Neeraja K.] Manipal Acad Higher Educ, Manipal 576104, India.
   [Shaji, Feba] Reg Ctr Biotechnol, Faridabad 121001, Haryana, India.
   [Prabhashankar, Arathi Bangalore; Sundaresan, Nagalingam R.] Indian Inst Sci, Dept Microbiol & Cell Biol, Bengaluru 560012, India.
C3 Department of Biotechnology (DBT) India; Rajiv Gandhi Centre for
   Biotechnology (RGCB); Manipal Academy of Higher Education (MAHE);
   Department of Biotechnology (DBT) India; Regional Centre for
   Biotechnology; Indian Institute of Science (IISC) - Bangalore
RP Laishram, RS (corresponding author), Rajiv Gandhi Ctr Biotechnol, Cardiovasc Dis & Diabet Biol Grp, Thiruvananthapuram 695014, India.
EM laishram@rgcb.res.in
FU Swarnajayanti Fellowship [SB/SJF/2019-20/09]; SERB, Ministry of Science
   and Technology [CRG/2019/003230]; Council of Scientific and Industrial
   Research; University Grants Commission
FX This work was supported from Swarnajayanti Fellowship
   (SB/SJF/2019-20/09) and SERB, Ministry of Science and Technology
   (CRG/2019/003230) to RSL, and SRF fellowship from Council of Scientific
   and Industrial Research to FS and University Grants Commission to NKM.
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NR 78
TC 1
Z9 1
U1 1
U2 1
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 0024-3205
EI 1879-0631
J9 LIFE SCI
JI Life Sci.
PD MAR 15
PY 2024
VL 341
AR 122482
DI 10.1016/j.lfs.2024.122482
EA FEB 2024
PG 18
WC Medicine, Research & Experimental; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine; Pharmacology & Pharmacy
GA KM7X9
UT WOS:001180460500001
PM 38309577
OA hybrid
DA 2025-04-10
ER

PT J
AU Jiao, L
   Gong, MY
   Yang, XW
   Li, MM
   Shao, YC
   Wang, YQ
   Li, HD
   Yu, Q
   Sun, LH
   Xuan, LA
   Huang, J
   Wang, YY
   Liu, DP
   Qu, YM
   Lan, XW
   Zhang, YW
   Zhang, XY
   Sun, H
   Zhang, Y
   Zhang, Y
   Yang, BF
AF Jiao, Lei
   Gong, Manyu
   Yang, Xuewen
   Li, Mengmeng
   Shao, Yingchun
   Wang, Yaqi
   Li, Haodong
   Yu, Qi
   Sun, Lihua
   Xuan, Lina
   Huang, Jian
   Wang, Yanying
   Liu, Dongping
   Qu, Yunmeng
   Lan, Xiuwen
   Zhang, Yanwei
   Zhang, Xiyang
   Sun, Han
   Zhang, Yong
   Zhang, Ying
   Yang, Baofeng
TI NAD plus attenuates cardiac injury after myocardial infarction in
   diabetic mice through regulating alternative splicing of VEGF in
   macrophages
SO VASCULAR PHARMACOLOGY
LA English
DT Article
DE Diabetic mellitus; Myocardial infarction; NAD plus; Alternative
   splicing; VEGF
ID HEART-FAILURE; ANGIOGENESIS
AB Diabetic mellitus (DM) complicated with myocardial infarction (MI) is a serious clinical issue that remained poorly comprehended. The aim of the present study was to investigate the role of NAD+ in attenuating cardiac damage following MI in diabetic mice. The cardiac dysfunction in DM mice with MI was more severe compared with the non-diabetic mice and NAD+ administration could significantly improve the cardiac function in both non-diabetic and diabetic mice after MI for both 7 days and 28 days. Moreover, application of NAD+ could markedly reduce the cardiac injury area of DM complicated MI mice. Notably, the level of NAD+ was robustly decreased in the cardiac tissue of MI mice, which was further reduced in the DM complicated mice and NAD+ administration could significantly restore the NAD+ level. Furthermore, NAD+ was verified to facilitate the angiogenesis in the MI area of both diabetic mice and non-diabetic mice by microfil perfusion assay and immunofluorescence. Additionally, we demonstrated that NAD+ promoted cardiac angiogenesis after myocardial infarction in diabetic mice by promoting the M2 polarization of macrophages. At the molecular level, NAD+ promoted the secretion of VEGF in macrophages and therefore facilitating migration and tube formation of endothelial cells. Mechanistically, NAD+ was found to promote the generation of pro-angionesis VEGF165 and inhibit the generation of anti-angionesis VEGF165b via regulating the alternative splicing factors of VEGF (SRSF1 and SRSF6) in macrophages. The effects of NAD+ were readily reversible on deficiency of it. Collectively, our data showed that NAD+ could attenuate myocardial injury via regulating the alternative splicing of VEGF and promoting angiogenesis in diabetic mice after myocardial infarction. NAD+ administration may therefore be considered a potential new approach for the treatment of diabetic patients with myocardial infarction.
C1 [Jiao, Lei; Gong, Manyu; Yang, Xuewen; Li, Mengmeng; Shao, Yingchun; Wang, Yaqi; Li, Haodong; Yu, Qi; Sun, Lihua; Xuan, Lina; Wang, Yanying; Liu, Dongping; Qu, Yunmeng; Zhang, Yanwei; Zhang, Xiyang; Sun, Han; Zhang, Yong; Zhang, Ying; Yang, Baofeng] Harbin Med Univ, Coll Pharm, State Prov Key Labs Biomed Pharmaceut China, Key Lab Cardiovasc Med Res,Dept Pharmacol,Minist E, Harbin 150081, Heilongjiang, Peoples R China.
   [Huang, Jian] Harbin Med Univ, Canc Hosp, Dept Med Oncol 4, 150 Haping Rd, Harbin 150040, Peoples R China.
   [Lan, Xiuwen] Harbin Med Univ, Canc Hosp, Dept Crit Care Med, 150 Haping Rd, Harbin 150040, Peoples R China.
   [Yang, Baofeng] Univ Melbourne, Fac Med Dent & Hlth Sci, Melbourne Sch Biomed Sci, Dept Pharmacol & Therapeut, Melbourne, Australia.
   [Yang, Baofeng] Chinese Acad Med Sci, Res Unit Noninfect Chron Dis Frigid Zone, 2019RU070, Beijing, Peoples R China.
   [Zhang, Ying; Yang, Baofeng] Harbin Med Univ, Dept Pharmacol, State Prov Key Labs Biomed Pharmaceut China, 157 Baojian Rd, Harbin, Heilongjiang, Peoples R China.
C3 Harbin Medical University; Harbin Medical University; Harbin Medical
   University; University of Melbourne; Chinese Academy of Medical Sciences
   - Peking Union Medical College; Harbin Medical University
RP Zhang, Y; Yang, BF (corresponding author), Harbin Med Univ, Dept Pharmacol, State Prov Key Labs Biomed Pharmaceut China, 157 Baojian Rd, Harbin, Heilongjiang, Peoples R China.
EM jennying223@hrbmu.edu.cn; yangbf@ems.hrbmu.edu.cn
RI Liu, Dongping/AAW-8846-2021
FU National Natural Science Foundation of China [82003749, 81970320]; CAMS
   Innovation Fund for Medical Sciences (CIFMS) [2020-I2M-5-003];
   Outstanding Young Talent Research Fund of College of Pharmacy, Harbin
   Medical University [2019-JQ-05]; Outstanding Youth Project of
   Heilongjiang Provincial Natural Science Foundation [YQ2020H009,
   LC2018034]; Young Talents Startup Fund of Pharmacy, Harbin Medical
   University [2019-QD-03]
FX This work was supported by the National Natural Science Foundation of
   China (82003749 and 81970320) , CAMS Innovation Fund for Medical
   Sciences (CIFMS) 2020-I2M-5-003; the Outstanding Young Talent Research
   Fund of College of Pharmacy, Harbin Medical University (2019-JQ-05) ,
   the Outstanding Youth Project of Heilongjiang Provincial Natural Science
   Foundation (YQ2020H009, LC2018034) and the Young Talents Startup Fund of
   Pharmacy, Harbin Medical University (2019-QD-03) .
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NR 34
TC 8
Z9 9
U1 1
U2 18
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA STE 800, 230 PARK AVE, NEW YORK, NY 10169 USA
SN 1537-1891
EI 1879-3649
J9 VASC PHARMACOL
JI Vasc. Pharmacol.
PD DEC
PY 2022
VL 147
AR 107126
DI 10.1016/j.vph.2022.107126
EA NOV 2022
PG 13
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA 6O8DD
UT WOS:000890468500001
PM 36351515
DA 2025-04-10
ER

PT J
AU Ferreira, JCB
   Koyanagi, T
   Palaniyandi, SS
   Fajardo, G
   Churchill, EN
   Budas, G
   Disatnik, MH
   Bernstein, D
   Brum, PC
   Mochly-Rosen, D
AF Ferreira, Julio C. B.
   Koyanagi, Tomoyoshi
   Palaniyandi, Suresh S.
   Fajardo, Giovanni
   Churchill, Eric N.
   Budas, Grant
   Disatnik, Marie-Helene
   Bernstein, Daniel
   Brum, Patricia C.
   Mochly-Rosen, Daria
TI Pharmacological inhibition of βIIPKC is cardioprotective in late-stage
   hypertrophy
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Article
DE Protein kinase C; Cardiac remodeling; Hypertension; Contractility
   dysfunction; Heart failure
ID PROTEIN-KINASE-C; INDUCED HEART-FAILURE; TROPONIN-I PHOSPHORYLATION;
   PKC-BETA; ANGIOTENSIN-II; MYOCARDIAL FIBROSIS; HYPERTENSIVE-RATS;
   CARDIAC-FUNCTION; GENETIC MODEL; EPSILON-PKC
AB We previously found that in the hearts of hypertensive Dahl salt-sensitive rats, beta IIPKC levels increase during the transition from compensated cardiac hypertrophy to cardiac dysfunction. Here we showed that a six-week treatment of these hypertensive rats with a beta IIPKC-specific inhibitor, beta IIV5-3, prolonged their survival by at least 6 weeks, suppressed myocardial fibrosis and inflammation, and delayed the transition from compensated hypertrophy to cardiac dysfunction. In addition, changes in the levels of the Ca2+-handling proteins, SERCA2 and the Na+/Ca2+ exchanger, as well as troponin I phosphorylation, seen in the control-treated hypertensive rats were not observed in the beta IIPKC-treated rats, suggesting that beta IIPKC contributes to the regulation of calcium levels in the myocardium. In contrast, treatment with the selective inhibitor of beta IPKC, an alternative spliced form of beta IIPKC, had no beneficial effects in these rats. We also found that beta IIV5-3, but not beta IV5-3, improved calcium handling in isolated rat cardiomyocytes and enhanced contractility in isolated rat hearts. In conclusion, our data using an in vivo model of cardiac dysfunction (late-phase hypertrophy), suggest that beta IIPKC contributes to the pathology associated with heart failure and thus an inhibitor of beta IIPKC may be a potential treatment for this disease. (C) 2011 Elsevier Ltd. All rights reserved.
C1 [Mochly-Rosen, Daria] Stanford Univ, Sch Med, Dept Chem & Syst Biol, CCSR, Stanford, CA 94305 USA.
   [Ferreira, Julio C. B.; Brum, Patricia C.] Univ Sao Paulo, Sch Phys Educ & Sport, BR-05508900 Sao Paulo, Brazil.
   [Fajardo, Giovanni; Bernstein, Daniel] Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA.
C3 Stanford University; Universidade de Sao Paulo; Stanford University
RP Mochly-Rosen, D (corresponding author), Stanford Univ, Sch Med, Dept Chem & Syst Biol, CCSR, Rm 3145A,269 Campus Dr, Stanford, CA 94305 USA.
EM mochly@stanford.edu
RI Brum, Patricia/E-6605-2011; Ferreira, Julio Cesar Batista/I-3177-2012
OI Bernstein, Daniel/0000-0001-7761-5853; Mochly-Rosen,
   Daria/0000-0002-6691-8733; Ferreira, Julio Cesar
   Batista/0000-0003-2694-239X
FU National Institute of Health [HL076675, HL52141]; Fundacao de Amparo a
   Pesquisa do Estado de Sao Paulo - Brasil (FAPESP) [2009/03143-1];
   Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
   [09/03143-1] Funding Source: FAPESP
FX This study was supported by National Institute of Health Grant HL076675
   and HL52141 to DMR. J.C.B.F. holds a post-doctoral fellowship from
   Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - Brasil (FAPESP
   2009/03143-1).
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NR 41
TC 33
Z9 34
U1 0
U2 3
PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
PI LONDON
PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD DEC
PY 2011
VL 51
IS 6
BP 980
EP 987
DI 10.1016/j.yjmcc.2011.08.025
PG 8
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA 847AH
UT WOS:000296943800014
PM 21920368
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Granzier, H
   Wu, YM
   Siegfried, L
   LeWinter, M
AF Granzier, H
   Wu, YM
   Siegfried, L
   LeWinter, M
TI Thin: Physiological function and role in cardiomyopathy and failure
SO HEART FAILURE REVIEWS
LA English
DT Review
DE diastole; passive stiffness; titin isoforms; stretch sensing
ID TITIN ISOFORM EXPRESSION; FRANK-STARLING MECHANISM; TIBIAL
   MUSCULAR-DYSTROPHY; ANKYRIN REPEAT PROTEIN; RAT CARDIAC MYOCYTES;
   C-TERMINAL REGION; Z-LINE REGION; Z-DISC; MYOCARDIAL STIFFNESS; PASSIVE
   STIFFNESS
AB Titin is a giant protein that constitutes the third myofilament of the sarcomere. Single titin molecules anchor in the Z-disk and extend all the way to the M-line region of the sarcomere. Successive titin molecules are arranged head-to-head and tall-to-tail, providing a continuous filament along the full length of the myofibril. The majority of titin's I-band region is extensible and functions as a molecular spring that when extended develops passive force. We will discuss mechanisms for adjusting titin-based force, including alternative splicing and posttranslational modifica tions. Multiple biological functions can be assigned to different regions of the titin molecule. In addition to titin's role in determining passive muscle stiffness, recent evidence suggests a role in protein metabolism, compartmentalization of metabolic enzymes, binding of chaperones, and positioning of the membrane systems of the T-tubules and sarcoplasmic reticulum. We will also discus titin-based force adjustments that occur in various muscle diseases and several disease-causing titin mutations that have been discovered. We will focus on the role of titin in heart failure patients that was recently investigated in patients with end-stage heart failure due to non-ischemic dilated cardiomyopathy. In end-stage failing hearts, compliant titin isoforms comprise a greater percentage of titin and changes in titin isoform. expression in heart failure patients with DCM significantly impact diastolic filling by lowering myocardial stiffness.
C1 Washington State Univ, Dept Vet & Comparat Anat Pharmacol & Physiol, Pullman, WA 99164 USA.
   Heidelberg Univ, Klinikum Mannheim, Inst Anasthesiol & Operat Intens Med, D-68167 Mannheim, Germany.
   Fletcher Allen Hlth Care, Burlington, VT 05401 USA.
C3 Washington State University; Ruprecht Karls University Heidelberg;
   University of Vermont Medical Center
RP Washington State Univ, Dept Vet & Comparat Anat Pharmacol & Physiol, Wegner Hall 205, Pullman, WA 99164 USA.
EM granzier@wsunix.wsu.edu
RI LeWinter, Martin/JLK-9787-2023
FU NHLBI NIH HHS [HL61487, HL62881] Funding Source: Medline
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NR 99
TC 64
Z9 79
U1 0
U2 5
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 1382-4147
EI 1573-7322
J9 HEART FAIL REV
JI Heart Fail. Rev.
PD SEP
PY 2005
VL 10
IS 3
BP 211
EP 223
DI 10.1007/s10741-005-5251-7
PG 13
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 002DH
UT WOS:000234591200005
PM 16416044
DA 2025-04-10
ER

PT J
AU Zhang, HY
   Liao, P
   Wang, JJ
   Yu, DJ
   Soong, TW
AF Zhang, Heng Yu
   Liao, Ping
   Wang, Jue Jin
   Yu, De Jie
   Soong, Tuck Wah
TI Alternative splicing modulates diltiazem sensitivity of cardiac and
   vascular smooth muscle Cav1.2 calcium channels
SO BRITISH JOURNAL OF PHARMACOLOGY
LA English
DT Article
DE alternative splicing; calcium channel; diltiazem; smooth muscle; heart
ID CA2+ CHANNELS; MOLECULAR DETERMINANTS; CA2+-DEPENDENT INACTIVATION;
   SUBUNIT; HEART; BLOCK; MECHANISM; AUTISM; DOMAIN; CELLS
AB Background and purpose:
   As a calcium channel blocker, diltiazem acts mainly on the voltage-gated calcium channels, Ca(v)1.2, for its beneficial effects in cardiovascular diseases such as hypertension, angina and/or supraventricular arrhythmias. However, the effects of diltiazem on different isoforms of Ca(v)1.2 channels expressed in heart and vascular smooth muscles remain to be investigated. Here, we characterized the effects of diltiazem on the splice variants of Ca(v)1.2 channels, predominant in cardiac and vascular smooth muscles.
   Experimental approach:
   Cardiac and smooth muscle isoforms of Ca(v)1.2 channels were expressed in human embryonic kidney cells and their electrophysiological properties were characterized using whole-cell patch-clamp techniques.
   Key results:
   Under closed-channel and use-dependent block (0.03 Hz), cardiac splice variant Ca(v)1.2CM was less sensitive to diltiazem than two major smooth muscle splice variants, Ca(v)1.2SM and Ca(v)1.2b. Ca(v)1.2CM has a more positive half-inactivation potential than the smooth muscle channels, and diltiazem shifted it less to negative potential. Additionally, the current decay was slower in Ca(v)1.2CM channels. When we modified alternatively spliced exons of cardiac Ca(v)1.2CM channels into smooth muscle exons, we found that all three loci contribute to the different diltiazem sensitivity between cardiac and smooth muscle splice isoforms.
   Conclusions and implications:
   Alternative splicing of Ca(v)1.2 channels modifies diltiazem sensitivity in the heart and blood vessels. Gating properties altered by diltiazem are different in the three channels.
C1 [Zhang, Heng Yu; Yu, De Jie; Soong, Tuck Wah] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore.
   [Zhang, Heng Yu] Sichuan Univ, W China Sch Med, Dept Cardiol, Chengdu 610064, Peoples R China.
   [Liao, Ping; Wang, Jue Jin; Soong, Tuck Wah] Natl Inst Neurosci, Singapore, Singapore.
C3 National University of Singapore; Sichuan University; National
   Neuroscience Institute (NNI)
RP Soong, TW (corresponding author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore.
EM phsstw@nus.edu.sg
RI Yu, Dejie/AAT-3293-2021; Wang, Jue/GVU-0480-2022; Liao,
   Ping/LBI-1504-2024
OI Liao, Ping/0000-0002-6205-4042
FU Sichuan Science and Technology Bureau [2009HH0026]; National Medical
   Research Council; Biomedical Research Council of Singapore
FX HY Zhang is supported by a grant from Sichuan Science and Technology
   Bureau (2009HH0026). This work is supported by grants from the National
   Medical Research Council and Biomedical Research Council of Singapore.
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NR 31
TC 23
Z9 24
U1 0
U2 4
PU WILEY-BLACKWELL
PI MALDEN
PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA
SN 0007-1188
J9 BRIT J PHARMACOL
JI Br. J. Pharmacol.
PD AUG
PY 2010
VL 160
IS 7
BP 1631
EP 1640
DI 10.1111/j.1476-5381.2010.00798.x
PG 10
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA 621WM
UT WOS:000279616400008
PM 20649567
OA Green Published
DA 2025-04-10
ER

PT J
AU Biquand, A
   Spinozzi, S
   Tonino, P
   Cosette, J
   Strom, J
   Elbeck, Z
   Knöll, R
   Granzier, H
   Lostal, W
   Richard, I
AF Biquand, Ariane
   Spinozzi, Simone
   Tonino, Paola
   Cosette, Jeremie
   Strom, Joshua
   Elbeck, Zaher
   Knoll, Ralph
   Granzier, Henk
   Lostal, William
   Richard, Isabelle
TI Titin M-line insertion sequence 7 is required for proper cardiac
   function in mice
SO JOURNAL OF CELL SCIENCE
LA English
DT Article
DE Cardiomyopathy; Heart failure; Titin; Mex5; is7; Alternative splicing
ID C-TERMINAL TITIN; M-BAND TITIN; SARCOPLASMIC-RETICULUM; TISSUE
   INHIBITOR; GENE-EXPRESSION; REGION LEADS; MUSCLE; SARCOMERE; OBSCURIN;
   MUTATIONS
AB Thin is a giant sarcomeric protein that is involved in a large number of functions, with a primary role in skeletal and cardiac sarcomere organization and stiffness. The titin gene (TTN) is subject to various alternative splicing events, but in the region that is present at the Mline, the only exon that can be spliced out is Mex5, which encodes for the insertion sequence 7 (is7). Interestingly, in the heart, the majority of titin isoforms are Mex5+, suggesting a cardiac role for is7. Here, we performed comprehensive functional, histological, transcriptomic, microscopic and molecular analyses of a mouse model lacking the Ttn Mex5 exon (Delta Mex5), and revealed that the absence of the is7 is causative for dilated cardiomyopathy. Delta Mex5 mice showed altered cardiac function accompanied by increased fibrosis and ultrastructural alterations. Abnormal expression of excitation- contraction coupling proteins was also observed. The results reported here confirm the importance of the C-terminal region of titin in cardiac function and are the first to suggest a possible relationship between the is7 and excitation-contraction coupling. Finally, these findings give important insights for the identification of new targets in the treatment of titinopathies.
C1 [Biquand, Ariane; Spinozzi, Simone; Cosette, Jeremie; Lostal, William; Richard, Isabelle] Genethon, F-91000 Evry, France.
   [Biquand, Ariane; Spinozzi, Simone; Lostal, William; Richard, Isabelle] Univ Evry, Univ Paris Saclay, INSERM, Genethon,Integrare Res Unit UMR S951, F-91000 Evry, France.
   [Tonino, Paola; Strom, Joshua; Granzier, Henk] Univ Arizona, Dept Cellular & Mol Med, Tucson, AZ 85721 USA.
   [Elbeck, Zaher; Knoll, Ralph] Karolinska Inst, Integrated Cardio Metab Ctr ICMC, Dept Med, Heart & Vasc Theme, S-14157 Huddinge, Sweden.
   [Knoll, Ralph] AstraZeneca, Biosci Cardiovasc Res & Early Dev, Cardiovasc Renal & Metab CVRM, BioPharmaceut R&D, S-43150 Gothenburg, Sweden.
C3 Universite Paris Saclay; Institut National de la Sante et de la
   Recherche Medicale (Inserm); University of Arizona; Karolinska
   Institutet; AstraZeneca
RP Richard, I (corresponding author), Genethon, F-91000 Evry, France.; Richard, I (corresponding author), Univ Evry, Univ Paris Saclay, INSERM, Genethon,Integrare Res Unit UMR S951, F-91000 Evry, France.
EM richard@genethon.fr
RI Knöll, Ralph/GOH-3587-2022
OI Spinozzi, Simone/0000-0001-8593-5558; Biquand,
   Ariane/0009-0002-1525-1489
FU Fondation Leducq project [13CVD04]; European Commission [645648];
   National Heart, Lung, and Blood Institute [R35HL144998]
FX This work was supported by the Fondation Leducq project [Mechanical
   Triggers to Programmed Cell Death in Cardiomyocytes -and how to prevent
   their Action in Failing Hearts (13CVD04)], by the European Commission
   MSCA-RISE-2014, H2020 Marie Sklodowska-Curie Actions staff exchange
   project [Muscle Stress Relief (645648)], and by National Heart, Lung,
   and Blood Institute grant R35HL144998. Deposited in PMC for release
   after 12 months.
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NR 75
TC 2
Z9 3
U1 1
U2 4
PU COMPANY BIOLOGISTS LTD
PI CAMBRIDGE
PA BIDDER BUILDING, STATION RD, HISTON, CAMBRIDGE CB24 9LF, ENGLAND
SN 0021-9533
EI 1477-9137
J9 J CELL SCI
JI J. Cell Sci.
PD SEP
PY 2021
VL 134
IS 18
AR jcs258684
DI 10.1242/jcs.258684
PG 13
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA WC9VO
UT WOS:000704598000012
PM 34401916
OA Bronze, Green Published, Green Submitted
DA 2025-04-10
ER

PT J
AU Wang, ZY
   Liu, XX
   Deng, YF
AF Wang, Zhi-Yan
   Liu, Xiao-Xiao
   Deng, Yun-Fei
TI Negative feedback of SNRK to circ-SNRK regulates cardiac function
   post-myocardial infarction
SO CELL DEATH AND DIFFERENTIATION
LA English
DT Article
ID KINASE ENZYME; IDENTIFICATION; CELLS; HEART; RNAS
AB A limited delivery of oxygen and metabolic substrate to the heart caused by myocardial infarction (MI) impairs the cardiac function, and often results in heart failure. Here, we identified a circRNA (circ-SNRK) from SNRK (sucrose nonfermenting 1-related kinase, which can increase the cardiac mitochondrial efficiency) in cardiomyocytes (CMs). Circ-SNRK can sponge the miR-33 and in turn improved the ATP synthesis via SNRK, proving the existence of circ-SNRK - miR-33 - SNRK axis. Furthermore, we found that protein NOVA1 (NOVA alternative splicing regulator 1) could accelerate the circ-SNRK formation; a cleaved peptide (similar to 55 kDa) from SNRK enters the nucleus and blocks the cyclization of circ-SNRK via binding to NOVA1. The aforementioned negative feedback of SNRK to circ-SNRK limited the SNRK at a proper level, and inhibited the protective role of circ-SNRK in ischemic heart. In addition, our in vivo experiment indicated that the overexpression of exogenic circ-SNRK could break this loop and improves the cardiac function post-MI in rats. Together, our results demonstrated that the negative loop of circ-SNRK with SNRK regulates the energy metabolism in CMs, thus might be a potential therapeutic target for heart failure.
C1 [Wang, Zhi-Yan] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Cardiovasc Med, Shanghai, Peoples R China.
   [Liu, Xiao-Xiao] Fudan Univ, Shanghai Med Coll, Zhongshan Hosp, Dept Cardiol,Shanghai Inst Cardiovasc, Shanghai, Peoples R China.
   [Deng, Yun-Fei] Nanjing Med Univ, Nanjing Hosp 1, Dept Cardiol, Nanjing, Peoples R China.
C3 Shanghai Jiao Tong University; Fudan University; Nanjing Medical
   University
RP Deng, YF (corresponding author), Nanjing Med Univ, Nanjing Hosp 1, Dept Cardiol, Nanjing, Peoples R China.
EM yunfeideng_1988@126.com
RI Liu, Xiaoxiao/HNI-6180-2023; deng, yunfei/AAA-2292-2022
OI Deng, Yun-Fei/0000-0002-1327-724X
FU Natural Science Foundation of Jiangsu Province
FX This work was supported by funds from Natural Science Foundation of
   Jiangsu Province (NO.BK20210030).
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NR 28
TC 17
Z9 20
U1 2
U2 27
PU SPRINGERNATURE
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON, N1 9XW, ENGLAND
SN 1350-9047
EI 1476-5403
J9 CELL DEATH DIFFER
JI Cell Death Differ.
PD APR
PY 2022
VL 29
IS 4
BP 709
EP 721
DI 10.1038/s41418-021-00885-x
EA OCT 2021
PG 13
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 0L6BA
UT WOS:000705760200001
PM 34621049
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Rexiati, M
   Sun, MM
   Guo, W
AF Rexiati, Maimaiti
   Sun, Mingming
   Guo, Wei
TI Muscle-Specific Mis-Splicing and Heart Disease Exemplified by RBM20
SO GENES
LA English
DT Review
DE alternative splicing; muscle-specific splicing factor; heart disease;
   RNA-binding motif 20; titin
ID BINDING-PROTEIN; MYOTONIC-DYSTROPHY; TITIN ISOFORMS; MOUSE MODEL;
   DILATED CARDIOMYOPATHY; SARCOMERIC GENES; CARDIAC TITIN; RNA;
   IDENTIFICATION; MECHANISMS
AB Alternative splicing is an essential post-transcriptional process to generate multiple functional RNAs or proteins from a single transcript. Progress in RNA biology has led to a better understanding of muscle-specific RNA splicing in heart disease. The recent discovery of the muscle-specific splicing factor RNA-binding motif 20 (RBM20) not only provided great insights into the general alternative splicing mechanism but also demonstrated molecular mechanism of how this splicing factor is associated with dilated cardiomyopathy. Here, we review our current knowledge of muscle-specific splicing factors and heart disease, with an emphasis on RBM20 and its targets, RBM20-dependent alternative splicing mechanism, RBM20 disease origin in induced Pluripotent Stem Cells (iPSCs), and RBM20 mutations in dilated cardiomyopathy. In the end, we will discuss the multifunctional role of RBM20 and manipulation of RBM20 as a potential therapeutic target for heart disease.
C1 [Rexiati, Maimaiti; Sun, Mingming; Guo, Wei] Univ Wyoming, Anim Sci, Laramie, WY 82071 USA.
   [Rexiati, Maimaiti; Sun, Mingming; Guo, Wei] Univ Wyoming, Ctr Cardiovasc Res & Integrat Med, Laramie, WY 82071 USA.
C3 University of Wyoming; University of Wyoming
RP Guo, W (corresponding author), Univ Wyoming, Anim Sci, Laramie, WY 82071 USA.; Guo, W (corresponding author), Univ Wyoming, Ctr Cardiovasc Res & Integrat Med, Laramie, WY 82071 USA.
EM rmaimait@uwyo.edu; msun2@uwyo.edu; wguo3@uwyo.edu
RI Guo, Wei/KJM-4941-2024
OI Rexiati, Maimaiti/0000-0001-6751-2113; guo, wei/0000-0002-9158-8107
FU National Institute of Health/National Institute of General Medical
   Sciences [NIGMSP20GM103432]; Beginning Grand-in-Aid (BGIA) from the
   American Heart Association [16BGIA27790136]; United States Department of
   Agriculture (USDA) National Institute of Food and Agriculture (NIFA)
   [1009266]; NIFA [1009266, 913202] Funding Source: Federal RePORTER;
   American Heart Association (AHA) [16BGIA27790136] Funding Source:
   American Heart Association (AHA)
FX This work was supported by the National Institute of Health/National
   Institute of General Medical Sciences [NIGMSP20GM103432]; the Beginning
   Grand-in-Aid (BGIA) from the American Heart Association [16BGIA27790136
   to WG]; the United States Department of Agriculture (USDA) National
   Institute of Food and Agriculture (NIFA) [Hatch project 1009266 to WG].
   The authors would like to thank Richard J. McCormick for proofreading
   the manuscript.
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NR 75
TC 23
Z9 27
U1 0
U2 8
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 2073-4425
J9 GENES-BASEL
JI Genes
PD JAN
PY 2018
VL 9
IS 1
AR 18
DI 10.3390/genes9010018
PG 13
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA FU8PQ
UT WOS:000424116500018
PM 29304022
OA Green Published, Green Submitted, gold
DA 2025-04-10
ER

PT J
AU Yang, YB
   Chen, XW
   Margulies, K
   Jeevanandam, V
   Pollack, P
   Bailey, BA
   Houser, SR
AF Yang, YB
   Chen, XW
   Margulies, K
   Jeevanandam, V
   Pollack, P
   Bailey, BA
   Houser, SR
TI L-type Ca<SUP>2+</SUP> channel α1c subunit isoform switching
   in failing human ventricular myocardium
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Article
DE congestive heart failure; excitation-contraction coupling; Ca channels
ID DEPENDENT CALCIUM-CHANNEL; FUNCTIONAL EXPRESSION; CARDIAC-HYPERTROPHY;
   HEART-FAILURE; CONTRACTION; MUSCLE; MODULATION; RAT
AB The objectives of this study were to determine the relative abundance of the L-type Ca channel alpha(1c) IVS3 isoforms that result from alternative splicing in normal human ventricular myocytes and to measure the changes in isoform expression in end stage heart failure. Methods: mRNA was isolated from left ventricular tissue and myocytes From non-failing and failing human hearts. RT-PCR with isoform-specific primers was used to obtain cDNAs that were then mutated for use in competitive PCR reactions. An RNase protection assay was also used to confirm the presence of one of the novel isoforms. Results: Four different alpha(1c) IVS3 isoforms were found in non-failing human ventricular myocytes using RT-PCR. Two isoforms contained exon 31 (termed IVS3A isoforms) and two isoforms contained exon 32 (termed IVS3B isoforms). One of these isoforms has not been observed previously and contains exon 31 and all but the last six base pairs of exon 32. in non-failing human ventricular myocytes the IVS3A isoform is 2.5 times more abundant than the IVS3B isoform. There were significant changes in the relative abundance of these isoforms in failing hearts, with the IVS3B isoform being twice as abundant as the IVS3A isoform. All isoforms were confirmed by RNase protection analysis. Conclusions: These experiments show that there are at least four L-type Ca channel mRNA isoforms in the normal human heart and that the relative abundance of these isoforms changes significantly in heart failure. These alpha(1c) isoform changes in heart failure are associated with dysfunctional electromechanical disturbances, but the specific physiological role of each L-type Ca channel isoform in normal and failing hearts. (C) 2000 Academic Press.
C1 Temple Univ, Sch Med, Cardiovasc Res Grp, Philadelphia, PA 19140 USA.
   Ursinus Coll, Collegeville, PA 19426 USA.
C3 Pennsylvania Commonwealth System of Higher Education (PCSHE); Temple
   University
RP Houser, SR (corresponding author), Temple Univ, Sch Med, Cardiovasc Res Grp, 3420 N Broad St, Philadelphia, PA 19140 USA.
EM srhouser@unix.temple.edu
RI Chen, Xiongwen/D-5988-2012
OI Chen, Xiongwen/0000-0002-3829-5815
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NR 25
TC 66
Z9 75
U1 0
U2 3
PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
PI LONDON
PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD JUN
PY 2000
VL 32
IS 6
BP 973
EP 984
DI 10.1006/jmcc.2000.1138
PG 12
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA 321ZF
UT WOS:000087484700010
PM 10888251
DA 2025-04-10
ER

PT J
AU Zorn, P
   Sánchez, JC
   Alakhras, T
   Schreier, B
   Gekle, M
   Hüttelmaier, S
   Köhn, M
AF Zorn, Peter
   Sanchez, Jaime Calvo
   Alakhras, Tala
   Schreier, Barbara
   Gekle, Michael
   Huettelmaier, Stefan
   Koehn, Marcel
TI Rbfox1 controls alternative splicing of focal adhesion genes in cardiac
   muscle cells
SO JOURNAL OF MOLECULAR CELL BIOLOGY
LA English
DT Article
DE Rbfox1; alternative splicing; focal adhesion; cardiac muscle cells
ID SMOOTH-MUSCLE; REGULATORY NETWORK; META-VINCULIN; PROTEIN; EXPRESSION;
   FOX-1; CARDIOMYOPATHY; PAXILLIN; SEQUENCE; SWITCH
AB Alternative splicing is one of the major cellular processes that determine the tissue-specific expression of protein variants. However, it remains challenging to identify physiologically relevant and tissue-selective proteins that are generated by alternative splicing. Hence, we investigated the target spectrum of the splicing factor Rbfox1 in the cardiac muscle context in more detail. By using a combination of in silico target prediction and in-cell validation, we identified several focal adhesion proteins as alternative splicing targets of Rbfox1. We focused on the alternative splicing patterns of vinculin (metavinculin isoform) and paxillin (extended paxillin isoform) and identified both as potential Rbfox1 targets. Minigene analyses suggested that both isoforms are promoted by Rbfox1 due to binding in the introns. Focal adhesions play an important role in the cardiac muscle context, since they mainly influence cell shape, cytoskeletal organization, and cell-matrix association. Our data confirmed that depletion of Rbfox1 changed cardiomyoblast morphology, cytoskeletal organization, and multinuclearity after differentiation, which might be due to changes in alternative splicing of focal adhesion proteins. Hence, our results indicate that Rbfox1 promotes alternative splicing of focal adhesion genes in cardiac muscle cells, which might contribute to heart disease progression, where downregulation of Rbfox1 is frequently observed.
C1 [Zorn, Peter; Sanchez, Jaime Calvo; Alakhras, Tala; Koehn, Marcel] Univ Halle Wittenberg, Med Fac, Jr Grp Noncoding RNAs & RBPs Human Dis, D-06120 Halle, Saale, Germany.
   [Schreier, Barbara; Gekle, Michael] Univ Halle Wittenberg, Julius Bernstein Inst Physiol, Med Fac, D-06112 Halle, Saale, Germany.
   [Huettelmaier, Stefan] Univ Halle Wittenberg, Inst Mol Med, Med Fac, D-06120 Halle, Saale, Germany.
C3 Martin Luther University Halle Wittenberg; Martin Luther University
   Halle Wittenberg; Martin Luther University Halle Wittenberg
RP Köhn, M (corresponding author), Univ Halle Wittenberg, Med Fac, Jr Grp Noncoding RNAs & RBPs Human Dis, D-06120 Halle, Saale, Germany.
RI Hüttelmaier, Stefan/AAQ-1203-2021; Gekle, Michael/ADG-9543-2022
OI Calvo Sanchez, Jaime/0000-0002-2953-6605; Kohn,
   Marcel/0000-0003-3292-8447
FU Deutsche Forschungsgemeinschaft [DFG, German Research Foundation [RTG
   2467, 391498659, FOR 5433, 468534282]; Wilhelm-Roux-Program (Medical
   Faculty, Martin-Luther-University Halle-Wittenberg)
FX This work was supported by grants from the Deutsche
   Forschungsgemeinschaft [DFG, German Research Foundation; RTG 2467,
   project number 391498659 'Intrinsically disordered proteins-molecular
   principles, cellular functions, and diseases'; FOR 5433, project number
   468534282 'RNA in focus (RIF): from mechanisms to novel therapeutic
   strategies in cancer treatment'] and the Wilhelm-Roux-Program (Medical
   Faculty, Martin-Luther-University Halle-Wittenberg).
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NR 61
TC 0
Z9 0
U1 2
U2 4
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 1674-2788
EI 1759-4685
J9 J MOL CELL BIOL
JI J. Mol. Cell Biol.
PD JUL 1
PY 2024
VL 16
IS 1
AR mjae003
DI 10.1093/jmcb/mjae003
EA JUL 2024
PG 12
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA XF0H1
UT WOS:001260145700002
PM 38253401
OA gold
DA 2025-04-10
ER

PT J
AU Kelemen, O
   Convertini, P
   Zhang, ZY
   Wen, Y
   Shen, ML
   Falaleeva, M
   Stamm, S
AF Kelemen, Olga
   Convertini, Paolo
   Zhang, Zhaiyi
   Wen, Yuan
   Shen, Manli
   Falaleeva, Marina
   Stamm, Stefan
TI Function of alternative splicing
SO GENE
LA English
DT Review
DE Alternative splicing; Pre-mRNA; Gene function
ID PROTEIN-COUPLED RECEPTOR; SINGLE NUCLEOTIDE POLYMORPHISM;
   DOMINANT-NEGATIVE ACTIVITY; VENTRICULAR ASSIST DEVICE; SHOW DIFFERENT
   EXPRESSION; BETA TRANSCRIPT VARIANTS; RNAP-II TRANSCRIPTION; HIDDEN
   MARKOV MODEL; BREAST-CANCER CELLS; MU-OPIOID RECEPTOR
AB Almost all polymerase II transcripts undergo alternative pre-mRNA splicing. Here, we review the functions of alternative splicing events that have been experimentally determined. The overall function of alternative splicing is to increase the diversity of mRNAs expressed from the genome. Alternative splicing changes proteins encoded by mRNAs, which has profound functional effects. Experimental analysis of these protein isoforms showed that alternative splicing regulates binding between proteins, between proteins and nucleic acids as well as between proteins and membranes. Alternative splicing regulates the localization of proteins, their enzymatic properties and their interaction with ligands. In most cases, changes caused by individual splicing isoforms are small. However, cells typically coordinate numerous changes in 'splicing programs', which can have strong effects on cell proliferation, cell survival and properties of the nervous system. Due to its widespread usage and molecular versatility, alternative splicing emerges as a central element in gene regulation that interferes with almost every biological function analyzed. (C) 2012 Elsevier B.V. All rights reserved.
C1 [Kelemen, Olga; Convertini, Paolo; Zhang, Zhaiyi; Wen, Yuan; Shen, Manli; Falaleeva, Marina; Stamm, Stefan] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY USA.
C3 University of Kentucky
RP Stamm, S (corresponding author), B283 Biomed Biol Sci Res Bldg,741 S Limestone, Lexington, KY 40536 USA.
EM stefan@stamms-lab.net
OI Wen, Yuan/0000-0002-3210-1629; Convertini, Paolo/0000-0001-7250-0678
FU NIH [RO1 GM083187]; Endowment of the University of Kentucky
FX This work is supported by NIH RO1 GM083187 and an Endowment of the
   University of Kentucky. We thank Eva R. McEnrue for editorial help.
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NR 557
TC 555
Z9 675
U1 10
U2 278
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0378-1119
EI 1879-0038
J9 GENE
JI Gene
PD FEB 1
PY 2013
VL 514
IS 1
BP 1
EP 30
DI 10.1016/j.gene.2012.07.083
PG 30
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 081KM
UT WOS:000314321100001
PM 22909801
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Kowalczyk, J
   Domal-Kwiatkowska, D
   Mazurek, U
   Zembala, M
   Michalski, B
   Zembala, M
AF Kowalczyk, Jacek
   Domal-Kwiatkowska, Dorota
   Mazurek, Urszula
   Zembala, Michal
   Michalski, Bogdan
   Zembala, Marian
TI Post-transcriptional modifications of VEGF-A mRNA in non-ischemic
   dilated cardiomyopathy
SO CELLULAR & MOLECULAR BIOLOGY LETTERS
LA English
DT Article
DE vascular endothelial growth factor ( VEGF); alternative splicing;
   angiogenesis; dilated cardiomyopathy; transcriptional activity
ID ENDOTHELIAL GROWTH-FACTOR; ACUTE MYOCARDIAL-INFARCTION; GENE-TRANSFER;
   DOWN-REGULATION; SERUM-LEVELS; EXPRESSION; ANGIOGENESIS; RECEPTORS;
   IDENTIFICATION; STIMULATION
AB Vascular endothelial growth factor (VEGF-A) is one of the most important proangiogenic factors. It has many isoforms encoded by one gene. The occurrence of these isoforms is associated with the process of alternative splicing of mRNA. Some of the splice forms are perceived as tissue specific. The aim of this study was to determine the alternative splicing of VEGF-A mRNA in dilated cardiomyopathy, especially at the level of particular myocardial layers. The assessment of post-transcriptional modifications of VEGF-A mRNA was made on specimens taken from the explanted hearts of patients undergoing cardiac transplantation. Molecular and histopathological studies were perfomed on particular layers of the myocardial muscle ( endocardium, myocardium, epicardium). A molecular analysis of cardiac samples was performed by quantitative analysis of the mRNA of the studied VEGF-A isoforms ( VEGF121, -145, -165, -183, -189, and -206) using QRT-PCR with an ABI-PRISM 7700-TaqMan sequence detector. 72 cardiac specimens taken from the explanted hearts were analyzed. Each of the studied VEGF-A splice forms was present in the evaluated hearts, but the types of alternative splicing of mRNA were different in particular layers. Quantitative analysis revealed different amounts of the studied isoforms. Generally, significantly increased expression of the VEGF-A isoforms was observed in samples taken from hearts with post-inflammatory etiology of cardiomyopathy. Our conclusions are: 1. All the studied VEGF- A isoforms were found in the human hearts, including those thusfar considered characteristic for other tissues. 2. Significant differences were observed in the expression of the VEGF-A splice forms with respect to the myocardial layers and the location of the cardiac biopsy. 3. Repetitive and comparable results for samples with post-inflammatory etiology were obtained, and they revealed considerably higher amounts of VEGF-A isoforms compared to specimens with idiopathic etiology.
C1 Silesian Ctr Heart Dis, Dept Cardiol 1, Zabrze, Poland.
   Med Univ Silesia, Katowice, Poland.
   Dept Biochem, Sosnowiec, Poland.
   Dept Mol Biol & Genet, Sosnowiec, Poland.
   Dept Obstet & Gynaecol, Tychy, Poland.
   Silesian Ctr Heart Dis, Dept Cardiac Surg & Transplantol, Zabrze, Poland.
C3 Silesian Center for Heart Diseases; Medical University Silesia; Silesian
   Center for Heart Diseases
RP Kowalczyk, J (corresponding author), Silesian Ctr Heart Dis, Dept Cardiol 1, Zabrze, Poland.
EM jacekmed@poczta.onet.pl
RI Zembala, Michal/GNP-2971-2022; Kowalczyk, Jacek/AAK-4417-2020
OI Kowalczyk, Jacek/0000-0003-3836-9041; Michalski,
   Bogdan/0000-0002-0674-636X
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NR 44
TC 3
Z9 3
U1 0
U2 10
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1425-8153
EI 1689-1392
J9 CELL MOL BIOL LETT
JI Cell. Mol. Biol. Lett.
PD SEP
PY 2007
VL 12
IS 3
BP 331
EP 347
DI 10.2478/s11658-007-0006-1
PG 17
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 221CN
UT WOS:000250205100002
PM 17297559
OA hybrid, Green Published
DA 2025-04-10
ER

PT J
AU Kim, T
   Kim, JO
   Oh, JG
   Hong, SE
   Kim, DH
AF Kim, Taeyong
   Kim, Jin Ock
   Oh, Jae Gyun
   Hong, Seong-Eui
   Kim, Do Han
TI Pressure-Overload Cardiac Hypertrophy Is Associated with Distinct
   Alternative Splicing Due to Altered Expression of Splicing Factors
SO MOLECULES AND CELLS
LA English
DT Article
DE cardiac hypertrophy; ESRP1; PTB; RNA-Seq; SF2/ASF; splicing factor
ID EPITHELIAL-MESENCHYMAL TRANSITION; MESSENGER-RNA; BINDING-PROTEIN;
   GENE-EXPRESSION; CELF FAMILY; ELEMENTS; NETWORK; CANCER; IDENTIFICATION;
   REGULATOR
AB Chronic pressure-overload cardiac hypertrophy is associated with an increased risk of morbidity/mortality, largely due to maladaptive remodeling and dilatation that progresses to dilated cardiomyopathy. Alternative splicing is an important biological mechanism that generates proteomic complexity and diversity. The recent development of next-generation RNA sequencing has improved our understanding of the qualitative signatures associated with alternative splicing in various biological conditions. However, the role of alternative splicing in cardiac hypertrophy is yet unknown. The present study employed RNA-Seq and a bioinformatic approach to detect the RNA splicing regulatory elements involved in alternative splicing during pressure-overload cardiac hypertrophy. We found GC-rich exonic motifs that regulate intron retention in 5' UTRs and AT-rich exonic motifs that are involved in exclusion of the AT-rich elements that cause mRNA instability in 3' UTRs. We also identified motifs in the intronic regions involved in exon exclusion and inclusion, which predicted splicing factors that bind to these motifs. We found, through Western blotting, that the expression levels of three splicing factors, ESRP1, PTB and SF2/ASF, were significantly altered during cardiac hypertrophy. Collectively, the present results suggest that chronic pressure-overload hypertrophy is closely associated with distinct alternative splicing due to altered expression of splicing factors.
C1 [Kim, Taeyong; Kim, Jin Ock; Hong, Seong-Eui; Kim, Do Han] Gwangju Inst Sci & Technol, Sch Life Sci, Kwangju 500712, South Korea.
   [Kim, Taeyong; Kim, Jin Ock; Hong, Seong-Eui; Kim, Do Han] Gwangju Inst Sci & Technol, Syst Biol Res Ctr, Kwangju 500712, South Korea.
   [Oh, Jae Gyun] Icahn Sch Med Mt Sinai, Cardiovasc Res Ctr, New York, NY 10029 USA.
C3 Gwangju Institute of Science & Technology (GIST); Gwangju Institute of
   Science & Technology (GIST); Icahn School of Medicine at Mount Sinai
RP Kim, DH (corresponding author), Gwangju Inst Sci & Technol, Sch Life Sci, Kwangju 500712, South Korea.
EM hse354@gist.ac.kr; dhkim@gist.ac.kr
OI Kim, Taeyong/0000-0002-4147-3635; Kim, Jin Ock/0000-0002-5323-7808
FU Bio & Medical Technology Development Program of the National Research
   Foundation (NRF) - Ministry of Science, ICT & Future Planning
   [NRF-2013M3A9A7046297, NRF-2012R1A1A2043217]; GIST Systems Biology
   Infrastructure Establishment Grant
FX This work was supported by the Bio & Medical Technology Development
   Program of the National Research Foundation (NRF) funded by the Ministry
   of Science, ICT & Future Planning (NRF-2013M3A9A7046297,
   NRF-2012R1A1A2043217) and the 2013 GIST Systems Biology Infrastructure
   Establishment Grant. We thank Dr. Hai-Hong Shen (Gwangju Institute of
   Science and Technology, Korea) for the generous gifts of PTB, SF2/ASF,
   SRp30c, and SRp40 antibodies.
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NR 37
TC 14
Z9 15
U1 0
U2 2
PU KOREAN SOC MOLECULAR & CELLULAR  BIOLOGY
PI SEOUL
PA 635-4, YUCKSAM-DONG, GANGNAM-GU, SEOUL 135-703, SOUTH KOREA
SN 1016-8478
EI 0219-1032
J9 MOL CELLS
JI Mol. Cells
PD JAN 31
PY 2014
VL 37
IS 1
BP 81
EP 87
DI 10.14348/molcells.2014.2337
PG 7
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA AQ1RQ
UT WOS:000342559100012
PM 24552714
OA Green Published, hybrid, Green Submitted
DA 2025-04-10
ER

PT J
AU Qi, WC
   Fu, HJ
   Luo, XY
   Ren, YR
   Liu, XY
   Dai, HY
   Zheng, QH
   Liang, FR
AF Qi, Wenchuan
   Fu, Hongjuan
   Luo, Xinye
   Ren, Yanrong
   Liu, Xueying
   Dai, Hongyuan
   Zheng, Qianhua
   Liang, Fanrong
TI Electroacupuncture at PC6 (Neiguan) Attenuates Angina Pectoris in Rats
   with Myocardial Ischemia-Reperfusion Injury Through Regulating the
   Alternative Splicing of the Major Inhibitory Neurotransmitter Receptor
   GABRG2
SO JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
LA English
DT Article
DE Electroacupuncture; PC6 (Neiguan) acupoint; Angina pectoris;
   Ischemia-reperfusion injury; Alternative splicing; Nova1; GABRG2
ID AMINOBUTYRIC-ACID GABA; PROTEIN-COUPLED RECEPTORS; LONG-TERM
   POTENTIATION; GAMMA-2 SUBUNIT; CELLULAR-DISTRIBUTION; MICE LACKING;
   SPINAL-CORD; MECHANISMS; ACUPUNCTURE; PAIN
AB Angina pectoris is the most common manifestation of coronary heart disease, causing suffering in patients. Electroacupuncture at PC6 can effectively alleviate angina by regulating the expression of genes, whether the alternative splicing (AS) of genes is affected by acupuncture is still unknown. We established a rat model of myocardial ischemia-reperfusion by coronary artery ligation and confirmed electroacupuncture alleviated the abnormal discharge caused by angina pectoris measured in EMG electromyograms. Analysis of the GSE61840 dataset established that AS events were altered after I/R and regulated by electroacupuncture. I/R decreased the expression of splicing factor Nova1 while electroacupuncture rescued it. Further experiments in dorsal root ganglion cells showed Nova1 regulated the AS of the GABRG2, specifically on its exon 9 where an important phosphorylation site is present. In vivo, results also showed that electroacupuncture can restore AS of GABRG2. Our results proved that electroacupuncture alleviates angina results by regulating alternative splicing.
C1 [Qi, Wenchuan; Fu, Hongjuan; Luo, Xinye; Ren, Yanrong; Liu, Xueying; Zheng, Qianhua; Liang, Fanrong] Chengdu Univ Tradit Chinese Med, Chengdu 610075, Sichuan, Peoples R China.
   [Ren, Yanrong; Liu, Xueying] Shanxi Univ Tradit Chinese Med, Jinzhong 030002, Shanxi, Peoples R China.
   [Dai, Hongyuan] Sichuan Univ, Coll Life Sci, Chengdu 610065, Sichuan, Peoples R China.
C3 Chengdu University of Traditional Chinese Medicine; Sichuan University
RP Liang, FR (corresponding author), Chengdu Univ Tradit Chinese Med, Chengdu 610075, Sichuan, Peoples R China.
EM acuresearch@126.com
RI Qi, Wenchuan/GXG-9496-2022
OI Qi, Wenchuan/0000-0002-3294-8870
FU National Natural Science Foundation of China [82074556]; China
   Postdoctoral Science Foundation [2020M683642XB]
FX This work was funded by the National Natural Science Foundation of China
   (No. 82074556), and the China Postdoctoral Science Foundation (No.
   2020M683642XB).
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NR 71
TC 4
Z9 5
U1 4
U2 25
PU SPRINGER
PI NEW YORK
PA ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES
SN 1937-5387
EI 1937-5395
J9 J CARDIOVASC TRANSL
JI J. Cardiovasc. Transl. Res.
PD OCT
PY 2022
VL 15
IS 5
BP 1176
EP 1191
DI 10.1007/s12265-022-10245-w
EA APR 2022
PG 16
WC Cardiac & Cardiovascular Systems; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Research & Experimental Medicine
GA 5W5MJ
UT WOS:000778228400002
PM 35377129
DA 2025-04-10
ER

PT J
AU Xia, BB
   Shen, JH
   Zhang, H
   Chen, SQ
   Zhang, X
   Song, MS
   Wang, J
AF Xia, Binbin
   Shen, Jianghua
   Zhang, Hao
   Chen, Siqi
   Zhang, Xuan
   Song, Moshi
   Wang, Jun
TI The alternative splicing landscape of infarcted mouse heart identifies
   isoform level therapeutic targets
SO SCIENTIFIC DATA
LA English
DT Article
AB Alternative splicing is an important process that contributes to highly diverse transcripts and protein products, which can affect the development of disease in various organisms. Cardiovascular disease (CVD) represents one of the greatest global threats to humans, particularly acute myocardial infarction (MI) and subsequent ischemic reperfusion (IR) injury, which involve complex transcriptomic changes in heart tissues associated with metabolic reshaping and immunological response. In this study, we used a newly developed ONT full-length transcriptomic approach and performed transcript-resolved differential expression profiling in murine models of MI and IR. We built an analytical pipeline to reliably identify and quantify alternative splicing products (isoforms), expanding on the currently available catalog of isoforms described in mice. The updated alternative splicing landscape included transcripts, genes, and pathways that were differentially regulated during IR and MI. Our study establishes a pipeline to profile highly diverse isoforms using state-of-the-art long-read sequencing, builds a landscape of alternative splicing in the mouse heart during MI and IR.
C1 [Xia, Binbin; Zhang, Xuan; Wang, Jun] Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing 100101, Peoples R China.
   [Xia, Binbin; Shen, Jianghua; Zhang, Hao; Chen, Siqi; Song, Moshi; Wang, Jun] Univ Chinese Acad Sci, Beijing 100049, Peoples R China.
   [Shen, Jianghua; Zhang, Hao; Chen, Siqi; Song, Moshi] Chinese Acad Sci, Inst Zool, State Key Lab Membrane Biol, Beijing 100101, Peoples R China.
   [Shen, Jianghua; Zhang, Hao; Chen, Siqi; Song, Moshi] Chinese Acad Sci, Key Lab Organ Regenerat & Reconstruct, Beijing 100101, Peoples R China.
   [Shen, Jianghua; Zhang, Hao; Chen, Siqi; Song, Moshi] Beijing Inst Stem Cell & Regenerat Med, Beijing 100101, Peoples R China.
   [Zhang, Xuan] Baotou Teachers Coll, Fac Biol Sci & Technol, Baotou 014030, Peoples R China.
C3 Chinese Academy of Sciences; Institute of Microbiology, CAS; Chinese
   Academy of Sciences; University of Chinese Academy of Sciences, CAS;
   Chinese Academy of Sciences; Institute of Zoology, CAS; Chinese Academy
   of Sciences; Beijing Institute for Stem Cell & Regenerative Medicine;
   Baotou Teachers College
RP Wang, J (corresponding author), Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing 100101, Peoples R China.; Song, MS; Wang, J (corresponding author), Univ Chinese Acad Sci, Beijing 100049, Peoples R China.; Song, MS (corresponding author), Chinese Acad Sci, Inst Zool, State Key Lab Membrane Biol, Beijing 100101, Peoples R China.; Song, MS (corresponding author), Chinese Acad Sci, Key Lab Organ Regenerat & Reconstruct, Beijing 100101, Peoples R China.; Song, MS (corresponding author), Beijing Inst Stem Cell & Regenerat Med, Beijing 100101, Peoples R China.
EM songmoshi@ioz.ac.cn; junwang@im.ac.cn
RI Wang, Jun/LXV-0504-2024; Chen, Siqi/HKN-8779-2023
OI Xia, Binbin/0000-0002-1174-5273; Song, Moshi/0000-0001-9929-8975; Wang,
   Jun/0000-0002-8859-7707
FU National Natural Science Foundation of China (National Science
   Foundation of China) [2020YFA0113400, 2022YFC2303200]; National Key
   Research and Development Program of China [92368112, 81921006]; National
   Natural Science Foundation of China [JQ22017]; Beijing Natural Science
   Foundation [YSBR-076]; CAS Project for Young Scientists in Basic
   Research; State Key Laboratory of Membrane Biology and Key Laboratory of
   Organ Regeneration and Reconstruction of the Chinese Academy of Sciences
FX This work is supported by the National Key Research and Development
   Program of China (2020YFA0113400, 2022YFC2303200), the National Natural
   Science Foundation of China (92368112, 81921006), Beijing Natural
   Science Foundation (JQ22017), CAS Project for Young Scientists in Basic
   Research (YSBR-076), the State Key Laboratory of Membrane Biology and
   Key Laboratory of Organ Regeneration and Reconstruction of the Chinese
   Academy of Sciences.
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U1 5
U2 5
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
EI 2052-4463
J9 SCI DATA
JI Sci. Data
PD OCT 18
PY 2024
VL 11
IS 1
AR 1154
DI 10.1038/s41597-024-03998-3
PG 9
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA J7W4X
UT WOS:001339127000004
PM 39424867
OA gold
DA 2025-04-10
ER

PT J
AU Willems, S
   Hoefer, I
   Pasterkamp, G
AF Willems, S.
   Hoefer, I.
   Pasterkamp, G.
TI The role of the Interleukin 1 receptor-like 1 (ST2) and Interleukin-33
   pathway in cardiovascular disease and cardiovascular risk assessment
SO MINERVA MEDICA
LA English
DT Article
DE Biological markers; Cardiovascular disease; Atherosclerosis
ID FAMILY-MEMBER ST2; SERUM-SOLUBLE ST2; CHRONIC HEART-FAILURE; LONG-TERM
   MORTALITY; EMERGENCY-DEPARTMENT; T-CELLS; PLASMA-CONCENTRATIONS;
   NATRIURETIC PEPTIDE; CYTOKINE PRODUCTION; PROGNOSTIC UTILITY
AB There is an ongoing search for biomarkers that can facilitate the diagnosis of subclinical or clinically manifest cardiovascular disease. One of the emerging biomarkers currently under investigation is ST2, which is the receptor of Interleukin-33 (IL-33). ST2 is a member of the Interleukin-1 receptor family and exists in a transmembrane (ST2L) and a soluble form (sST2) due to alternative splicing. Several groups have reported sST2 elevations in serum of cardiovascular disease patients. There is consisting evidence that sST2 is independently predictive for mortality in patients with heart failure or myocardial infarction. In addition to its potential as a biomarker for adverse cardiovascular events, ST2 is considered to play a causal role in chronic cardiovascular diseases such as atherosclerosis and heart failure. Signaling of IL-33 via ST2 has been shown to be cardioprotective in mouse models of myocardial infarction, heart transplantation and cardiac hypertrophy and fibrosis. Furthermore, treatment with IL-33 reduced the development of plaques in atherosclerotic mice. In this paper we will review the currently available literature on sST2 as a biomarker for adverse cardiovascular events. In addition, we will elaborate on the potential mechanistic role of the IL-33/ST2 pathway in chronic inflammatory cardiovascular diseases.
C1 [Willems, S.; Hoefer, I.; Pasterkamp, G.] Univ Med Ctr Utrecht, Expt Cardiol Lab, NL-3584 CX Utrecht, Netherlands.
C3 Utrecht University; Utrecht University Medical Center
RP Willems, S (corresponding author), Univ Med Ctr Utrecht, Expt Cardiol Lab, Heidelberglaan 100,Room G02-523, NL-3584 CX Utrecht, Netherlands.
EM S.Willems-3@umcutrecht.nl
FU BioMedical Materials institute [P1.03 PENT]; Dutch Ministry of Economic
   Affairs, Agriculture and Innovation; Dutch Heart Foundation
FX This research forms part of the Project P1.03 PENT of the research
   program of the BioMedical Materials institute, co-funded by the Dutch
   Ministry of Economic Affairs, Agriculture and Innovation. The financial
   contribution of the Dutch Heart Foundation is gratefully acknowledged.
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NR 114
TC 20
Z9 22
U1 0
U2 14
PU EDIZIONI MINERVA MEDICA
PI TURIN
PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY
SN 0026-4806
EI 1827-1669
J9 MINERVA MED
JI Minerva Med.
PD DEC
PY 2012
VL 103
IS 6
BP 513
EP 523
PG 11
WC Medicine, General & Internal
WE Science Citation Index Expanded (SCI-EXPANDED)
SC General & Internal Medicine
GA 070VB
UT WOS:000313539700007
PM 23229370
DA 2025-04-10
ER

PT J
AU Fochi, S
   Lorenzi, P
   Galasso, M
   Stefani, C
   Trabetti, E
   Zipeto, D
   Romanelli, MG
AF Fochi, Stefania
   Lorenzi, Pamela
   Galasso, Marilisa
   Stefani, Chiara
   Trabetti, Elisabetta
   Zipeto, Donato
   Romanelli, Maria Grazia
TI The Emerging Role of the RBM20 and PTBP1 Ribonucleoproteins in Heart
   Development and Cardiovascular Diseases
SO GENES
LA English
DT Review
DE alternative splicing; ribonucleoproteins; RRM motif; PTBP1; RBM20; DCM;
   heart development; titin; RNA binding proteins; exon exclusion
ID TRACT-BINDING-PROTEIN; ALTERNATIVE SPLICING ACTIVITY; RNA-BINDING;
   DILATED CARDIOMYOPATHY; HNRNP-I; FUNCTIONAL-CHARACTERIZATION;
   NUCLEAR-LOCALIZATION; TITIN PROPERTIES; EXPRESSION; REGULATOR
AB Alternative splicing is a regulatory mechanism essential for cell differentiation and tissue organization. More than 90% of human genes are regulated by alternative splicing events, which participate in cell fate determination. The general mechanisms of splicing events are well known, whereas only recently have deep-sequencing, high throughput analyses and animal models provided novel information on the network of functionally coordinated, tissue-specific, alternatively spliced exons. Heart development and cardiac tissue differentiation require thoroughly regulated splicing events. The ribonucleoprotein RBM20 is a key regulator of the alternative splicing events required for functional and structural heart properties, such as the expression of TTN isoforms. Recently, the polypyrimidine tract-binding protein PTBP1 has been demonstrated to participate with RBM20 in regulating splicing events. In this review, we summarize the updated knowledge relative to RBM20 and PTBP1 structure and molecular function; their role in alternative splicing mechanisms involved in the heart development and function; RBM20 mutations associated with idiopathic dilated cardiovascular disease (DCM); and the consequences of RBM20-altered expression or dysfunction. Furthermore, we discuss the possible application of targeting RBM20 in new approaches in heart therapies.
C1 [Fochi, Stefania; Lorenzi, Pamela; Galasso, Marilisa; Stefani, Chiara; Trabetti, Elisabetta; Zipeto, Donato; Romanelli, Maria Grazia] Univ Verona, Sect Biol & Genet, Dept Neurosci Biomed & Movement Sci, I-37134 Verona, Italy.
C3 University of Verona
RP Romanelli, MG (corresponding author), Univ Verona, Sect Biol & Genet, Dept Neurosci Biomed & Movement Sci, I-37134 Verona, Italy.
EM stefania.fochi@univr.it; pamela.lorenzi@univr.it;
   marilisa.galasso@univr.it; chiara.stefani@univr.it;
   elisabetta.trabetti@univr.it; donato.zipeto@univr.it;
   mariagrazia.romanelli@univr.it
RI GALASSO, MARILISA/HMU-9906-2023; Zipeto, Donato/P-3041-2019; Romanelli,
   Maria/AAS-7946-2020
OI Galasso, Marilisa/0000-0003-3028-1205; Stefani,
   Chiara/0000-0003-2327-9772; Zipeto, Donato/0000-0002-2168-4144;
   /0000-0002-7360-1195
FU Joint Project 2016 Romanelli; Ministero Progetto eccellenza;
   "Dipartimento di eccellenza" fellowship
FX This research was funded by Joint Project 2016 Romanelli and "Ministero
   Progetto eccellenza". SF was funded by an "Dipartimento di eccellenza"
   fellowship.
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NR 157
TC 25
Z9 28
U1 1
U2 17
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2073-4425
J9 GENES-BASEL
JI Genes
PD APR
PY 2020
VL 11
IS 4
AR 402
DI 10.3390/genes11040402
PG 21
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA LT7CM
UT WOS:000537224600094
PM 32276354
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Zhang, XL
   Wang, Z
   Xu, Q
   Chen, YH
   Liu, W
   Zhong, T
   Li, HC
   Quan, CS
   Zhang, LQ
   Cui, CP
AF Zhang, Xiaoli
   Wang, Ze
   Xu, Qing
   Chen, Yuhan
   Liu, Wen
   Zhong, Tong
   Li, Hongchang
   Quan, Chengshi
   Zhang, Lingqiang
   Cui, Chun-Ping
TI Splicing factor Srsf5 deletion disrupts alternative splicing and causes
   noncompaction of ventricular myocardium
SO ISCIENCE
LA English
DT Article
ID SPLIT GENES; PROTEIN; HEART; MYOMESIN; GENETICS; PROLIFERATION;
   EXPRESSION; REGULATOR; INCLUSION; INSIGHTS
AB The serine/arginine-rich (SR) family of splicing factors plays important roles in mRNA splicing activation, repression, export, stabilization, and translation. SR splicing factor 5 (SRSF5) is a glucose-inducible protein that promotes tumor cell growth. However, the functional role of SRSF5 in tissue development and disease remains unknown. Here, Srsf5 knockout (Srsf5(-/-)) mice were generated using CRISPR-Cas9. Mutant mice were perinatally lethal and exhibited cardiac dysfunction with noncompaction of the ventricular myocardium. The left ventricular internal diameter and volume were increased in Srsf5(-/-) mice during systole. Null mice had abnormal electrocardiogram patterns, indicative of a light atrioventricular block. Mechanistically, Srsf5 promoted the alternative splicing of Myom1 (myomesin-1), a protein that crosslinks myosin filaments to the sarcomeric M-line. The switch between embryonic and adult isoforms of Myom1 could not be completed in Srsf5-deficient heart. These findings indicate that Srsf5-regulated alternative splicing plays a critical role during heart development.
C1 [Zhang, Xiaoli; Quan, Chengshi] Jilin Univ, Coll Basic Med Sci, Minist Educ, Key Lab Pathobiol, 126 Xinmin Ave, Changchun 130021, Jilin, Peoples R China.
   [Zhang, Xiaoli; Wang, Ze; Chen, Yuhan; Liu, Wen; Zhong, Tong; Li, Hongchang; Zhang, Lingqiang; Cui, Chun-Ping] Beijing Inst Life, Natl Ctr Prot Sci Beijing, Beijing Proteome Res Ctr, State Key Lab Prote, 27 Taiping Rd, Beijing 100850, Peoples R China.
   [Xu, Qing] Capital Med Univ, Core Facil Ctr, Beijing 100069, Peoples R China.
C3 Jilin University; Capital Medical University
RP Quan, CS (corresponding author), Jilin Univ, Coll Basic Med Sci, Minist Educ, Key Lab Pathobiol, 126 Xinmin Ave, Changchun 130021, Jilin, Peoples R China.; Zhang, LQ; Cui, CP (corresponding author), Beijing Inst Life, Natl Ctr Prot Sci Beijing, Beijing Proteome Res Ctr, State Key Lab Prote, 27 Taiping Rd, Beijing 100850, Peoples R China.
EM quancs@jlu.edu.cn; zhanglq@nic.bmi.ac.cn; cui_chunping2000@aliyun.com
RI Zhang, Xiaoli/M-9016-2019; Li, Hongchang/AHC-2352-2022; Wang,
   Ze/LXW-2568-2024
OI Quan, Chengshi/0000-0001-9307-5279; Cui, Chun-Ping/0000-0003-0251-3259
FU National Natural Science Foundation of China (NSFC) [31471326]
FX This work was supported by the general project of National Natural
   Science Foundation of China (NSFC) (grant number 31471326) .
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NR 56
TC 6
Z9 7
U1 3
U2 14
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
EI 2589-0042
J9 ISCIENCE
JI iScience
PD OCT 22
PY 2021
VL 24
IS 10
AR 103097
DI 10.1016/j.isci.2021.103097
PG 18
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA WQ4WZ
UT WOS:000713819900001
PM 34622152
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Choi, J
   Dixon, DM
   Dansithong, W
   Abdallah, WF
   Roos, KP
   Jordan, MC
   Trac, B
   Lee, HS
   Comai, L
   Reddy, S
AF Choi, Jongkyu
   Dixon, Donald M.
   Dansithong, Warunee
   Abdallah, Walid F.
   Roos, Kenneth P.
   Jordan, Maria C.
   Trac, Brandon
   Lee, Han Shin
   Comai, Lucio
   Reddy, Sita
TI Muscleblind-like 3 deficit results in a spectrum of age-associated
   pathologies observed in myotonic dystrophy
SO SCIENTIFIC REPORTS
LA English
DT Article
ID INSULIN-RESISTANCE; CTG REPEAT; CONDUCTION ABNORMALITIES; INTERMEDIARY
   METABOLISM; MOUSE MODELS; MICE LACKING; HEART; SIX5; PROTEINS; EXPANSION
AB Myotonic dystrophy type I (DM1) exhibits distinctive disease specific phenotypes and the accelerated onset of a spectrum of age-associated pathologies. In DM1, dominant effects of expanded CUG repeats result in part from the inactivation of the muscleblind-like (MBNL) proteins. To test the role of MBNL3, we deleted Mbnl3 exon 2 (Mbnl3(Delta E2)) in mice and examined the onset of age-associated diseases over 4 to 13 months of age. Accelerated onset of glucose intolerance with elevated insulin levels, cardiac systole deficits, left ventricle hypertrophy, a predictor of a later onset of heart failure and the development of subcapsular and cortical cataracts is observed in Mbnl3(Delta E2) mice. Retention of embryonic splice isoforms in adult organs, a prominent defect in DM1, is not observed in multiple RNAs including the Insulin Receptor (Insr), Cardiac Troponin T (Tnnt2), Lim Domain Binding 3 (Ldb3) RNAs in Mbnl3(Delta E2) mice. Although rare DM1-like splice errors underlying the observed phenotypes cannot be excluded, our data in conjunction with the reported absence of alternative splice errors in embryonic muscles of a similar Mbnl3(Delta E2) mouse by RNA-seq studies, suggest that mechanisms distinct from the adult retention of embryonic splice patterns may make important contributions to the onset of age-associated pathologies in DM1.
C1 [Choi, Jongkyu; Dixon, Donald M.; Dansithong, Warunee; Trac, Brandon; Lee, Han Shin; Reddy, Sita] Univ Southern Calif, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA.
   [Abdallah, Walid F.] USC Eye Inst, Los Angeles, CA 90033 USA.
   [Abdallah, Walid F.] Zagazig Univ, Dept Ophthalmol, Fac Med, Zagazig, Egypt.
   [Roos, Kenneth P.; Jordan, Maria C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA.
   [Comai, Lucio] Univ Southern Calif, Dept Microbiol & Immunol, Los Angeles, CA 90033 USA.
   [Dansithong, Warunee] Univ Utah, Dept Neurol, Clin Neurosci Ctr, Salt Lake City, UT 84132 USA.
C3 University of Southern California; Egyptian Knowledge Bank (EKB);
   Zagazig University; University of California System; University of
   California Los Angeles; University of California Los Angeles Medical
   Center; David Geffen School of Medicine at UCLA; University of Southern
   California; Utah System of Higher Education; University of Utah
RP Reddy, S (corresponding author), Univ Southern Calif, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA.
EM sitaredd@usc.edu
RI Comai, Lucio/L-5905-2019; Jordan, Maria/HHN-5358-2022
OI Comai, Lucio/0000-0003-3109-1841
FU NIH/NINDS award [NS50861, NS060839]
FX We thank Lawrence Rife and the USC CTSI core for assistance with ERG
   studies and statistical analysis respectively. Research reported in this
   publication was supported by NIH/NINDS award numbers NS50861 and
   NS060839 (SR).
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NR 59
TC 17
Z9 18
U1 0
U2 5
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD AUG 3
PY 2016
VL 6
AR 30999
DI 10.1038/srep30999
PG 10
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA DS2VI
UT WOS:000380641300001
PM 27484195
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Williams, AL
   Khadka, V
   Tang, MX
   Avelar, A
   Schunke, KJ
   Menor, M
   Shohet, RV
AF Williams, Allison Lesher
   Khadka, Vedbar
   Tang, Mingxin
   Avelar, Abigail
   Schunke, Kathryn J.
   Menor, Mark
   Shohet, Ralph, V
TI HIF1 mediates a switch in pyruvate kinase isoforms after myocardial
   infarction
SO PHYSIOLOGICAL GENOMICS
LA English
DT Article
DE alternative splicing; hypoxia; myocardial infarction; pyruvate kinase;
   RNA sequencing
ID METABOLIC REQUIREMENTS; M2; EXPRESSION; CARDIOMYOCYTES; ALIGNMENT;
   BINDING; GENE
AB Alternative splicing of RNA is an underexplored area of transcriptional response. We expect that early changes in alternatively spliced genes may be important for responses to cardiac injury. Hypoxia inducible factor 1 (HIF1) is a key transcription factor that rapidly responds to loss of oxygen through alteration of metabolism and angiogenesis. The goal of this study was to investigate the transcriptional response after myocardial infarction (MI) and to identify novel, hypoxia-driven changes. including alternative splicing. After ligation of the left anterior descending artery in mice, we observed an abrupt loss of cardiac contractility and upregulation of hypoxic signaling. We then performed RNA sequencing on ischemic heart tissue 1 and 3 days after infarct to assess early transcriptional changes and identified 89 transcripts with altered splicing. Of particular interest was the switch in Pkm isoform expression (pyruvate kinase, muscle). The usually predominant Pkm1 isoform was less abundant in ischemic hearts, while Pkm2 and associated splicing factors (hnRNPA1, hnRNPA2B1, Ptbp1) rapidly increased. Despite increased Pkm2 expression, total pyruvate kinase activity remained reduced in ischemic myocardial tissue. We also demonstrated HIF1 binding to PKM by chromatin immunoprecipitation, indicating a direct role for HIF1 in mediating this isoform switch. Our study provides a new, detailed characterization of the early transcriptome after MI. From this analysis. we identified an HIF1-mediated alternative splicing event in the PKM gene. Pkm1 and Pkm2 play distinct roles in glycolytic metabolism and the upregulation of Pkm2 is likely to have important consequences for ATP synthesis in infarcted cardiac muscle.
C1 [Williams, Allison Lesher; Tang, Mingxin; Avelar, Abigail; Schunke, Kathryn J.; Shohet, Ralph, V] Univ Hawaii, Ctr Cardiovasc Res, John A Burns Sch Med, Honolulu, HI 96822 USA.
   [Khadka, Vedbar; Menor, Mark] Univ Hawaii, John A Burns Sch Med, Bioinformat Core, Honolulu, HI 96822 USA.
C3 University of Hawaii System; University of Hawaii System
RP Shohet, RV (corresponding author), John A Burns Sch Med, Ctr Cardiovasc Res, 651 Ilalo St,BSA 311, Honolulu, HI 96813 USA.
EM shohet@hawaii.edu
RI Williams, Allison/AAG-1481-2019; Schunke, Kathryn/AAQ-1524-2020; Khadka,
   Vedbar/O-4156-2018
OI Williams, Allison/0000-0002-2920-1733; Schunke,
   Kathryn/0000-0002-0815-8457; Khadka, Vedbar/0000-0002-8652-2904
FU National Institutes of Health [R01 HL-080532, P30 GM-103341, T32
   HL-115505, P30 CA-071789, 5G12 MD-007601, P20 GM-103466, U54 MD-007584,
   5P30 GM-114737]; American Heart Association [16POST29960013]; American
   Heart Association (AHA) [16POST29960013] Funding Source: American Heart
   Association (AHA)
FX This work was supported by National Institutes of Health Grants R01
   HL-080532 and P30 GM-103341 to R. V. Shohet, T32 HL-115505 to A. L.
   Williams, P30 CA-071789 and 5G12 MD-007601 to the Microscopy and Imaging
   Core, and P20 GM-103466, U54 MD-007584, and 5P30 GM-114737 to the
   Bioinformatics Core. This work was also supported by the American Heart
   Association: 16POST29960013 to A. L. Williams.
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NR 49
TC 54
Z9 58
U1 1
U2 9
PU AMER PHYSIOLOGICAL SOC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 1094-8341
EI 1531-2267
J9 PHYSIOL GENOMICS
JI Physiol. Genomics
PD JUL
PY 2018
VL 50
IS 7
BP 479
EP 494
DI 10.1152/physiolgenomics.00130.2017
PG 16
WC Cell Biology; Genetics & Heredity; Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Genetics & Heredity; Physiology
GA GP6FS
UT WOS:000440973800001
PM 29652636
OA Green Published, Bronze
DA 2025-04-10
ER

PT J
AU Medina, MW
   Krauss, RM
AF Medina, Marisa W.
   Krauss, Ronald M.
TI Alternative splicing in the regulation of cholesterol homeostasis
SO CURRENT OPINION IN LIPIDOLOGY
LA English
DT Review
DE 3-hydroxy-3-methylglutaryl coenzyme A reductase; low-density lipoprotein
   receptor; polypyrimidine tract binding protein 1; SFRS10; statin
ID TRACT-BINDING-PROTEIN; COENZYME-A REDUCTASE; MESSENGER-RNA DECAY;
   DENSITY-LIPOPROTEIN; LOWERING RESPONSE; HUMAN OBESITY; GENE; EXPRESSION;
   HMGCR; ATORVASTATIN
AB Purpose of review
   With the advent of whole-transcriptome sequencing, or RNA-seq, we now know that alternative splicing is a generalized phenomenon, with nearly all multiexonic genes subject to alternative splicing. In this review, we highlight recent studies examining alternative splicing as a modulator of cellular cholesterol homeostasis and as an underlying mechanism of dyslipidemia.
   Recent findings
   A number of key genes involved in cholesterol metabolism are known to undergo functionally relevant alternative splicing. Recently, we have identified coordinated changes in alternative splicing in multiple genes in response to alterations in cellular sterol content. We and others have implicated several splicing factors as regulators of lipid metabolism. Furthermore, a number of cis-acting human gene variants that modulate alternative splicing have been implicated in a variety of human metabolic diseases.
   Summary
   Alternative splicing is of importance in various types of genetically influenced dyslipidemias and in the regulation of cellular cholesterol metabolism.
C1 [Medina, Marisa W.; Krauss, Ronald M.] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA.
C3 Children's Hospital Oakland Research Institute; University of California
   System; University of California San Francisco; UCSF Medical Center;
   UCSF Benioff Children's Hospital Oakland
RP Medina, MW (corresponding author), 5700 Martin Luther King Jr Way, Oakland, CA 94609 USA.
EM mwmedina@chori.org
RI Krauss, Ronald M./LTD-4078-2024
FU [NIH NHLBI R01 HL 104133-01];  [U19 HL69757]; National Institute of
   Diabetes and Digestive and Kidney Diseases [P30DK026743] Funding Source:
   NIH RePORTER
FX This work was funded by the grants NIH NHLBI R01 HL 104133-01 and U19
   HL69757.
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NR 49
TC 20
Z9 26
U1 3
U2 24
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0957-9672
EI 1473-6535
J9 CURR OPIN LIPIDOL
JI Curr. Opin. Lipidology
PD APR
PY 2013
VL 24
IS 2
BP 147
EP 152
DI 10.1097/MOL.0b013e32835cf284
PG 6
WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral
   Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Endocrinology & Metabolism;
   Cardiovascular System & Cardiology
GA 106BJ
UT WOS:000316116100009
PM 23314925
OA Green Accepted, Green Submitted
DA 2025-04-10
ER

PT J
AU Romano, M
   Marcucci, R
   Baralle, FE
AF Romano, M
   Marcucci, R
   Baralle, FE
TI Splicing of constitutive upstream introns is essential for the
   recognition of intra-exonic suboptimal splice sites in the
   thrombopoietin gene
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID PRE-MESSENGER-RNA; HUMAN FIBRONECTIN; SECONDARY STRUCTURE; SELECTION;
   ENHANCER; BINDING; IIICS; TRANSCRIPT; SEQUENCE; SIGNALS
AB The human thrombopoietin (TPO) gene, which codes for the principal cytokine involved in platelet maturation, shows a peculiar alternative splicing of its last exon, where an intra-exonic 116 nt alternative intron is spliced out in: a fraction of its mRNA, To characterize the molecular mechanism underlying this alternative splicing, minigenes of TPO genomic constructs with variable exon-intron configurations or carrying exclusively the TPO cDNA were generated and transiently transfected in the Hep3B cell line. We have found that the final rate of the alternative intron splicing is determined by three elements: the presence of upstream constitutive introns, the suboptimal splice sites of the alternative intron and the length of the alternative intron itself, Our results indicate that the-recognition of suboptimal intra-exonic splice junctions in the TPO gene is influenced by the assembly of the spliceosome complex on constitutive introns and by a qualitative scanning of the sequence by-the transcriptional/splicing machinery complex primed by upstream splicing signals.
C1 Int Ctr Genet Engn & Biotechnol, I-34012 Trieste, Italy.
   Univ Trieste, Dept Physiol & Pathol, I-34127 Trieste, Italy.
C3 International Center for Genetic Engineering & Biotechnology (ICGEB);
   University of Trieste
RP Baralle, FE (corresponding author), Int Ctr Genet Engn & Biotechnol, Padriciano 99, I-34012 Trieste, Italy.
RI ; Romano, Maurizio/G-9431-2012
OI Baralle, Francisco/0000-0002-4645-2809; Romano,
   Maurizio/0000-0002-4820-2897
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NR 39
TC 27
Z9 30
U1 0
U2 1
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0305-1048
J9 NUCLEIC ACIDS RES
JI Nucleic Acids Res.
PD FEB 15
PY 2001
VL 29
IS 4
BP 886
EP 894
DI 10.1093/nar/29.4.886
PG 9
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 404BT
UT WOS:000167078100004
PM 11160920
OA Green Published
DA 2025-04-10
ER

PT J
AU Xu, XD
   Yang, DM
   Ding, JH
   Wang, W
   Chu, PH
   Dalton, ND
   Wang, HY
   Bermingham, JR
   Ye, Z
   Liu, F
   Rosenfeld, MG
   Manley, JL
   Ross, J
   Chen, J
   Xiao, RP
   Cheng, HP
   Fu, XD
AF Xu, XD
   Yang, DM
   Ding, JH
   Wang, W
   Chu, PH
   Dalton, ND
   Wang, HY
   Bermingham, JR
   Ye, Z
   Liu, F
   Rosenfeld, MG
   Manley, JL
   Ross, J
   Chen, J
   Xiao, RP
   Cheng, HP
   Fu, XD
TI ASF/SF2-Regulated CaMKIIδ alternative splicing temporally reprograms
   excitation-contraction coupling in cardiac muscle
SO CELL
LA English
DT Article
ID PROTEIN-KINASE-II; MESSENGER-RNA; DILATED CARDIOMYOPATHY; ISOFORM;
   ASF/SF2; GENE; SC35; HYPERTROPHY; DISRUPTION; MECHANISMS
AB The transition from juvenile to adult life is accompanied by programmed remodeling in many tissues and organs, which is key for organisms to adapt to the demand of the environment. Here we report a novel regulated alternative splicing program that is crucial for postnatnal heart remodeling in the mouse. We identify the essential splicing factor ASF/SF2 as a key component of the program, regulating a restricted set of tissue-specific alternative splicing events during heart remodeling. Cardiomyocytes deficient in ASF/SF2 display an unexpected hypercontraction phenotype due to a defect in postnatal splicing switch of the Ca2+/calmodulin-dependent kinase IIdelta (CaMKIIdelta) transcript. This failure results in mistargeting of the kinase to sarcolemmal membranes, causing severe excitation-contraction coupling defects. Our results validate ASF/SF2 as a fundamental splicing regulator in the reprogramming pathway and reveal the central contribution of ASF/SF2-regulated CaMKIIdelta alternative splicing to functional remodeling in developing heart.
C1 Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA.
   Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA.
   Univ Calif San Diego, Inst Mol Med, La Jolla, CA 92093 USA.
   Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA.
   NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA.
   Columbia Univ, Dept Biol Sci, New York, NY 10027 USA.
C3 University of California System; University of California San Diego;
   University of California System; University of California San Diego;
   University of California System; University of California San Diego;
   Howard Hughes Medical Institute; University of California System;
   University of California San Diego; National Institutes of Health (NIH)
   - USA; NIH National Institute on Aging (NIA); Columbia University
RP Univ Calif San Diego, Dept Cellular & Mol Med, 9500 Gilman Dr, La Jolla, CA 92093 USA.
EM xdfu@ucsd.edu
RI Xiao, Rui-Ping/AAE-2629-2019; Yimei, Wang/AAE-4083-2019; cheng,
   heping/A-7299-2011; Chen, Ju/E-5579-2011; Chu, Pao-Hsien/G-3685-2010;
   Bermingham, John/JQX-1836-2023; wang, wang/GWQ-7272-2022
OI Otsu, Makoto/0000-0002-9769-0217; Wang, Wang/0000-0001-9093-412X;
   Sanada, Masashi/0000-0003-0666-1996; Chu, Pao-Hsien/0000-0003-0361-6348;
   Manley, James/0000-0002-8341-1459; Xu, Xiangdong/0000-0003-2220-0890
FU NHLBI NIH HHS [R01 HL066100, R01 HL66100] Funding Source: Medline; NIGMS
   NIH HHS [R01 GM49369, R37 GM48259] Funding Source: Medline
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NR 54
TC 550
Z9 623
U1 0
U2 20
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
SN 0092-8674
EI 1097-4172
J9 CELL
JI Cell
PD JAN 14
PY 2005
VL 120
IS 1
BP 59
EP 72
DI 10.1016/j.cell.2004.11.036
PG 14
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 888HS
UT WOS:000226365400011
PM 15652482
OA Bronze
DA 2025-04-10
ER

PT J
AU van den Hoogenhof, MMG
   Pinto, YM
   Creemers, EE
AF van den Hoogenhof, Maarten M. G.
   Pinto, Yigal M.
   Creemers, Esther E.
TI RNA Splicing Regulation and Dysregulation in the Heart
SO CIRCULATION RESEARCH
LA English
DT Review
DE RNA-binding proteins; heart diseases; RNA splicing
ID FAMILIAL DILATED CARDIOMYOPATHY; MESSENGER-RNA; MYOTONIC-DYSTROPHY;
   BINDING-PROTEIN; POLYMERASE-II; MINOR SPLICEOSOME; DNA METHYLATION;
   GENE-EXPRESSION; SITE MUTATION; IN-VIVO
AB RNA splicing represents a post-transcriptional mechanism to generate multiple functional RNAs or proteins from a single transcript. The evolution of RNA splicing is a prime example of the Darwinian function follows form concept. A mutation that leads to a new mRNA (form) that encodes for a new functional protein (function) is likely to be retained, and this way, the genome has gradually evolved to encode for genes with multiple isoforms, thereby creating an enormously diverse transcriptome. Advances in technologies to characterize RNA populations have led to a better understanding of RNA processing in health and disease. In the heart, alternative splicing is increasingly being recognized as an important layer of post-transcriptional gene regulation. Moreover, the recent identification of several cardiac splice factors, such as RNA-binding motif protein 20 and SF3B1, not only provided important insight into the mechanisms underlying alternative splicing but also revealed how these splicing factors impact functional properties of the heart. Here, we review our current knowledge of alternative splicing in the heart, with a particular focus on the major and minor spliceosome, the factors controlling RNA splicing, and the role of alternative splicing in cardiac development and disease.
C1 [van den Hoogenhof, Maarten M. G.; Pinto, Yigal M.; Creemers, Esther E.] Univ Amsterdam, Acad Med Ctr, Dept Expt Cardiol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands.
C3 University of Amsterdam
RP Creemers, EE (corresponding author), Acad Med Ctr, Expt Cardiol, Room K2-104-2,Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands.
EM e.e.creemers@amc.uva.nl
OI van den Hoogenhof, Maarten/0000-0003-2768-3457; Creemers,
   Esther/0000-0002-9001-3854
FU Academic Medical Center PhD Scholarship; Netherlands Organisation for
   Scientific Research (NWO) [825.13.007, 836.12.002]; Netherlands
   Cardiovascular Research Initiative [CVON 2011-11]
FX M.M.G. van den Hoogenhof was supported by an Academic Medical Center PhD
   Scholarship, E.E. Creemers was supported by grants from the Netherlands
   Organisation for Scientific Research (NWO; grant numbers 825.13.007 and
   836.12.002) and Y.M. Pinto by a grant from the Netherlands
   Cardiovascular Research Initiative (CVON 2011-11).
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NR 131
TC 79
Z9 89
U1 1
U2 25
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7330
EI 1524-4571
J9 CIRC RES
JI Circ.Res.
PD FEB 5
PY 2016
VL 118
IS 3
BP 454
EP 468
DI 10.1161/CIRCRESAHA.115.307872
PG 15
WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Hematology
GA DF0FL
UT WOS:000371014400013
PM 26846640
DA 2025-04-10
ER

PT J
AU Murata, K
   Lu, WZ
   Hashimoto, M
   Ono, N
   Muratani, M
   Nishikata, K
   Kim, JD
   Ebihara, S
   Ishida, J
   Fukamizu, A
AF Murata, Kazuya
   Lu, Weizhe
   Hashimoto, Misuzu
   Ono, Natsumi
   Muratani, Masafumi
   Nishikata, Kana
   Kim, Jun-Dal
   Ebihara, Shizufumi
   Ishida, Junji
   Fukamizu, Akiyoshi
TI PRMT1 Deficiency in Mouse Juvenile Heart Induces Dilated Cardiomyopathy
   and Reveals Cryptic Alternative Splicing Products
SO ISCIENCE
LA English
DT Article
ID METHYLTRANSFERASE 1; ARGININE METHYLATION; MESSENGER-RNA; N-RAP;
   PROTEIN; GENE; MUSCLE; RBM20; TITIN; EXPRESSION
AB Protein arginine methyltransferase 1 (PRMT1) catalyzes the asymmetric dimethylation of arginine residues in proteins and methylation of various RNA-binding proteins and is associated with alternative Survival Dynamics, Tsukuba splicing in vitro. Although PRMT1 has essential in vivo roles in embryonic development, CNS development, and skeletal muscle regeneration, the functional importance of PRMT1 in the heart remains be elucidated. Here, we report that juvenile cardiomyocyte-specific PRMT1-deficient mice develop severe dilated cardiomyopathy and exhibit aberrant cardiac alternative splicing. Furthermore, we iden- tified previously undefined cardiac alternative splicing isoforms of four genes (Asb2, Fbxo40, Nrap,and Eif4a2) in PRMT1-cK0 mice and revealed that el 4A2 protein isoforms translated from alternatively spliced mRNA were differentially ubiquitinated and degraded by the ubiquitin-proteasome system. These findings highlight the essential roles of PRMT1 in cardiac homeostasis and alternative Japan splicing regulation.
C1 [Murata, Kazuya; Kim, Jun-Dal; Ishida, Junji; Fukamizu, Akiyoshi] Univ Tsukuba, Tsukuba Adv Res Alliance, Life Sci Ctr Survival Dynam, Tsukuba, Ibaraki 3058577, Japan.
   [Lu, Weizhe; Hashimoto, Misuzu] Univ Tsukuba, Sch Integrat Global Majors SIGMA, PhD Program Human Biol, Tsukuba, Ibaraki 3058577, Japan.
   [Hashimoto, Misuzu] Gifu Univ, Fac Appl Biol Sci, Dept Appl Life Sci, Gifu, Gifu 5011193, Japan.
   [Ono, Natsumi; Kim, Jun-Dal; Ishida, Junji; Fukamizu, Akiyoshi] Univ Tsukuba, Grad Sch Life & Environm Sci, Tsukuba, Ibaraki 3058577, Japan.
   [Muratani, Masafumi] Univ Tsukuba, Fac Med, Dept Genome Biol, Tsukuba, Ibaraki 3058575, Japan.
   [Muratani, Masafumi] Univ Tsukuba, Fac Med, Genome Biol Core, Transborder Med Res Ctr, Tsukuba, Ibaraki 3058575, Japan.
   [Murata, Kazuya; Nishikata, Kana; Ebihara, Shizufumi] Kwansei Gakuin Univ, Sch Sci & Technol, Dept Biomed Chem, Sanda, Hyogo 6691337, Japan.
   [Fukamizu, Akiyoshi] Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki 3058575, Japan.
C3 University of Tsukuba; University of Tsukuba; Gifu University;
   University of Tsukuba; University of Tsukuba; University of Tsukuba;
   Kwansei Gakuin University; University of Tsukuba
RP Fukamizu, A (corresponding author), Univ Tsukuba, Tsukuba Adv Res Alliance, Life Sci Ctr Survival Dynam, Tsukuba, Ibaraki 3058577, Japan.; Fukamizu, A (corresponding author), Univ Tsukuba, Grad Sch Life & Environm Sci, Tsukuba, Ibaraki 3058577, Japan.; Fukamizu, A (corresponding author), Univ Tsukuba, Int Inst Integrat Sleep Med WPI IIIS, Tsukuba, Ibaraki 3058575, Japan.
EM akif@tara.tsukuba.ac.jp
RI Murata, Kazuya/GLR-2334-2022; Muratani, Masafumi/A-6379-2011
OI Murata, Kazuya/0000-0002-3328-069X; Jun-Dal, Kim/0000-0002-7361-0999;
   Muratani, Masafumi/0000-0002-0276-8000
FU Uehara Memorial Foundation; Japan Society for the Promotion of Science
   (JSPS) [25252062, 23116004, 18K054298]; Grants-in-Aid for Scientific
   Research [25252062] Funding Source: KAKEN
FX We thank Dr. Tsuyoshi Waku for technical advice. We also thank members
   of the Fukamizu Laboratory for helpful discussions and encouragement.
   This work was supported by the Uehara Memorial Foundation (to A.F.),
   Grant-in-Aid for Scientific Research (A) (to A.F., Grant No. 25252062),
   for Scientific Research on Innovative Areas (23116004 to A.F.), and for
   Scientific Research (C) (to J.-D.K., Grant No. 18K054298) from the Japan
   Society for the Promotion of Science (JSPS).
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NR 77
TC 31
Z9 32
U1 0
U2 6
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
EI 2589-0042
J9 ISCIENCE
JI iScience
PD OCT 26
PY 2018
VL 8
BP 200
EP +
DI 10.1016/j.isci.2018.09.023
PG 27
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA GZ8JJ
UT WOS:000449736300017
PM 30321814
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Liang, XY
   Bai, ZC
   Wang, FF
   Han, YF
   Sun, HX
   Xiaokereti, J
   Zhang, L
   Zhou, XH
   Lu, YM
   Tang, BP
AF Liang, Xiaoyan
   Bai, Zechen
   Wang, Feifei
   Han, Yafan
   Sun, Huaxin
   Xiaokereti, Jiasuoer
   Zhang, Ling
   Zhou, Xianhui
   Lu, Yanmei
   Tang, Baopeng
TI Full-Length Transcriptome Sequencing: An Insight Into the Dog Model of
   Heart Failure
SO FRONTIERS IN CARDIOVASCULAR MEDICINE
LA English
DT Article
DE heart failure; target genes; helper T cell differentiation; full-length
   transcriptome sequencing; transcript expression analysis
ID EXPRESSION; PATHWAYS; GENES; RNAS
AB Heart failure (HF) leads to a progressive increase in morbidity and mortality rates. This study aimed to explore the transcriptional landscape during HF and identify differentially expressed transcripts (DETs) and alternative splicing events associated with HF. We generated a dog model of HF (n = 3) using right ventricular pacemaker implantation. We performed full-length transcriptome sequencing (based on nanopore platform) on the myocardial tissues and analyzed the transcripts using differential expression analysis and functional annotation methods [Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses]. Additionally, we estimated the expression of the selected genes by quantitative real-time PCR (qRT-PCR) and detected the proportion of immune cells using flow cytometry. We found that increased B-type natriuretic peptide reduced ejection fraction, and apparent clinical signs were observed in the dog model of HF. We identified 67,458 transcripts using full-length transcriptome sequencing. A total of 785 DETs were obtained from the HF and control groups. These DETs were mainly enriched in the immune responses, especially Th1, Th2, and Th17 cell differentiation processes. Furthermore, flow cytometry results revealed that the proportion of Th1 and Th17 cells increased in patients with HF compared to controls, while the proportion of Th2 cells decreased. Differentially expressed genes in the HF and control groups associated with Th1, Th2, and Th17 cell differentiation were quantified using qRT-PCR. We also identified variable splicing events of sarcomere genes (e.g., MYBPC3, TNNT2, TTN, FLNC, and TTNI3). In addition, we detected 4,892 transcription factors and 406 lncRNAs associated with HF. Our analysis based on full-length transcript sequencing provided an analysis perspective in a dog model of HF, which is valuable for molecular research in an increasingly relevant large animal model of HF.
C1 [Liang, Xiaoyan; Wang, Feifei; Han, Yafan; Sun, Huaxin; Xiaokereti, Jiasuoer; Zhou, Xianhui; Lu, Yanmei; Tang, Baopeng] Xinjiang Med Univ, Dept Pacing & Elect, Affiliated Hosp 1, Urumqi, Peoples R China.
   [Liang, Xiaoyan; Wang, Feifei; Han, Yafan; Sun, Huaxin; Xiaokereti, Jiasuoer; Zhang, Ling; Zhou, Xianhui; Lu, Yanmei; Tang, Baopeng] Xinjiang Med Univ, Xinjiang Key Lab Cardiac Elect & Cardiac Remodeli, Affiliated Hosp 1, Urumqi, Peoples R China.
   [Bai, Zechen] Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen, Peoples R China.
   [Wang, Feifei] Peoples Hosp Xinjiang Uygur Autonomous Reg, Xinjiang Aid Ctr 1, Urumqi, Peoples R China.
C3 Xinjiang Medical University; Xinjiang Medical University; Chinese
   Academy of Sciences; Shenzhen Institute of Advanced Technology, CAS
RP Lu, YM; Tang, BP (corresponding author), Xinjiang Med Univ, Dept Pacing & Elect, Affiliated Hosp 1, Urumqi, Peoples R China.; Lu, YM; Tang, BP (corresponding author), Xinjiang Med Univ, Xinjiang Key Lab Cardiac Elect & Cardiac Remodeli, Affiliated Hosp 1, Urumqi, Peoples R China.
EM 18909917855@189.cn; tangbaopeng1111@163.com
RI Liang, Xiaoyan/AAI-8849-2020
FU National Natural Science Foundation of China [81860081]
FX Funding This study was supported by the National Natural Science
   Foundation of China (project no: 81860081).
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NR 59
TC 5
Z9 6
U1 1
U2 18
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2297-055X
J9 FRONT CARDIOVASC MED
JI Front. Cardiovasc. Med.
PD DEC 16
PY 2021
VL 8
AR 712797
DI 10.3389/fcvm.2021.712797
PG 14
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA YA5XR
UT WOS:000738406200001
PM 34977163
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Zhang, XH
   Moor, AN
   Merkler, KA
   Liu, QY
   McLean, MP
AF Zhang, Xiaohui
   Moor, Andrea N.
   Merkler, Kathleen A.
   Liu, Qiyuan
   McLean, Mark P.
TI Regulation of alternative splicing of liver scavenger receptor class B
   gene by estrogen and the involved regulatory splicing factors
SO ENDOCRINOLOGY
LA English
DT Article
ID HIGH-DENSITY-LIPOPROTEIN; PRE-MESSENGER-RNA; REVERSE CHOLESTEROL
   TRANSPORT; CORONARY-HEART-DISEASE; SELECTIVE LIPID UPTAKE;
   APOPROTEIN-A-I; SR-BI; POSTMENOPAUSAL WOMEN; TARGETED MUTATION; PLUS
   PROGESTIN
AB The scavenger receptor class B isoforms (SR-B) type I and type II mediate the selective uptake of high-density lipoprotein cholesterol and promote reverse cholesterol transport, an important atherosclerosis protection mechanism, in the liver. Previously it was shown that the hepatic expression of SR-BI and SR-BII is regulated by estrogen. In the present study, we demonstrate that estrogen differentially regulates expression of the glycosylated and nonglycosylated forms of SR-BI and SR-BII in rat liver and hepatic cells. We report that estrogen mainly induces the down-regulation of glycosylated SR-BI and the up-regulation of nonglycosylated SR-BII. To study how estrogen regulates expression of the SR-B isoforms, we constructed a SR-B minigene containing minimal genomic sequences and were able to demonstrate that estrogen directly regulates the pre-mRNA alternative splicing of the exogenously expressed SR-B minigene in hepatic cells. Furthermore, we showed that the overexpression of splicing factors alternative splicing factor/splicing factor 2, Transformer (Tra)-2 alpha, and Tra2 beta changes the splicing pattern of SR-B dramatically, whereas other splicing factors, such as heterogeneous nuclear ribonucleoprotein-G, SC-35, and arginine/serine-rich p40, had no effect. We also demonstrate that estrogen regulates Tra2 beta expression levels in liver cells. These studies suggest that estrogen may regulate SR-B isoform expression at both the RNA splicing and posttranslational modification levels and that, for alternative splicing regulation, estrogen may function by regulating the expression of the splicing factors alternative splicing factor/splicing factor 2, Tra2 alpha, and especially Tra2 alpha.
C1 Univ S Florida, Coll Med, Dept Obstet & Gynecol, Tampa, FL 33612 USA.
   Univ S Florida, Coll Med, Dept Mol Pharmacol & Physiol, Tampa, FL 33612 USA.
C3 State University System of Florida; University of South Florida; State
   University System of Florida; University of South Florida
RP McLean, MP (corresponding author), Univ S Florida, Coll Med, Dept Obstet & Gynecol, 12901 Bruce B Downs Blvd,MDC037, Tampa, FL 33612 USA.
EM mmclean@health.usf.edu
RI Moor, Andrea/I-4978-2012; McLean, Mark/I-5621-2012
FU NHLBI NIH HHS [HL078817] Funding Source: Medline; NICHD NIH HHS
   [HD35163] Funding Source: Medline
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NR 55
TC 36
Z9 41
U1 0
U2 5
PU ENDOCRINE SOC
PI WASHINGTON
PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA
SN 0013-7227
EI 1945-7170
J9 ENDOCRINOLOGY
JI Endocrinology
PD NOV
PY 2007
VL 148
IS 11
BP 5295
EP 5304
DI 10.1210/en.2007-0376
PG 10
WC Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Endocrinology & Metabolism
GA 224JT
UT WOS:000250444000020
PM 17673517
OA Bronze
DA 2025-04-10
ER

PT J
AU Yang, JW
   Hung, LH
   Licht, T
   Kostin, S
   Looso, M
   Khrameeva, E
   Bindereif, A
   Schneider, A
   Braun, T
AF Yang, Jiwen
   Hung, Lee-Hsueh
   Licht, Thomas
   Kostin, Sawa
   Looso, Mario
   Khrameeva, Ekaterina
   Bindereif, Albrecht
   Schneider, Andre
   Braun, Thomas
TI RBM24 Is a Major Regulator of Muscle-Specific Alternative Splicing
SO DEVELOPMENTAL CELL
LA English
DT Article
ID BINDING MOTIFS; EXPRESSION; PROTEIN; PTB; GENE; CARDIOMYOPATHY;
   MUTATIONS; ISOFORM; EVENTS; SKNAC
AB Cell-type-specific splicing generates numerous alternatively spliced transcripts playing important roles for organ development and homeostasis, but only a few tissue-specific splicing factors have been identified. We found that RBM24 governs a large number of muscle-specific splicing events that are critically involved in cardiac and skeletal muscle development and disease. Targeted inactivation of RBM24 in mice disrupted cardiac development and impaired sarcomerogenesis in striated muscles. In vitro splicing assays revealed that recombinant RBM24 is sufficient to promote muscle-specific exon inclusion in nuclear extracts of nonmuscle cells. Furthermore, we demonstrate that binding of RBM24 to an intronic splicing enhancer (ISE) is essential and sufficient to overcome repression of exon inclusion by an exonic splicing silencer (ESS) containing PTB and hnRNP A1/A2 binding sites. Introduction of ESS and ISE converted a constitutive exon into an RMB24-dependent alternative exon. We reason that RBM24 is a major regulator of alternative splicing in striated muscles.
C1 [Yang, Jiwen; Licht, Thomas; Kostin, Sawa; Looso, Mario; Schneider, Andre; Braun, Thomas] Max Planck Inst Heart & Lung Res, Dept Cardiac Dev & Remodelling, D-61231 Bad Nauheim, Germany.
   [Hung, Lee-Hsueh; Bindereif, Albrecht] Univ Giessen, Inst Biochem, D-35392 Giessen, Germany.
   [Khrameeva, Ekaterina] Russian Acad Sci, Inst Informat Transmiss Problems, Moscow 127994, Russia.
C3 Max Planck Society; Justus Liebig University Giessen; Kharkevich
   Institute for Information Transmission Problems of the RAS; Russian
   Academy of Sciences
RP Schneider, A (corresponding author), Max Planck Inst Heart & Lung Res, Dept Cardiac Dev & Remodelling, Ludwigstr 43, D-61231 Bad Nauheim, Germany.
EM andre.schneider@mpi-bn.mpg.de; thomas.braun@mpi-bn.mpg.de
RI Braun, Thomas/B-2310-2008; Khrameeva, Ekaterina/I-3620-2015
OI Khrameeva, Ekaterina/0000-0001-6188-9139; Looso,
   Mario/0000-0003-1495-9530; Braun, Thomas/0000-0002-6165-4804
FU Max Planck Society; DFG (Excellence Cluster Cardiopulmonary System)
   [Br1416, SFB TRR81]; LOEWE Center for Cell and Gene Therapy; German
   Center for Cardiovascular Research; Universities of Giessen and Marburg
   Lung Center (UGMLC); Foundation Leducq
FX This work was supported by the Max Planck Society, by the DFG
   (Excellence Cluster Cardiopulmonary System, Br1416, and SFB TRR81), by
   the LOEWE Center for Cell and Gene Therapy, by the German Center for
   Cardiovascular Research, by the Universities of Giessen and Marburg Lung
   Center (UGMLC), and by a grant from the Foundation Leducq.
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NR 43
TC 120
Z9 137
U1 0
U2 23
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
SN 1534-5807
EI 1878-1551
J9 DEV CELL
JI Dev. Cell
PD OCT 13
PY 2014
VL 31
IS 1
BP 87
EP 99
DI 10.1016/j.devcel.2014.08.025
PG 13
WC Cell Biology; Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Developmental Biology
GA AQ9SE
UT WOS:000343195200010
PM 25313962
OA Bronze
DA 2025-04-10
ER

PT J
AU Rodriguez, JM
   Pozo, F
   di Domenico, T
   Vazquez, J
   Tress, ML
AF Manuel Rodriguez, Jose
   Pozo, Fernando
   di Domenico, Tomas
   Vazquez, Jesus
   Tress, Michael L.
TI An analysis of tissue-specific alternative splicing at the protein level
SO PLOS COMPUTATIONAL BIOLOGY
LA English
DT Article
ID RIBOSOME; ISOFORMS; GENE; RNA
AB Author summary We manually curated a set of 255 splice events detected in a large-scale tissue-based proteomics experiment and found that more than a third had evidence of significant tissue-specific differences. Events that were significantly tissue-specific at the protein level were highly conserved; almost 75% evolved over 400 million years ago. The tissues in which we found most evidence for tissue-specific splicing were nervous tissues and cardiac tissues. Genes with tissue-specific events in these two tissues had functions related to important cellular structures in brain and heart tissues. These splice events may have been essential for the development of vertebrate heart and muscle. However, our data set may not be representative of alternative exons as a whole. We found that most tissue specific splicing was strongly conserved, but just 5% of annotated alternative exons in the human gene set are ancient. More than three quarters of alternative exons are primate-derived. Although the analysis does not provide a definitive answer to the question of the functional role of alternative splicing, our results do indicate that alternative splice variants may have played a significant part in the evolution of brain and heart tissues in vertebrates.
   The role of alternative splicing is one of the great unanswered questions in cellular biology. There is strong evidence for alternative splicing at the transcript level, and transcriptomics experiments show that many splice events are tissue specific. It has been suggested that alternative splicing evolved in order to remodel tissue-specific protein-protein networks. Here we investigated the evidence for tissue-specific splicing among splice isoforms detected in a large-scale proteomics analysis. Although the data supporting alternative splicing is limited at the protein level, clear patterns emerged among the small numbers of alternative splice events that we could detect in the proteomics data. More than a third of these splice events were tissue-specific and most were ancient: over 95% of splice events that were tissue-specific in both proteomics and RNAseq analyses evolved prior to the ancestors of lobe-finned fish, at least 400 million years ago. By way of contrast, three in four alternative exons in the human gene set arose in the primate lineage, so our results cannot be extrapolated to the whole genome. Tissue-specific alternative protein forms in the proteomics analysis were particularly abundant in nervous and muscle tissues and their genes had roles related to the cytoskeleton and either the structure of muscle fibres or cell-cell connections. Our results suggest that this conserved tissue-specific alternative splicing may have played a role in the development of the vertebrate brain and heart.
C1 [Manuel Rodriguez, Jose; Vazquez, Jesus] Ctr Nacl Invest Cardiovasc CNIC, Cardiovasc Prote Lab, Calle Melchor Fernandez, Madrid, Spain.
   [Pozo, Fernando; di Domenico, Tomas; Tress, Michael L.] Spanish Natl Canc Res Ctr CNIO, Bioinformat Unit, Calle Melchor Fernandez, Madrid, Spain.
   [Vazquez, Jesus] Ctr Invest Biomed Red Enfermedades Cardiovasc CIB, Madrid, Spain.
C3 Centro Nacional de Investigaciones Cardiovasculares (CNIC); Centro
   Nacional de Investigaciones Oncologicas (CNIO); CIBER - Centro de
   Investigacion Biomedica en Red; CIBERCV
RP Tress, ML (corresponding author), Spanish Natl Canc Res Ctr CNIO, Bioinformat Unit, Calle Melchor Fernandez, Madrid, Spain.
EM mtress@cnio.es
RI Rodriguez, Jose/JGE-4733-2023; Pozo, Fernando/S-1821-2018; Vazquez,
   Jesus/B-7697-2015; Di Domenico, Tomas/N-3435-2013
OI Pozo, Fernando/0000-0001-7688-6045; Vazquez, Jesus/0000-0003-1461-5092;
   Di Domenico, Tomas/0000-0003-2887-815X; Tress,
   Michael/0000-0001-9046-6370; Rodriguez, Jose/0000-0002-9948-5073
FU National Institutes of Health [2 U41 HG007234]; Spanish Ministry of
   Science, Innovation and Universities [BIO2015-67580-P,
   PGC2018-097019-B-I00]; Carlos III Institute of HealthFondo de
   Investigacion Sanitaria grant [PRB3, IPT17/0019 -ISCIII-SGEFI/ERDF];
   Fundacio MaratoTV3 [122/C/2015]; "la Caixa" Banking Foundation
   [HR17-00247]
FX This study was supported by the National Institutes of Health
   (https://www.nih.gov) grant number 2 U41 HG007234 (FP and MLT), the
   Spanish Ministry of Science, Innovation and Universities
   (https://www.ciencia.gob.es) grants BIO2015-67580-P and
   PGC2018-097019-B-I00 (JMR and JV), the Carlos III Institute of
   HealthFondo de Investigacion (https://www.isciii.es) Sanitaria grant
   PRB3, IPT17/0019 -ISCIII-SGEFI/ERDF, ProteoRed (JMR and JV), the
   Fundacio MaratoTV3 (https://www.ccma.cat) grant 122/C/2015 (JMR and JV)
   and "la Caixa" Banking Foundation (https://obrasociallacaixa.org)
   project code HR17-00247 (JMR and JV). The funders had no role in study
   design, data collection and analysis, decision to publish, or
   preparation of the manuscript.
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NR 48
TC 52
Z9 59
U1 0
U2 20
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1553-734X
EI 1553-7358
J9 PLOS COMPUT BIOL
JI PLoS Comput. Biol.
PD OCT
PY 2020
VL 16
IS 10
AR e1008287
DI 10.1371/journal.pcbi.1008287
PG 24
WC Biochemical Research Methods; Mathematical & Computational Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Mathematical & Computational Biology
GA OB2GE
UT WOS:000578291000001
PM 33017396
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Zhao, FY
   Yan, YB
   Wang, YX
   Liu, Y
   Yang, RL
AF Zhao, Feiyang
   Yan, Yubin
   Wang, Yaxi
   Liu, Yuan
   Yang, Ruolin
TI Splicing complexity as a pivotal feature of alternative exons in
   mammalian species
SO BMC GENOMICS
LA English
DT Article
DE Alternative splicing; Splicing complexity; Machine learning; Development
   and evolution
ID EVOLUTIONARY DYNAMICS; GENES; EXPRESSION; CARDIOMYOPATHY; TRANSCRIPTOME;
   CONSEQUENCES; REGULATOR; EXPANSION; PROFILES; PROTEOME
AB BackgroundAs a significant process of post-transcriptional gene expression regulation in eukaryotic cells, alternative splicing (AS) of exons greatly contributes to the complexity of the transcriptome and indirectly enriches the protein repertoires. A large number of studies have focused on the splicing inclusion of alternative exons and have revealed the roles of AS in organ development and maturation. Notably, AS takes place through a change in the relative abundance of the transcript isoforms produced by a single gene, meaning that exons can have complex splicing patterns. However, the commonly used percent spliced-in (psi) values only define the usage rate of exons, but lose information about the complexity of exons' linkage pattern. To date, the extent and functional consequence of splicing complexity of alternative exons in development and evolution is poorly understood.ResultsBy comparing splicing complexity of exons in six tissues (brain, cerebellum, heart, liver, kidney, and testis) from six mammalian species (human, chimpanzee, gorilla, macaque, mouse, opossum) and an outgroup species (chicken), we revealed that exons with high splicing complexity are prevalent in mammals and are closely related to features of genes. Using traditional machine learning and deep learning methods, we found that the splicing complexity of exons can be moderately predicted with features derived from exons, among which length of flanking exons and splicing strength of downstream/upstream splice sites are top predictors. Comparative analysis among human, chimpanzee, gorilla, macaque, and mouse revealed that, alternative exons tend to evolve to an increased level of splicing complexity and higher tissue specificity in splicing complexity. During organ development, not only developmentally regulated exons, but also 10-15% of non-developmentally regulated exons show dynamic splicing complexity.ConclusionsOur analysis revealed that splicing complexity is an important metric to characterize the splicing dynamics of alternative exons during the development and evolution of mammals.
C1 [Zhao, Feiyang; Yan, Yubin; Wang, Yaxi; Liu, Yuan; Yang, Ruolin] Northwest A&F Univ, Coll Life Sci, Yangling, Shaanxi, Peoples R China.
C3 Northwest A&F University - China
RP Yang, RL (corresponding author), Northwest A&F Univ, Coll Life Sci, Yangling, Shaanxi, Peoples R China.
EM desert.ruolin@gmail.com
RI Yan, Yubin/ABY-6598-2022; Wang, Yaxi/IUO-6777-2023; Zhao,
   Fu-Yun/A-9036-2008
OI Yan, Yubin/0009-0003-4942-455X
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NR 62
TC 1
Z9 1
U1 2
U2 16
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1471-2164
J9 BMC GENOMICS
JI BMC Genomics
PD APR 12
PY 2023
VL 24
IS 1
AR 198
DI 10.1186/s12864-023-09247-y
PG 17
WC Biotechnology & Applied Microbiology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Genetics & Heredity
GA D4GO9
UT WOS:000968333100005
PM 37046221
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Sellier, C
   Cerro-Herreros, E
   Blatter, M
   Freyermuth, F
   Gaucherot, A
   Ruffenach, F
   Sarkar, P
   Puymirat, J
   Udd, B
   Day, JW
   Meola, G
   Bassez, G
   Fujimura, H
   Takahashi, MP
   Schoser, B
   Furling, D
   Artero, R
   Allain, FHT
   Llamusi, B
   Charlet-Berguerand, N
AF Sellier, Chantal
   Cerro-Herreros, Estefania
   Blatter, Markus
   Freyermuth, Fernande
   Gaucherot, Angeline
   Ruffenach, Frank
   Sarkar, Partha
   Puymirat, Jack
   Udd, Bjarne
   Day, John W.
   Meola, Giovanni
   Bassez, Guillaume
   Fujimura, Harutoshi
   Takahashi, Masanori P.
   Schoser, Benedikt
   Furling, Denis
   Artero, Ruben
   Allain, Frederic H. T.
   Llamusi, Beatriz
   Charlet-Berguerand, Nicolas
TI rbFOX1/MBNL1 competition for CCUG RNA repeats binding contributes to
   myotonic dystrophy type 1/type 2 differences
SO NATURE COMMUNICATIONS
LA English
DT Article
ID SPLICING REGULATOR RBFOX2; CONGENITAL HEART-DISEASE; PRE-MESSENGER-RNA;
   MUSCLEBLIND PROTEINS; SKELETAL-MUSCLE; CHLORIDE CHANNEL;
   MOLECULAR-BASIS; TRIPLET REPEAT; STEADY-STATE; CUG REPEATS
AB Myotonic dystrophy type 1 and type 2 (DM1, DM2) are caused by expansions of CTG and CCTG repeats, respectively. RNAs containing expanded CUG or CCUG repeats interfere with the metabolism of other RNAs through titration of the Muscleblind-like (MBNL) RNA binding proteins. DM2 follows a more favorable clinical course than DM1, suggesting that specific modifiers may modulate DM severity. Here, we report that the rbFOX1 RNA binding protein binds to expanded CCUG RNA repeats, but not to expanded CUG RNA repeats. Interestingly, rbFOX1 competes with MBNL1 for binding to CCUG expanded repeats and overexpression of rbFOX1 partly releases MBNL1 from sequestration within CCUG RNA foci in DM2 muscle cells. Furthermore, expression of rbFOX1 corrects alternative splicing alterations and rescues muscle atrophy, climbing and flying defects caused by expression of expanded CCUG repeats in a Drosophila model of DM2.
C1 [Sellier, Chantal; Freyermuth, Fernande; Gaucherot, Angeline; Ruffenach, Frank; Charlet-Berguerand, Nicolas] Univ Strasbourg, CNRS, INSERM, IGBMC,U964,UMR7104, F-67404 Illkirch Graffenstaden, France.
   [Cerro-Herreros, Estefania; Artero, Ruben; Llamusi, Beatriz] Univ Valencia, Translat Genom Grp, Interdisciplinary Res Struct Biotechnol & Biomed, Valencia 46010, Spain.
   [Cerro-Herreros, Estefania; Artero, Ruben; Llamusi, Beatriz] INCLIVA Hlth Res Inst, Valencia 46010, Spain.
   [Blatter, Markus; Allain, Frederic H. T.] Swiss Fed Inst Technol, Swiss Fed Inst Technol, Inst Mol Biol & Biophys, CH-8092 Zurich, Switzerland.
   [Sarkar, Partha] Univ Texas Med Branch, Dept Neurol, Galveston, TX 77555 USA.
   [Puymirat, Jack] Laval Univ, CHUQ, Human Genet Res Unit, Quebec City, PQ G1V 4G2, Canada.
   [Udd, Bjarne] Tampere Univ Hosp, Neuromuscular Res Ctr, Tampere 33521, Finland.
   [Udd, Bjarne] Univ Helsinki, Folkhalsan Inst Genet, Dept Med Genet, Helsinki 00290, Finland.
   [Udd, Bjarne] Vasa Cent Hosp, Dept Neurol, Vaasa 65130, Finland.
   [Day, John W.] Stanford Univ, Dept Neurol, Stanford, CA 94305 USA.
   [Meola, Giovanni] Univ Milan, Dept Biomed Sci Hlth, I-20097 Milan, Italy.
   [Meola, Giovanni] IRCCS Policlin San Donato, Neurol Unit, I-20097 Milan, Italy.
   [Bassez, Guillaume; Furling, Denis] Sorbonne Univ, INSERM, Assoc Inst Myol, Ctr Res Myol, F-75013 Paris, France.
   [Fujimura, Harutoshi] Toneyama Natl Hosp, Dept Neurol, Toyonaka, Osaka 5600045, Japan.
   [Takahashi, Masanori P.] Osaka Univ, Grad Sch Med, Dept Neurol, Suita, Osaka 5650871, Japan.
   [Schoser, Benedikt] Ludwig Maximilians Univ Munchen, Dept Neurol, Friedrich Baur Inst, D-80539 Munich, Germany.
   [Charlet-Berguerand, Nicolas] CNRS, UMR7104, F-67404 Illkirch Graffenstaden, France.
   [Charlet-Berguerand, Nicolas] INSERM, U964, F-67404 Illkirch Graffenstaden, France.
   [Charlet-Berguerand, Nicolas] Univ Strasbourg, F-67404 Illkirch Graffenstaden, France.
C3 Centre National de la Recherche Scientifique (CNRS); CNRS - National
   Institute for Biology (INSB); Institut National de la Sante et de la
   Recherche Medicale (Inserm); Universites de Strasbourg Etablissements
   Associes; Universite de Strasbourg; University of Valencia; Swiss
   Federal Institutes of Technology Domain; ETH Zurich; University of Texas
   System; University of Texas Medical Branch Galveston; Laval University;
   Laval University Hospital; Tampere University; Tampere University
   Hospital; University of Helsinki; Vaasa Central Hospital; Stanford
   University; University of Milan; IRCCS Policlinico San Donato; Institut
   National de la Sante et de la Recherche Medicale (Inserm); Sorbonne
   Universite; The University of Osaka; University of Munich; Centre
   National de la Recherche Scientifique (CNRS); CNRS - National Institute
   for Biology (INSB); Institut National de la Sante et de la Recherche
   Medicale (Inserm); Universites de Strasbourg Etablissements Associes;
   Universite de Strasbourg
RP Charlet-Berguerand, N (corresponding author), Univ Strasbourg, CNRS, INSERM, IGBMC,U964,UMR7104, F-67404 Illkirch Graffenstaden, France.; Llamusi, B (corresponding author), Univ Valencia, Translat Genom Grp, Interdisciplinary Res Struct Biotechnol & Biomed, Valencia 46010, Spain.; Llamusi, B (corresponding author), INCLIVA Hlth Res Inst, Valencia 46010, Spain.; Charlet-Berguerand, N (corresponding author), CNRS, UMR7104, F-67404 Illkirch Graffenstaden, France.; Charlet-Berguerand, N (corresponding author), INSERM, U964, F-67404 Illkirch Graffenstaden, France.; Charlet-Berguerand, N (corresponding author), Univ Strasbourg, F-67404 Illkirch Graffenstaden, France.
EM Mbeatriz.Llamusi@uv.es; ncharlet@igbmc.fr
RI llamusi, Beatriz/M-4449-2015; Inerbaev, Talgat/AAB-7633-2020; Herreros,
   Estefanía Cerro/AAD-6166-2021; Udd, Bjarne/JBE-3483-2023; Bassez,
   Guillaume/AAD-3033-2022; Takahashi, Masanori/O-8946-2019; Sarkar,
   Partha/LWK-4196-2024; Charlet-Berguerand, Nicolas/GZM-6636-2022;
   Charlet-Berguerand, Nicolas/I-6727-2016; meola, giovanni/K-4775-2016;
   Furling, Denis/M-2346-2017; Artero, Ruben/K-6815-2014
OI Day, John/0000-0002-0086-9529; Charlet-Berguerand,
   Nicolas/0000-0002-4423-4920; meola, giovanni/0000-0001-6396-717X;
   Schoser, Benedikt/0000-0002-2757-8131; Furling,
   Denis/0000-0001-7912-4409; Sellier, Chantal/0000-0003-2933-5464;
   Takahashi, Masanori P/0000-0002-5513-5012; Cerro Herreros,
   Estefania/0000-0003-3247-5900; Artero, Ruben/0000-0003-1596-047X
FU ERC-2012-StG [310659]; RNA DISEASES [18833]; Model DM
   [ANR-10-LABX-0030-INRT, ANR-10-IDEX-0002-02]; HEART DM; PrometeoII;
   Fondazione Malattie Miotoniche; UPMC/INSERM/CNRS/AIM; Research Resource
   Network Japan [26-8]; Ministry of Health, Labor and Welfare; European
   Research Council (ERC) [310659] Funding Source: European Research
   Council (ERC)
FX We thank Tom Cooper for the gift of the DT960 vector, RTB300 and INSR
   exon 11 minigenes, Kunio Inoue for the gift of the human mitochondrial
   ATP synthase gamma-subunit exon 9 minigene (F1gamma), Christiane
   Branlant and Maury Swanson for the gift of the pGEX-MBNL1-Delta 101 and
   PGEX-MBNL1-HIS vectors, Douglas Black for the gift of the rbFOX1 and
   rbFOX2 expression plasmids and the kind gift of monoclonal anti-rbFOX1
   antibody, Glenn Morris for the gift of the anti-MBNL1 monoclonal
   antibody, Charles Thornton for the gift of the anti-MBNL1 polyclonal
   antibody. This work was supported by ERC-2012-StG # 310659 "RNA
   DISEASES"; AFM # 18833 "Model DM" (NCB), ANR-10-LABX-0030-INRT (IGBMC);
   ANR-10-IDEX-0002-02 (IGBMC); ERARE-12-059 "HEART DM" (NCB, BL, DF),
   PrometeoII (BL), Fondazione Malattie Miotoniche (GM),
   UPMC/INSERM/CNRS/AIM (DF), Research Resource Network Japan (HF),
   grants-in-aids from JSPS (MPT), Intramural Research Grant of NCNP 26-8
   (MPT) and research Grants for Intractable Disease from the Ministry of
   Health, Labor and Welfare (MPT).
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NR 79
TC 53
Z9 62
U1 0
U2 11
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD MAY 22
PY 2018
VL 9
AR 2009
DI 10.1038/s41467-018-04370-x
PG 15
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA GG4KQ
UT WOS:000432665900004
PM 29789616
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU de Bruin, RG
   Rabelink, TJ
   van Zonneveld, AJ
   van der Veer, EP
AF de Bruin, Ruben G.
   Rabelink, Ton J.
   van Zonneveld, Anton Jan
   van der Veer, Eric P.
TI Emerging roles for RNA-binding proteins as effectors and regulators of
   cardiovascular disease
SO EUROPEAN HEART JOURNAL
LA English
DT Review
DE Cardiovascular disease; Post-transcriptional gene regulation;
   RNA-binding proteins; Alternative splicing; RNA therapeutics
ID LONG NONCODING RNAS; ENDOTHELIAL GROWTH-FACTOR; PRE-MESSENGER-RNA;
   NECROSIS-FACTOR-ALPHA; SMOOTH-MUSCLE; GENE-EXPRESSION; HEART-FAILURE;
   SINGLE-GENE; KNOCKOUT MICE; ENOS GENE
AB The cardiovascular system comprises multiple cell types that possess the capacity to modulate their phenotype in response to acute or chronic injury. Transcriptional and post-transcriptional mechanisms play a key role in the regulation of remodelling and regenerative responses to damaged cardiovascular tissues. Simultaneously, insufficient regulation of cellular phenotype is tightly coupled with the persistence and exacerbation of cardiovascular disease. Recently, RNA-binding proteins such as Quaking, HuR, Muscleblind, and SRSF1 have emerged as pivotal regulators of these functional adaptations in the cardiovascular system by guiding a wide-ranging number of post-transcriptional events that dramatically impact RNA fate, including alternative splicing, stability, localization and translation. Moreover, homozygous disruption of RNA-binding protein genes is commonly associated with cardiac-and/or vascular complications. Here, we summarize the current knowledge on the versatile role of RNA-binding proteins in regulating the transcriptome during phenotype switching in cardiovascular health and disease. We also detail existing and potential DNA-and RNA-based therapeutic approaches that could impact the treatment of cardiovascular disease in the future.
C1 [de Bruin, Ruben G.; Rabelink, Ton J.; van Zonneveld, Anton Jan; van der Veer, Eric P.] Leiden Univ, Med Ctr, Einthoven Lab Expt Vasc Med, Albinusdreef 2, NL-2300 RC Leiden, Netherlands.
   [de Bruin, Ruben G.; Rabelink, Ton J.; van Zonneveld, Anton Jan; van der Veer, Eric P.] Leiden Univ, Med Ctr, Dept Internal Med, Div Nephrol, Albinusdreef 2, NL-2300 RC Leiden, Netherlands.
C3 Leiden University - Excl LUMC; Leiden University; Leiden University
   Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University;
   Leiden University Medical Center (LUMC)
RP van der Veer, EP (corresponding author), Leiden Univ, Med Ctr, Einthoven Lab Expt Vasc Med, Albinusdreef 2, NL-2300 RC Leiden, Netherlands.; van der Veer, EP (corresponding author), Leiden Univ, Med Ctr, Dept Internal Med, Div Nephrol, Albinusdreef 2, NL-2300 RC Leiden, Netherlands.
EM e.p.van_der_veer@lumc.nl
RI Rabelink, Ton/A-5316-2008; van Zonneveld, Anton Jan/D-8060-2018
OI Rabelink, Ton/0000-0001-6780-5186; van Zonneveld, Anton
   Jan/0000-0002-1676-7738
FU Netherlands Institute for Regenerative Medicine [FES0908]; Department of
   Internal Medicine, Leiden University Medical Center
FX Netherlands Institute for Regenerative Medicine research grants
   (FES0908) to R.G.B. and E.P.V.Funding to pay the Open Access publication
   charges for this article was provided by the Department of Internal
   Medicine, Leiden University Medical Center.
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NR 188
TC 106
Z9 112
U1 0
U2 28
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0195-668X
EI 1522-9645
J9 EUR HEART J
JI Eur. Heart J.
PD MAY 7
PY 2017
VL 38
IS 18
BP 1380
EP 1388D
DI 10.1093/eurheartj/ehw567
PG 13
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA ET9PB
UT WOS:000400638300010
PM 28064149
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Xu, Q
   Modrek, B
   Lee, C
AF Xu, Q
   Modrek, B
   Lee, C
TI Genome-wide detection of tissue-specific alternative splicing in the
   human transcriptome
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID PRE-MESSENGER-RNA; INTERFERON REGULATORY FACTOR-3; FATTY ALDEHYDE
   DEHYDROGENASE; FUNCTIONAL-CHARACTERIZATION; VIRUS-INFECTION;
   GAMMA-SUBUNIT; PROFILIN-II; EXPRESSION; DATABASE; VARIANT
AB We have developed an automated method for discovering tissue-specific regulation of alternative splicing through a genome-wide analysis of expressed sequence tags (ESTs). Using this approach, we have identified 667 tissue-specific alternative splice forms of human genes. We validated our muscle-specific and brain-specific splice forms for known genes. A high fraction (8/10) were reported to have a matching tissue specificity by independent studies in the published literature. The number of tissue-specific alternative splice forms is highest in brain, while eye_retina, muscle, skin, testis and lymph have the greatest enrichment of tissue-specific splicing. Overall, 10-30% of human alternatively spliced genes in our data show evidence of tissue-specific splice forms. Seventy-eight percent of our tissue-specific alternative splices appear to be novel discoveries. We present bioinformatics analysis of several tissue-specific splice forms, including automated protein isoform sequence and domain prediction, showing how our data can provide valuable insights into gene function in different tissues. For example, we have discovered a novel kidney-specific alternative splice form of the WNK1 gene, which appears to specifically disrupt its N-terminal kinase domain and may play a role in PHAII hypertension. Our database greatly expands knowledge of tissue-specific alternative splicing and provides a comprehensive dataset for investigating its functional roles and regulation in different human tissues.
C1 Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA.
   Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA.
C3 University of California System; University of California Los Angeles;
   University of California System; University of California Los Angeles
RP Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA.
EM leec@mbi.ucla.edu
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NR 79
TC 324
Z9 384
U1 2
U2 29
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0305-1048
EI 1362-4962
J9 NUCLEIC ACIDS RES
JI Nucleic Acids Res.
PD SEP 1
PY 2002
VL 30
IS 17
BP 3754
EP 3766
DI 10.1093/nar/gkf492
PG 13
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 593NK
UT WOS:000177998100018
PM 12202761
OA Bronze, Green Published
DA 2025-04-10
ER

PT J
AU Xie, YL
   Yang, ZB
   Chen, WX
   Zhong, CS
   Li, MY
   Zhang, L
   Cheng, T
   Deng, Q
   Wang, HF
   Ju, J
   Du, ZM
   Liang, HH
AF Xie, Yilin
   Yang, Zhenbo
   Chen, Wenxian
   Zhong, Changsheng
   Li, Mengyang
   Zhang, Lei
   Cheng, Ting
   Deng, Qin
   Wang, Huifang
   Ju, Jin
   Du, Zhimin
   Liang, Haihai
TI Splicing factor SRSF1 attenuates cardiomyocytes apoptosis via regulating
   alternative splicing of Bcl2L12
SO CELL AND BIOSCIENCE
LA English
DT Article
DE Alternative splicing; SRSF1; Myocardial infarction; Apoptosis
ID BCL-2; INHIBITION; MECHANISMS; GENE; P53; AUTOPHAGY; PROTEIN; SR
AB BackgroundAberrant alternative splicing (AS) events, triggered by the alterations in serine/arginine splicing factor 1 (SRSF1), a member of the SR protein family, have been implicated in various pathological processes. However, the function and mechanism of SRSF1 in cardiovascular diseases remain unclear.ResultsIn this study, we found that the expression of SRSF1 was significantly down-regulated in the hearts of mice with acute myocardial infarction (AMI) and H9C2 cells exposed to H2O2. Moreover, in vivo experiments utilizing adeno-associated virus serotype 9-mediated SRSF1 overexpression improved cardiac function and reduced infarct size in AMI mice. Mechanistically, we employed RNA-seq assay to identify AS aberrations associated with altered SRSF1 level in cardiomyocytes, and found that SRSF1 regulates the splice switching of Bcl2L12. Further study showed that silencing SRSF1 inhibits the inclusion of exon7 in Bcl2L12. Importantly, the truncated Bcl2L12 lacked the necessary structural elements and failed to interact with p53, thus compromising its ability to suppress apoptosis.ConclusionsOur study unraveled the role of SRSF1 as a splicing factor involved in the regulation of Bcl2L12 splice switching, thereby exerting an anti-apoptotic effect through the p53 pathway, which provides new insights into potential approaches targeting cardiomyocyte apoptosis in cardiovascular diseases.
C1 [Xie, Yilin; Du, Zhimin; Liang, Haihai] Jinan Univ, Zhuhai Clin Med Coll, Zhuhai Peoples Hosp, Guangdong Prov Key Lab Tumor Intervent Diag & Trea, Zhuhai 519000, Guangdong, Peoples R China.
   [Du, Zhimin] Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Taipa 999078, Macao, Peoples R China.
   [Xie, Yilin] Shenzhen Univ, Affiliated Hosp 3, Luohu Hosp, Dept Pharm, Shenzhen 518000, Guangdong, Peoples R China.
   [Liang, Haihai] Harbin Med Univ, Coll Pharm, Dept Pharmacol,State Key Lab Prov Key Lab Biomed P, State Key Lab Frigid Zone Cardiovasc Dis SKLFZCD,K, Harbin 150081, Peoples R China.
   [Yang, Zhenbo; Chen, Wenxian; Zhong, Changsheng; Li, Mengyang; Zhang, Lei; Cheng, Ting; Wang, Huifang; Ju, Jin] Shenzhen Univ, Coll Pharm, Med Sch, Shenzhen 518055, Guangdong, Peoples R China.
   [Deng, Qin] Shenzhen Univ, Coll Basic Med Sci, Med Sch, Shenzhen 518055, Guangdong, Peoples R China.
   [Liang, Haihai] Chinese Acad Med Sci, Res Unit Noninfect Chron Dis Frigid Zone 2019RU070, Harbin 150081, Peoples R China.
C3 Jinan University; Macau University of Science & Technology; Shenzhen
   University; Harbin Medical University; Shenzhen University; Shenzhen
   University; Chinese Academy of Medical Sciences - Peking Union Medical
   College
RP Du, ZM; Liang, HH (corresponding author), Jinan Univ, Zhuhai Clin Med Coll, Zhuhai Peoples Hosp, Guangdong Prov Key Lab Tumor Intervent Diag & Trea, Zhuhai 519000, Guangdong, Peoples R China.; Du, ZM (corresponding author), Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Taipa 999078, Macao, Peoples R China.; Liang, HH (corresponding author), Harbin Med Univ, Coll Pharm, Dept Pharmacol,State Key Lab Prov Key Lab Biomed P, State Key Lab Frigid Zone Cardiovasc Dis SKLFZCD,K, Harbin 150081, Peoples R China.; Liang, HH (corresponding author), Chinese Acad Med Sci, Res Unit Noninfect Chron Dis Frigid Zone 2019RU070, Harbin 150081, Peoples R China.
EM dzm1956@126.com; lianghaihai@ems.hrbmu.edu.cn
RI Zhang, Lei/N-7527-2015; Peng, Gongxin/GYR-1891-2022
FU National Natural Science Foundation of China [U21A20339, 32171127];
   Scientific Fund Project of Heilongjiang Province (China) [JQ2022H001];
   CAMS Innovation Fund for Medical Sciences (CIFMS) [2019-I2M-5-078]
FX This study was supported by the National Natural Science Foundation of
   China (U21A20339, 32171127); the Scientific Fund Project of Heilongjiang
   Province (JQ2022H001, China); and the CAMS Innovation Fund for Medical
   Sciences (CIFMS, 2019-I2M-5-078)
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NR 43
TC 0
Z9 0
U1 5
U2 5
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 2045-3701
J9 CELL BIOSCI
JI Cell Biosci.
PD NOV 22
PY 2024
VL 14
IS 1
AR 142
DI 10.1186/s13578-024-01324-3
PG 16
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA N1Z2G
UT WOS:001362389800001
PM 39578852
OA gold
DA 2025-04-10
ER

PT J
AU Lee, HC
   Rudy, Y
   Po-Yuan
   Sheu, SH
   Chang, JG
   Cui, JM
AF Lee, Hsiang-Chun
   Rudy, Yoram
   Po-Yuan
   Sheu, Sheng-Hsiung
   Chang, Jan-Gowth
   Cui, Jianmin
TI Modulation of KCNQ1 alternative splicing regulates cardiac
   IKs and action potential repolarization
SO HEART RHYTHM
LA English
DT Article
DE Action potential; Alternative splicing; Amiloride; I-Ks; KCNQ1
ID LONG QT SYNDROME; CANINE VENTRICULAR MYOCYTES; DELAYED RECTIFIER
   CURRENT; PURKINJE-FIBERS; AMILORIDE; POTASSIUM; AFTERDEPOLARIZATIONS;
   CONTRIBUTES; DISPERSION; INTERVAL
AB BACKGROUND Slow delayed-rectifier potassium current (I-Ks) channels, made of the pore-forming KCNQ1 and auxiliary KCNE1 subunits, play a key role in determining action potential duration (APD) in cardiac myocytes. The consequences of drug-induced KCNQ1 splice alteration remain unknown.
   OBJECTIVE To study the modulation of KCNQ1 alternative splicing by amiloride and the consequent changes in I-Ks and action potentials (APs) in ventricular myocytes.
   METHODS Canine endocardial, midmyocardial, and epicardial ventricular myocytes were isolated. Levels of KCNQ1a and KCNQ1b as well as a series of splicing factors were quantified by using the reverse transcriptase-polymerase chain reaction and Western blot. The effect of amiloride-induced changes in the KCNQ1b/total KCNQ1 ratio on AP was measured by using whole-cell patch damp with and without isoproterenol.
   RESULTS With 50 mu mol/L of amiloride for 6 hours, KCNQ1a at transcriptional and translational levels increased in midmyocardial myocytes but decreased in endo- and epicardial myocytes. Likewise, changes in splicing factors in midmyocardial were opposite to that in endo- and epicardial myocytes. In midmyocardial myocytes amiloride shortened APD and decreased isoproterenol-induced early afterdepolarizations significantly. The same amiloride-induced effects were demonstrated by using human ventricular myocyte model for AP simulations under beta-adrenergic stimulation. Moreover, amiloride reduced the transmural dispersion of repolarization in pseudo-electrocardiogram.
   CONCLUSIONS Amiloride regulates I-Ks and APs with transmural differences and reduces arrhythmogenicity through the modulation of KCNQ1 splicing. We suggested that the modulation of KCNQ1 splicing may help prevent arrhythmia.
C1 [Lee, Hsiang-Chun; Rudy, Yoram; Cui, Jianmin] Washington Univ, Dept Biomed Engn, Cardiac Bioelect & Arrhythmia Ctr, St Louis, MO 63130 USA.
   [Lee, Hsiang-Chun; Sheu, Sheng-Hsiung] Kaohsiung Med Univ Hosp, Dept Internal Med, Div Cardiol, Kaohsiung, Taiwan.
   [Lee, Hsiang-Chun; Sheu, Sheng-Hsiung] Kaohsiung Med Univ, Grad Inst Med, Sch Med, Kaohsiung, Taiwan.
   [Lee, Hsiang-Chun; Sheu, Sheng-Hsiung] Kaohsiung Med Univ, Sch Med, Dept Internal Med, Fac Med, Kaohsiung, Taiwan.
   [Po-Yuan] Natl Cheng Kung Univ, Coll Elect Engn & Comp Sci, Tainan 70101, Taiwan.
   [Chang, Jan-Gowth] China Med Univ Hosp, Dept Lab Med, Epigenome Res Ctr, Taichung, Taiwan.
   [Chang, Jan-Gowth] China Med Univ, Sch Med, Taichung, Taiwan.
C3 Washington University (WUSTL); Kaohsiung Medical University; Kaohsiung
   Medical University Hospital; Kaohsiung Medical University; Kaohsiung
   Medical University; National Cheng Kung University; China Medical
   University Taiwan; China Medical University Hospital - Taiwan; China
   Medical University Taiwan
RP Cui, JM (corresponding author), Washington Univ, Dept Biomed Engn, Cardiac Bioelect & Arrhythmia Ctr, 290C Whitaker Hall,1 Brookings Dr, St Louis, MO 63130 USA.
EM jcui@wustl.edu
RI Sheu, Sheng-Hsiung/C-7445-2009
OI Lee, Hsiang-Chun/0000-0002-5877-9059
FU Taiwan National Science Council [NSC 99-2221-E-037-001]; American Heart
   Association [0440066N]; NIH [R01 NS060706]; NIH-NHLBI [R01-HL-049054-20,
   R01-HL-033343-28]; Leducq Foundation; American Heart Association (AHA)
   [0440066N] Funding Source: American Heart Association (AHA)
FX This work was supported by the Taiwan National Science Council grant NSC
   99-2221-E-037-001 (to Dr Lee) and American Heart Association Established
   Investigator Award 0440066N and NIH grant R01 NS060706 (to Dr Cui),
   NIH-NHLBI grants R01-HL-049054-20 and R01-HL-033343-28, and a Leducq
   Foundation Award (to Y. Rudy).
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NR 31
TC 12
Z9 15
U1 0
U2 9
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 1547-5271
EI 1556-3871
J9 HEART RHYTHM
JI Heart Rhythm
PD AUG
PY 2013
VL 10
IS 8
BP 1220
EP 1228
DI 10.1016/j.hrthm.2013.04.014
PG 9
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 206CB
UT WOS:000323492700023
PM 23608591
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Duran, J
   Nickel, L
   Estrada, M
   Backs, J
   van den Hoogenhof, MMG
AF Duran, Javier
   Nickel, Lennart
   Estrada, Manuel
   Backs, Johannes
   van den Hoogenhof, Maarten M. G.
TI CaMKIIδ Splice Variants in the Healthy and Diseased Heart
SO FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
LA English
DT Review
DE RNA splicing; heart; CaMKII delta; splice variant; therapeutics
ID PROTEIN-KINASE-II; ENHANCES CARDIOMYOCYTE CONTRACTILITY; PATHOLOGICAL
   CARDIAC-HYPERTROPHY; NUCLEAR-LOCALIZATION SIGNAL; HISTONE H3
   PHOSPHORYLATION; VASCULAR SMOOTH-MUSCLE; PRESSURE-OVERLOAD; MYOCARDIAL
   ISCHEMIA/REPERFUSION; ANTISENSE OLIGONUCLEOTIDES; DILATED CARDIOMYOPATHY
AB RNA splicing has been recognized in recent years as a pivotal player in heart development and disease. The Ca2+/calmodulin dependent protein kinase II delta (CaMKII delta) is a multifunctional Ser/Thr kinase family and generates at least 11 different splice variants through alternative splicing. This enzyme, which belongs to the CaMKII family, is the predominant family member in the heart and functions as a messenger toward adaptive or detrimental signaling in cardiomyocytes. Classically, the nuclear CaMKII delta B and cytoplasmic CaMKII delta C splice variants are described as mediators of arrhythmias, contractile function, Ca2+ handling, and gene transcription. Recent findings also put CaMKII delta A and CaMKII delta 9 as cardinal players in the global CaMKII response in the heart. In this review, we discuss and summarize the new insights into CaMKII delta splice variants and their (proposed) functions, as well as CaMKII-engineered mouse phenotypes and cardiac dysfunction related to CaMKII delta missplicing. We also discuss RNA splicing factors affecting CaMKII splicing. Finally, we discuss the translational perspective derived from these insights and future directions on CaMKII delta splicing research in the healthy and diseased heart.
C1 [Duran, Javier; Nickel, Lennart; Backs, Johannes; van den Hoogenhof, Maarten M. G.] Heidelberg Univ, Inst Expt Cardiol, Heidelberg, Germany.
   [Duran, Javier; Nickel, Lennart; Backs, Johannes; van den Hoogenhof, Maarten M. G.] German Ctr Cardiovasc Res DZHK, Partner Site Heidelberg Mannheim, Heidelberg, Germany.
   [Estrada, Manuel] Univ Chile, Inst Biomed Sci, Fac Med, Santiago, Chile.
C3 Ruprecht Karls University Heidelberg; German Centre for Cardiovascular
   Research; Universidad de Chile
RP van den Hoogenhof, MMG (corresponding author), Heidelberg Univ, Inst Expt Cardiol, Heidelberg, Germany.; van den Hoogenhof, MMG (corresponding author), German Ctr Cardiovasc Res DZHK, Partner Site Heidelberg Mannheim, Heidelberg, Germany.
EM maarten.vandenhoogenhof@med.uni-heidelberg.de
RI Estrada, Manuel/AAS-5605-2020; Estrada, Manuel/C-1269-2014
OI Estrada, Manuel/0000-0001-7877-8160; Nickel,
   Lennart/0000-0001-5535-4402; van den Hoogenhof,
   Maarten/0000-0003-2768-3457
FU German Center for Cardiovascular Research (DZHK) [81X3500122]; German
   Research Foundation (DFG) [HO 6446/1-1]; German Society of Cardiology
   (DGK) [DGK02/2019]
FX MH was supported by grants from the German Center for Cardiovascular
   Research (DZHK; grant#81X3500122), the German Research Foundation (DFG;
   grant#HO 6446/1-1), and the German Society of Cardiology (DGK;
   grant#DGK02/2019).
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NR 155
TC 18
Z9 19
U1 0
U2 12
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 2296-634X
J9 FRONT CELL DEV BIOL
JI Front. Cell. Dev. Biol.
PD MAR 11
PY 2021
VL 9
AR 644630
DI 10.3389/fcell.2021.644630
PG 17
WC Cell Biology; Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Developmental Biology
GA RB9HX
UT WOS:000632417000001
PM 33777949
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Kemp, PR
   Ellis, PD
   Smith, CWJ
AF Kemp, PR
   Ellis, PD
   Smith, CWJ
TI Visualization of alternative splicing in vivo
SO METHODS
LA English
DT Article
DE transgenic; mice; fluorescence; quantitative real-time PCR; alternative
   splicing
ID SMOOTH-MUSCLE-CELLS; TRANSGENIC MICE; REGULATORY ELEMENTS; PROMOTER
   REGIONS; GENE-EXPRESSION; BINDING-PROTEIN; TRANSCRIPTION;
   CARDIOMYOPATHY; ISOFORMS; DELETION
AB The analysis of sequences required for alternative splicing of mRNA has predominantly been performed using cell culture systems. However, the phenotype of cultured cells is almost invariably different from that of cells in the intact animal. It is therefore possible that there are significant differences in the regulation of specific splicing reactions in vivo compared to in cell culture. Here, we describe methods for the visualization and analysis of alternative splicing in vivo using transgenic mice. These methods allow for the analysis of the temporal and tissue-specific regulation of alternative splicing both visually and quantitatively. (c) 2005 Elsevier Inc. All rights reserved.
C1 Univ Cambridge, Dept Biochem, Cambridge CB2 1GA, England.
C3 University of Cambridge
RP Univ Cambridge, Dept Biochem, 80,Tennis Court Rd, Cambridge CB2 1GA, England.
EM cwjs1@cam.ac.uk
OI Kemp, Paul/0000-0001-8975-7293
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NR 33
TC 4
Z9 5
U1 0
U2 1
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 1046-2023
EI 1095-9130
J9 METHODS
JI Methods
PD DEC
PY 2005
VL 37
IS 4
BP 360
EP 367
DI 10.1016/j.ymeth.2005.07.017
PG 8
WC Biochemical Research Methods; Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 994ML
UT WOS:000234035800009
PM 16314265
DA 2025-04-10
ER

PT J
AU Liu, XM
   He, PY
   Zhang, Z
   Gong, PF
   Niu, YX
   Bao, Z
   Yang, YC
   Gan, L
   Muhuyati
AF Liu, Xuemei
   He, Pengyi
   Zhang, Ze
   Gong, Pengfei
   Niu, Yunxia
   Bao, Zhen
   Yang, Yuchun
   Gan, Lin
   Muhuyati
TI Candidate genes and their alternative splicing may be potential
   biomarkers of acute myocardial infarction: a study of mouse model
SO BMC CARDIOVASCULAR DISORDERS
LA English
DT Article
DE Acute myocardial infarction; RNA sequencing; Gene; Alternative splicing;
   Biomarkers
ID PERIOSTIN EXPRESSION; CARDIAC-HYPERTROPHY; KAPPA-B; PROTEIN; RATS;
   TRANSCRIPTOME; APOPTOSIS; REVEALS; FHL1
AB Background Acute myocardial infarction (AMI) is one of the leading causes of death in human being, and an effective diagnostic biomarker is still lacking. Whilst some gene association with AMI has been identified by RNA sequencing (RNA-seq), the relationship between alternative splicing and AMI is not clear. Methods We retrieved myocardial tissues within 24 h from mice with induced AMI and sham, and analysed the differentially expressed genes (DEGs) and differential alternative splicing genes (DASGs) by RNA-seq. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and protein interaction network analysis were performed on DEGs-DASGs-overlap genes. PCR was used to verify the expression levels of representative genes and alternative splicing in myocardial tissues of AMI and sham mice. Results 1367 DEGs were identified, including 242 up-regulated and 1125 down-regulated genes, among which there were 42 DASGs. GO analysis showed that the cellular component was primarily enriched in plasma membrane, cell membrane integrity and extracellular region. The molecular function was enriched in protein binding and metal ion binding. The biological process was primarily enriched in cell adhesion, immune system process and cell differentiation. KEGG analysis showed the enrichment was mainly in JAK-STAT and PI3K-AKT signalling pathway. Postn, Fhl1, and Fn1 were low-expressed while Postn alternative splicing was high-expressed in myocardial tissue of AMI mice, which was consistent with sequencing results. Conclusions The pathogenesis of AMI involves differentially expressed genes and differential alternative splicing. These differentially expressed genes and their alternative splicing, especially, Fhl1, Fn1 and Postn may become new biomarkers of AMI.
C1 [Liu, Xuemei; He, Pengyi; Zhang, Ze; Gong, Pengfei; Niu, Yunxia; Bao, Zhen; Yang, Yuchun; Muhuyati] Xinjiang Med Univ, Affiliated Hosp 1, Urumqi, Peoples R China.
   [Gan, Lin] Macquarie Univ, Fac Med & Hlth Sci, Sydney, NSW, Australia.
C3 Xinjiang Medical University; Macquarie University
RP Muhuyati (corresponding author), Xinjiang Med Univ, Affiliated Hosp 1, Urumqi, Peoples R China.
EM mhyt567@163.com
RI Gan, Lin/JCE-8154-2023; Bao, Zhen/MCX-4430-2025; Liu,
   Xuemei/AAE-1768-2020
FU Tianshan Innovation Team Plan of Xinjiang, China [2020D14012]
FX This work was supported by the Tianshan Innovation Team Plan of
   Xinjiang, China (Grant Numbers: 2020D14012) in administrative support,
   data analysis and the language editing.
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NR 44
TC 7
Z9 7
U1 1
U2 10
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1471-2261
J9 BMC CARDIOVASC DISOR
JI BMC Cardiovasc. Disord.
PD NOV 26
PY 2022
VL 22
IS 1
AR 505
DI 10.1186/s12872-022-02961-7
PG 12
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 6M3YX
UT WOS:000888808000003
PM 36435743
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Kalsotra, A
   Wang, K
   Li, PF
   Cooper, TA
AF Kalsotra, Auinash
   Wang, Kun
   Li, Pei-Feng
   Cooper, Thomas A.
TI MicroRNAs coordinate an alternative splicing network during mouse
   postnatal heart development
SO GENES & DEVELOPMENT
LA English
DT Article
DE Alternative splicing networks; CELFproteins; heart development; microRNA
ID 3' UNTRANSLATED REGIONS; MESSENGER-RNAS; EXPRESSION; DELETION; ADULT;
   CELLS; DICER
AB Alternative splicing transitions have been identified recently as a conserved component of vertebrate heart remodeling during postnatal development. Here we report that the targeted deletion of Dicer, specifically in adult mouse myocardium, reveals the role of microRNAs ( miRNAs) in regulating networks of postnatal splicing transitions and in maintaining adult splicing programs. We demonstrate a direct role for miR-23a/b in the dramatic postnatal down-regulation of CUGBP and ETR-3-like factor ( CELF) proteins that regulate nearly half of developmentally regulated splicing transitions in the heart. These findings define a hierarchy in which rapid postnatal up-regulation of specific miRNAs controls expression of alternative splicing regulators and the subsequent splicing transitions of their downstream targets.
C1 [Kalsotra, Auinash; Cooper, Thomas A.] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA.
   [Wang, Kun; Li, Pei-Feng] Chinese Acad Sci, Div Cardiovasc Res, Natl Key Lab Biomembrane & Membrane Biotechnol, Inst Zool, Beijing 100101, Peoples R China.
   [Cooper, Thomas A.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Chinese Academy of Sciences; Institute of
   Zoology, CAS; Baylor College of Medicine
RP Cooper, TA (corresponding author), Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA.
EM tcooper@bcm.edu
RI Liu, Haifeng/ABB-7769-2021; li, peifeng/AHE-6906-2022
OI Kalsotra, Auinash/0000-0002-1011-0006; li, peifeng/0000-0002-0969-9407
FU NIH [R01GM076493]; Myotonic Dystrophy Foundation; NNSFC [G30730045]
FX We thank Dr. A. Tarakhovsky for providing Dicer f/f mice, Dr. J.
   Molkentin for providing MCM mice and heart tissues from PKC alpha-Tg
   mice, and Dr. M. Schneider and Dr. X. Wehrens for providing heart
   tissues from CycT1/Gq alpha-BiTg mice and TAC operated mice,
   respectively. We are also grateful to Dr. W. Claycomb for providing HL-1
   cells, and to Dr. S. Anakk for help with luciferase assays. This project
   was funded by the NIH grant R01GM076493 to T. A. C., Myotonic Dystrophy
   Foundation Postdoctoral award to A. K., and NNSFC grant G30730045 to P.
   F. L.
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NR 28
TC 107
Z9 119
U1 0
U2 14
PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
PI COLD SPRING HARBOR
PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA
SN 0890-9369
EI 1549-5477
J9 GENE DEV
JI Genes Dev.
PD APR 1
PY 2010
VL 24
IS 7
BP 653
EP 658
DI 10.1101/gad.1894310
PG 6
WC Cell Biology; Developmental Biology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Developmental Biology; Genetics & Heredity
GA 577PD
UT WOS:000276235400004
PM 20299448
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Du, HZ
   Zhao, YR
   Wen, JP
   Dai, BB
   Hu, G
   Zhou, YF
   Yin, ZW
   Ding, N
   Li, HP
   Fan, JH
   Nie, X
   Wang, F
   Liu, Q
   Wen, Z
   Xu, G
   Wang, DW
   Chen, C
AF Du, Hengzhi
   Zhao, Yanru
   Wen, Jianpei
   Dai, Beibei
   Hu, Guo
   Zhou, Yufei
   Yin, Zhongwei
   Ding, Nan
   Li, Huaping
   Fan, Jiahui
   Nie, Xiang
   Wang, Feng
   Liu, Qian
   Wen, Zheng
   Xu, Gang
   Wang, Dao Wen
   Chen, Chen
TI LncRNA DCRT Protects Against Dilated Cardiomyopathy by Preventing NDUFS2
   Alternative Splicing by Binding to PTBP1
SO CIRCULATION
LA English
DT Article
DE alternative splicing; cardiomyopathy, dilated; mitochondria
ID LONG NONCODING RNAS; COENZYME Q(10); HEART-FAILURE; FIBROBLAST; DISEASE;
   DYSFUNCTION; STATEMENT
AB BACKGROUND:Dilated cardiomyopathy is characterized by left ventricular dilation and continuous systolic dysfunction. Mitochondrial impairment is critical in dilated cardiomyopathy; however, the underlying mechanisms remain unclear. Here, we explored the cardioprotective role of a heart-enriched long noncoding RNA, the dilated cardiomyopathy repressive transcript (DCRT), in maintaining mitochondrial function.METHODS:The DCRT knockout (DCRT-/-) mice and DCRT knockout cells were developed using CRISPR-Cas9 technology. Cardiac-specific DCRT transgenic mice were generated using alpha-myosin heavy chain promoter. Chromatin coimmunoprecipitation, RNA immunoprecipitation, Western blot, and isoform sequencing were performed to investigate the underlying mechanisms.RESULTS:We found that the long noncoding RNA DCRT was highly enriched in the normal heart tissues and that its expression was significantly downregulated in the myocardium of patients with dilated cardiomyopathy. DCRT-/- mice spontaneously developed cardiac dysfunction and enlargement with mitochondrial impairment. DCRT transgene or overexpression with the recombinant adeno-associated virus system in mice attenuated cardiac dysfunction induced by transverse aortic constriction treatment. Mechanistically, DCRT inhibited the third exon skipping of NDUFS2 (NADH dehydrogenase ubiquinone iron-sulfur protein 2) by directly binding to PTBP1 (polypyrimidine tract binding protein 1) in the nucleus of cardiomyocytes. Skipping of the third exon of NDUFS2 induced mitochondrial dysfunction by competitively inhibiting mitochondrial complex I activity and binding to PRDX5 (peroxiredoxin 5) and suppressing its antioxidant activity. Furthermore, coenzyme Q10 partially alleviated mitochondrial dysfunction in cardiomyocytes caused by DCRT reduction.CONCLUSIONS:Our study revealed that the loss of DCRT contributed to PTBP1-mediated exon skipping of NDUFS2, thereby inducing cardiac mitochondrial dysfunction during dilated cardiomyopathy development, which could be partially treated with coenzyme Q10 supplementation.
C1 [Xu, Gang] Huazhong Univ Sci & Technol, Div Cardiol, Wuhan, Peoples R China.
   [Xu, Gang] Huazhong Univ Sci & Technol, Div Nephrol, Wuhan, Peoples R China.
   [Liu, Qian] Huazhong Univ Sci & Technol, Tongji Hosp, Wuhan, Peoples R China.
   [Liu, Qian] Huazhong Univ Sci & Technol, Dept Forens Med, Wuhan, Peoples R China.
   [Du, Hengzhi; Wen, Jianpei; Dai, Beibei; Hu, Guo; Zhou, Yufei; Yin, Zhongwei; Ding, Nan; Li, Huaping; Fan, Jiahui; Nie, Xiang; Wang, Feng; Wen, Zheng; Wang, Dao Wen; Chen, Chen] Huazhong Univ Sci & Technol, Tongji Med Coll, Wuhan, Peoples R China.
   [Du, Hengzhi; Zhao, Yanru; Wen, Jianpei; Dai, Beibei; Hu, Guo; Zhou, Yufei; Yin, Zhongwei; Ding, Nan; Li, Huaping; Fan, Jiahui; Nie, Xiang; Wang, Feng; Wen, Zheng; Wang, Dao Wen; Chen, Chen] Hubei Key Lab Genet & Mol Mech Cardiol Disorders, Wuhan, Peoples R China.
C3 Huazhong University of Science & Technology; Huazhong University of
   Science & Technology; Huazhong University of Science & Technology;
   Huazhong University of Science & Technology; Huazhong University of
   Science & Technology
RP Chen, C (corresponding author), Huazhong Univ Sci & Technol, Div Cardiol, Internal Med, 1095 Jiefang Ave, Wuhan 430030, Peoples R China.
EM duhengzhi_tongji@163.com; zyrecho@163.com; wenzheng_85@126.com;
   mingche1992@163.com; huguo0815@163.com; 15207176990@163.com;
   mind560@126.com; ding_ding1112@163.com; lhp@tjh.tjmu.edu.cn;
   342750147@qq.com; niexiang555@163.com; dwwang@tjh.tjmu.edu.cn;
   8674910@qq.com; wenzheng_85@126.com; xugang@tjh.tjmu.edu.cn;
   dwwang@tjh.tjmu.edu.cn; chenchen@tjh.tjmu.edu.cn
RI Wang, Feng/F-2653-2015; Wang, Yiru/JMB-2281-2023; du,
   hengzhi/IWM-7319-2023; Liu, Qian/L-2237-2017
OI hengzhi, du/0009-0002-9242-8233; Wang, Dao Wen/0000-0002-9774-3980
FU National Natural Science Foundation of China [U22A20266, 82270363,
   81822002, 81630010, 81790624, 82000387]; Natural Science Foundation of
   Hubei Province [2020CFA016]; Fundamental Research Funds for the Central
   Universities [2019kfyXM-BZ035]
FX This work was supported by grants from the National Natural Science
   Foundation of China (U22A20266, 82270363, 81822002, 81630010, 81790624,
   and 82000387), the Natural Science Foundation of Hubei Province
   (2020CFA016), and the Fundamental Research Funds for the Central
   Universities (2019kfyXM-BZ035). The funders had no role in the study
   design, data collection and analysis, manuscript preparation, or
   publication decisions.
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TC 7
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U1 20
U2 22
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7322
EI 1524-4539
J9 CIRCULATION
JI Circulation
PD SEP 24
PY 2024
VL 150
IS 13
BP 1030
EP 1049
DI 10.1161/CIRCULATIONAHA.123.067861
PG 20
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA L2G2I
UT WOS:001348949400004
PM 38841852
DA 2025-04-10
ER

PT J
AU Tharp, CA
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AF Tharp, Charles A.
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   Taylor, Matthew R. G.
   Mestroni, Luisa
TI The Giant Protein Titin's Role in Cardiomyopathy: Genetic,
   Transcriptional, and Post-translational Modifications of TTN and Their
   Contribution to Cardiac Disease
SO FRONTIERS IN PHYSIOLOGY
LA English
DT Review
DE titin; dilated cardiomyopathy; sarcomere; truncation variants;
   proportion-spliced-in; RBM20; phosphorylation; phosphosites
ID DILATED CARDIOMYOPATHY; PASSIVE STIFFNESS; MUTATIONS; RBM20;
   PHOSPHORYLATION; MUSCLE; ACTIVATION; PHENOTYPE; MECHANISM; STATEMENT
AB Dilated cardiomyopathy (DCM) is a leading cause of heart failure, sudden cardiac death and heart transplant. DCM is inherited in approximately 50% of cases, in which the most frequent genetic defects are truncation variants of the titin gene (TTNtv). TTN encodes titin, which is the largest protein in the body and is an essential component of the sarcomere. Titin serves as a biological spring, spanning half of the sarcomere and connecting the Z-disk to the M-line, with scaffold and signaling functions. Truncations of titin are believed to lead to either haploinsufficiency and loss-of-function, or to a "poison peptide" effect. However, other titin mechanisms are postulated to influence cardiac function including post-translational modifications, in particular changes in titin phosphorylation that alters the stiffness of the protein, and diversity of alternative splicing that generates different titin isoforms. In this article, we review the role of TTN mutations in development of DCM, how differential expression of titin isoforms relate to DCM pathophysiology, and discuss how post-translational modifications of titin can affect cardiomyocyte function. Current research efforts aim to elucidate the contribution of titin to myofibril assembly, stability, and signal transduction, and how mutant titin leads to cardiac dysfunction and human disease. Future research will need to translate this knowledge toward novel therapeutic approaches that can modulate titin transcriptional and post-translational defects to treat DCM and heart failure.
C1 [Tharp, Charles A.; Haywood, Mary E.; Taylor, Matthew R. G.; Mestroni, Luisa] Univ Colorado, Adult Med Genet Program, Anschutz Med Campus, Aurora, CO 80045 USA.
   [Tharp, Charles A.; Haywood, Mary E.; Taylor, Matthew R. G.; Mestroni, Luisa] Univ Colorado, Cardiovasc Inst, Anschutz Med Campus, Aurora, CO 80045 USA.
   [Sbaizero, Orfeo] Univ Trieste, Dept Engn & Architecture, Trieste, Italy.
C3 University of Colorado System; University of Colorado Anschutz Medical
   Campus; University of Colorado System; University of Colorado Anschutz
   Medical Campus; University of Trieste
RP Mestroni, L (corresponding author), Univ Colorado, Adult Med Genet Program, Anschutz Med Campus, Aurora, CO 80045 USA.; Mestroni, L (corresponding author), Univ Colorado, Cardiovasc Inst, Anschutz Med Campus, Aurora, CO 80045 USA.
EM luisa.mestroni@cuanschutz.edu
RI Taylor, Matthew/HMP-1929-2023
OI Tharp, Charles/0000-0002-0653-4105; Mestroni, Luisa/0000-0003-1116-2286;
   Taylor, Matthew/0000-0001-9043-0810
FU National Institutes of Health [R01 HL69071, HL116906, AHA17GRNT33670495,
   1K23HI067915, R01HL109209]; TransAtlantic Network of Excellence grant
   from the Leducq Foundation [14-CVD 03]
FX This work was supported by the National Institutes of Health grants R01
   HL69071, HL116906, and AHA17GRNT33670495 (to LM); National Institutes of
   Health grants 1K23HI067915 and R01HL109209 (toMT), and in part by the
   TransAtlantic Network of Excellence 14-CVD 03 grant from the Leducq
   Foundation (to OS, MT, and LM).
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NR 62
TC 93
Z9 102
U1 0
U2 7
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 1664-042X
J9 FRONT PHYSIOL
JI Front. Physiol.
PD NOV 28
PY 2019
VL 10
AR 1436
DI 10.3389/fphys.2019.01436
PG 8
WC Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Physiology
GA JW0IH
UT WOS:000502742600001
PM 31849696
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Dirksen, WP
   Mohamed, SA
   Fisher, SA
AF Dirksen, WP
   Mohamed, SA
   Fisher, SA
TI Splicing of a myosin phosphatase targeting subunit 1 alternative exon is
   regulated by intronic cis-elements and a novel bipartite exonic
   enhancer/silencer element
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID PRE-MESSENGER-RNA; IMMUNODEFICIENCY-VIRUS TYPE-1; SECONDARY STRUCTURE;
   SITE SELECTION; IN-VIVO; MUSCLE; ENHANCER; GENE; IDENTIFICATION;
   3'-SPLICE-SITE
AB Isoforms of the smooth muscle myosin phosphatase targeting subunit 1 (MYPT1) are generated by cassette-type alternative splicing of exons. Tissue-specific expression of these isoforms is thought to determine smooth muscle-relaxant properties and unique responses to signaling pathways. We used mini-gene deletion/mutation constructs to identify cis regulators of splicing of the chicken MYPT1 central alternative exon. Comparisons of alternative exon splicing were made between smooth muscle cells of the fast-phasic contractile phenotype (gizzard), in which the central alternative exon is skipped, and slow tonic contractile phenotype (aorta), in which the alternative exon is included. We demonstrate that splicing of the alternative exon requires a cis-enhancer complex in the vicinity of the alternative exon 5'-splice site. This complex consists of two UCUU motifs in an intronic U-rich sequence (putative PTB (polypyrimidine tract binding) or T cell inhibitor of apoptosis-1 binding sites), an intronic 67-nucleotide enhancer that has similarities with the cardiac Troponin T MSE3 enhancer, and a potentially novel exonic splicing enhancer. The exonic enhancer contains the palindromic sequence UCCUACAUCCU present in many other transcripts where alternative splicing of exons occurs, suggesting that it may be more broadly active. The exonic enhancer is adjacent to a potentially novel exonic silencer element that contains a 13-nucleotide imperfect palindromic sequence. This silencer, in conjunction with a distal intronic silencer, is proposed to mediate the silencing of splicing of the MYPT1 central alternative exon in the fast phasic smooth muscle phenotype.
C1 Case Western Reserve Univ, Sch Med, Dept Med Cardiol, Cleveland, OH 44106 USA.
   Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA.
C3 University System of Ohio; Case Western Reserve University; University
   System of Ohio; Case Western Reserve University
RP Fisher, SA (corresponding author), 422 Biomed Res Bldg,2109 Adelbert Rd, Cleveland, OH 44106 USA.
RI Mohamed, Salah/AAF-8171-2021
FU NHLBI NIH HHS [K08HL-03275, T32-HL07887, R01 HL-66171] Funding Source:
   Medline
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NR 44
TC 27
Z9 30
U1 0
U2 3
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
SN 0021-9258
J9 J BIOL CHEM
JI J. Biol. Chem.
PD MAR 14
PY 2003
VL 278
IS 11
BP 9722
EP 9732
DI 10.1074/jbc.M207969200
PG 11
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 654YF
UT WOS:000181524000112
PM 12509424
OA hybrid
DA 2025-04-10
ER

PT J
AU Striessnig, J
AF Striessnig, J
TI Pharmacology, structure and function of cardiac L-type Ca<SUP>2+</SUP>
   channels
SO CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
LA English
DT Review
DE Ca2+ channels; heart; biochemistry; modulation
ID PROTEIN-KINASE-C; DEPENDENT CALCIUM-CHANNEL; NITRIC-OXIDE SYNTHASE;
   HUMAN ATRIAL MYOCYTES; OXYGEN-FREE-RADICALS; AFFINITY DIHYDROPYRIDINE
   BINDING; BETA-SUBUNIT HETEROGENEITY; SMOOTH-MUSCLE CELLS; MOLECULAR
   DETERMINANTS; ALPHA(1C) SUBUNIT
AB Voltage-gated L-type Ca2+ channels control depolarization-induced Ca2+ entry in different electrically excitable cells, including mammalian heart. Important molecular and functional details providing new insight into L-type channel structure and modulation are reviewed in this article. This includes the identification of amino acid residues responsible for drug binding, the role of accessory subunits and alternative splicing for fine-tuning channel activity and modulation by protein kinases (A, C, tyrosine kinases), cGMP-dependent pathways, calmodulin and Ca2+. Alterations in Ca2+ channel activity under pathological conditions such as in heart failure or during ischemia could provide new clues for the development of drugs to treat cardiovascular diseases. Copyright (C) 1999 S. Karger AG, Basel.
C1 Inst Biochem Pharmacol, A-6020 Innsbruck, Austria.
RP Inst Biochem Pharmacol, Peter Mayrstr 1, A-6020 Innsbruck, Austria.
EM joerg.striessnig@uibk.ac.at
RI Striessnig, Joerg/S-9334-2017
OI Striessnig, Joerg/0000-0002-9406-7120
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NR 158
TC 147
Z9 174
U1 0
U2 13
PU KARGER
PI BASEL
PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND
SN 1015-8987
EI 1421-9778
J9 CELL PHYSIOL BIOCHEM
JI Cell. Physiol. Biochem.
PD JUL-OCT
PY 1999
VL 9
IS 4-5
BP 242
EP 269
DI 10.1159/000016320
PG 28
WC Cell Biology; Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Physiology
GA 262GL
UT WOS:000084057500007
PM 10575201
DA 2025-04-10
ER

PT J
AU Singh, S
   Gaur, A
   Sharma, RK
   Kumari, R
   Prakash, S
   Kumari, S
   Chaudhary, AD
   Prasun, P
   Pant, P
   Hunkler, H
   Thum, T
   Jagavelu, K
   Bharati, P
   Hanif, K
   Chitkara, P
   Kumar, S
   Mitra, K
   Gupta, SK
AF Singh, Sandhya
   Gaur, Aakash
   Sharma, Rakesh Kumar
   Kumari, Renu
   Prakash, Shakti
   Kumari, Sunaina
   Chaudhary, Ayushi Devendrasingh
   Prasun, Pankaj
   Pant, Priyanka
   Hunkler, Hannah
   Thum, Thomas
   Jagavelu, Kumaravelu
   Bharati, Pragya
   Hanif, Kashif
   Chitkara, Pragya
   Kumar, Shailesh
   Mitra, Kalyan
   Gupta, Shashi Kumar
TI Musashi-2 causes cardiac hypertrophy and heart failure by inducing
   mitochondrial dysfunction through destabilizing Cluh and
   Smyd1 mRNA
SO BASIC RESEARCH IN CARDIOLOGY
LA English
DT Article
DE RNA-binding protein; MSI2; Cardiac hypertrophy; Heart failure;
   Mitochondrial dysfunction
ID EXPRESSION; BIOGENESIS; TARGETS; CELLS
AB Regulation of RNA stability and translation by RNA-binding proteins (RBPs) is a crucial process altering gene expression. Musashi family of RBPs comprising Msi1 and Msi2 is known to control RNA stability and translation. However, despite the presence of MSI2 in the heart, its function remains largely unknown. Here, we aim to explore the cardiac functions of MSI2. We confirmed the presence of MSI2 in the adult mouse, rat heart, and neonatal rat cardiomyocytes. Furthermore, Msi2 was significantly enriched in the heart cardiomyocyte fraction. Next, using RNA-seq data and isoform-specific PCR primers, we identified Msi2 isoforms 1, 4, and 5, and two novel putative isoforms labeled as Msi2 6 and 7 to be expressed in the heart. Overexpression of Msi2 isoforms led to cardiac hypertrophy in cultured cardiomyocytes. Additionally, Msi2 exhibited a significant increase in a pressure-overload model of cardiac hypertrophy. We selected isoforms 4 and 7 to validate the hypertrophic effects due to their unique alternative splicing patterns. AAV9-mediated overexpression of Msi2 isoforms 4 and 7 in murine hearts led to cardiac hypertrophy, dilation, heart failure, and eventually early death, confirming a pathological function for Msi2. Using global proteomics, gene ontology, transmission electron microscopy, seahorse, and transmembrane potential measurement assays, increased MSI2 was found to cause mitochondrial dysfunction in the heart. Mechanistically, we identified Cluh and Smyd1 as direct downstream targets of Msi2. Overexpression of Cluh and Smyd1 inhibited Msi2-induced cardiac malfunction and mitochondrial dysfunction. Collectively, we show that Msi2 induces hypertrophy, mitochondrial dysfunction, and heart failure.
C1 [Singh, Sandhya; Gaur, Aakash; Kumari, Renu; Prakash, Shakti; Kumari, Sunaina; Chaudhary, Ayushi Devendrasingh; Prasun, Pankaj; Jagavelu, Kumaravelu; Bharati, Pragya; Hanif, Kashif; Gupta, Shashi Kumar] CSIR Cent Drug Res Inst, Pharmacol Div, Sect 10, Lucknow 226031, India.
   [Gaur, Aakash; Sharma, Rakesh Kumar; Kumari, Renu; Prakash, Shakti; Chaudhary, Ayushi Devendrasingh; Pant, Priyanka; Jagavelu, Kumaravelu; Bharati, Pragya; Hanif, Kashif; Mitra, Kalyan; Gupta, Shashi Kumar] Acad Sci & Innovat Res AcSIR, Ghaziabad, India.
   [Sharma, Rakesh Kumar; Mitra, Kalyan] CSIR Cent Drug Res Inst, Div Sophisticated Analyt Instrument Facil & Res, Lucknow, India.
   [Pant, Priyanka] CSIR Ctr Cellular & Mol Biol, Hyderabad, India.
   [Hunkler, Hannah; Thum, Thomas] Hannover Med Sch, Inst Mol & Translat Therapeut Strategies, Hannover, Germany.
   [Thum, Thomas] Fraunhofer Inst Toxicol & Expt Med, Hannover, Germany.
   [Chitkara, Pragya; Kumar, Shailesh] Natl Inst Plant Genome Res, New Delhi, India.
C3 Council of Scientific & Industrial Research (CSIR) - India; CSIR -
   Central Drug Research Institute (CDRI); Academy of Scientific &
   Innovative Research (AcSIR); Council of Scientific & Industrial Research
   (CSIR) - India; CSIR - Central Drug Research Institute (CDRI); Council
   of Scientific & Industrial Research (CSIR) - India; CSIR - Centre for
   Cellular & Molecular Biology (CCMB); Hannover Medical School; Fraunhofer
   Gesellschaft; Fraunhofer Germany; Fraunhofer Toxicology & Experimental
   Medicine; Department of Biotechnology (DBT) India; National Institute of
   Plant Genome Research (NIPGR)
RP Gupta, SK (corresponding author), CSIR Cent Drug Res Inst, Pharmacol Div, Sect 10, Lucknow 226031, India.; Gupta, SK (corresponding author), Acad Sci & Innovat Res AcSIR, Ghaziabad, India.
EM shashik.gupta1@cdri.res.in
RI Thum, Thomas/ABD-3487-2022; Sharma, Anil/KYQ-8842-2024; Kumar,
   Shailesh/M-1876-2015
OI Mitra, Dr. Kalyan/0000-0002-7252-1716
FU We want to thank Dr. Rajdeep Guha, Head of Animal Facility, CSIR-CDRI,
   for his help with animal experiments. We want to thank Director
   CSIR-CDRI, Dr. Manoj Kumar Barthwal, Dr. Amit Lahiri, Dr. Chandra
   Prakash Pandey, Dr. Hobby Aggarwal, Dr. Jayanta Sarkar, [10680];
   Indraprastha Institute of Information Technology, Delhi, India
FX We want to thank Dr. Rajdeep Guha, Head of Animal Facility, CSIR-CDRI,
   for his help with animal experiments. We want to thank Director
   CSIR-CDRI, Dr. Manoj Kumar Barthwal, Dr. Amit Lahiri, Dr. Chandra
   Prakash Pandey, Dr. Hobby Aggarwal, Dr. Jayanta Sarkar, and Mr. Ajay
   Singh from CSIR-CDRI, for their help with the instruments and training.
   We acknowledge the FACS facility, CSIR-CDRI. We acknowledge the valuable
   suggestions of Dr. Regalla Kumarswamy, CSIR- Centre for Cellular and
   Molecular Biology, Hyderabad, India, Dr. Marisol Ruiz- Meana,
   Valld'Hebron Hospital Universitari, Barcelona, Spain, and Dr. Gaurav
   Ahuja, Indraprastha Institute of Information Technology, Delhi, India.
   This manuscript has CSIR-CDRI communication number 10680.
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NR 44
TC 4
Z9 4
U1 2
U2 6
PU SPRINGER HEIDELBERG
PI HEIDELBERG
PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY
SN 0300-8428
EI 1435-1803
J9 BASIC RES CARDIOL
JI Basic Res. Cardiol.
PD NOV 3
PY 2023
VL 118
IS 1
AR 46
DI 10.1007/s00395-023-01016-y
PG 25
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA X3BY7
UT WOS:001097252600001
PM 37923788
OA Green Submitted
DA 2025-04-10
ER

PT J
AU Giudice, J
   Xia, Z
   Li, W
   Cooper, TA
AF Giudice, Jimena
   Xia, Zheng
   Li, Wei
   Cooper, Thomas A.
TI Neonatal cardiac dysfunction and transcriptome changes caused by the
   absence of Celf1
SO SCIENTIFIC REPORTS
LA English
DT Article
ID GU-RICH ELEMENTS; RNA-BINDING PROTEINS; ELAV-LIKE FAMILY;
   GENE-EXPRESSION; CUGBP1; INSIGHTS; QUANTIFICATION; FETAL; DECAY
AB The RNA binding protein Celf1 regulates alternative splicing in the nucleus and mRNA stability and translation in the cytoplasm. Celf1 is strongly down-regulated during mouse postnatal heart development. Its re-induction in adults induced severe heart failure and reversion to fetal splicing and gene expression patterns. However, the impact of Celf1 depletion on cardiac transcriptional and posttranscriptional dynamics in neonates has not been addressed. We found that homozygous Celf1 knock-out neonates exhibited cardiac dysfunction not observed in older homozygous animals, although homozygous mice are smaller than wild type littermates throughout development. RNA-sequencing of mRNA from homozygous neonatal hearts identified a network of cell cycle genes significantly upregulated and down-regulation of ion transport and circadian genes. Cell cycle genes are enriched for Celf1 binding sites supporting a regulatory role in mRNA stability of these transcripts. We also identified a cardiac splicing network coordinated by Celf1 depletion. Target events contain multiple Celf1 binding sites and enrichment in GU-rich motifs. Identification of direct Celf1 targets will advance our knowledge in the mechanisms behind developmental networks regulated by Celf1 and diseases where Celf1 is misregulated.
C1 [Giudice, Jimena; Cooper, Thomas A.] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA.
   [Giudice, Jimena] Univ North Carolina Chapel Hill, Sch Med, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA.
   [Xia, Zheng; Li, Wei; Cooper, Thomas A.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
   [Xia, Zheng; Li, Wei] Baylor Coll Med, Dan L Duncan Canc Ctr, Div Biostat, Houston, TX 77030 USA.
   [Cooper, Thomas A.] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA.
C3 Baylor College of Medicine; University of North Carolina School of
   Medicine; University of North Carolina; University of North Carolina
   Chapel Hill; Baylor College of Medicine; Baylor College of Medicine;
   Baylor College of Medicine
RP Cooper, TA (corresponding author), Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA.; Cooper, TA (corresponding author), Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.; Cooper, TA (corresponding author), Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA.
EM cooper@bcm.edu
RI Li, Wei/AFW-2599-2022; Xia, Zheng/AAC-5360-2022; Giudice,
   Jimena/N-5156-2016; Xia, Zheng/F-6561-2014
OI Giudice, Jimena/0000-0002-3330-7784; Xia, Zheng/0000-0003-3364-8324
FU National Institutes of Health (NIH) [R01AR045653, R01HL045565,
   R01AR060733, R01HG007538, R01CA193466]; American Heart Association
   Postdoctoral Fellowship [14POST20270001]; Pew Charitable Trusts
   Postdoctoral Fellowship [2933]; University of North Carolina at Chapel
   Hill; Mouse Phenotyping Core at Baylor College of Medicine; NIH [U54
   HG006348]; American Heart Association (AHA) [14POST20270001] Funding
   Source: American Heart Association (AHA); National Cancer Institute
   [R01CA193466] Funding Source: NIH RePORTER
FX We thank Luc Paillard for providing Celf1-/+ mice. We thank Dr. Xander
   Wehrens (Baylor College of Medicine) for helping in ECG and
   echocardiogram result interpretation. This project has been supported by
   the following funding sources: National Institutes of Health (NIH)
   grants R01AR045653 (TAC), R01HL045565 (TAC), R01AR060733 (TAC),
   R01HG007538 (WL) R01CA193466 (WL), the American Heart Association
   Postdoctoral Fellowship 14POST20270001 (JG), the Pew Charitable Trusts
   Postdoctoral Fellowship #2933 (JG), start up funds from The University
   of North Carolina at Chapel Hill (JG). RNA-seq was performed in the
   Genomic and RNA Profiling Core (Baylor College of Medicine) with the
   assistance of the Core Director (Dr. Lisa D. White). This project was
   also supported by the Mouse Phenotyping Core at Baylor College of
   Medicine with funding from the NIH (U54 HG006348).
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NR 45
TC 17
Z9 21
U1 0
U2 9
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD OCT 19
PY 2016
VL 6
AR 35550
DI 10.1038/srep35550
PG 13
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA DZ8KZ
UT WOS:000386120600001
PM 27759042
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Lorenzi, P
   Sangalli, A
   Fochi, S
   Dal Molin, A
   Malerba, G
   Zipeto, D
   Romanelli, MG
AF Lorenzi, P.
   Sangalli, A.
   Fochi, S.
   Dal Molin, A.
   Malerba, G.
   Zipeto, D.
   Romanelli, M. G.
TI RNA-binding proteins RBM20 and PTBP1 regulate the alternative splicing
   of FHOD3
SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
LA English
DT Article
DE RBM20; FHOD3; Alternative splicing; PTBP1; RRM; Sarcomere
ID SARCOMERIC GENES; HEART; CARDIOMYOPATHY; IDENTIFICATION; MUTATIONS;
   INSIGHTS; PHOSPHORYLATION; CARDIOGENESIS; ORGANIZATION; EXPRESSION
AB Regulation of alternative splicing events is an essential step required for the expression of functional cytoskeleton and sarcomere proteins in cardiomyocytes. About 3% of idiopathic dilated cardiomyopathy cases present mutations in the RNA binding protein RBM20, a tissue specific regulator of alternative splicing. Transcripts expressed preferentially in skeletal and cardiac muscle, including TTN, CAMK2D, LDB3, LMO7, PDLIM3, RTN4, and RYR2, are RBM20-dependent splice variants. In the present study, we investigated the RBM20 involvement in post-transcriptional regulation of splicing variants expressed by Formin homology 2 domain containing 3 (FHOD3) gene. FHOD3 is a sarcomeric protein highly expressed in the cardiac tissue and required for the assembly of the contractile apparatus. Recently, FHOD3 mutations have been found associated with heart diseases. We identified novel FHOD3 splicing variants differentially expressed in human tissues and provided evidences that FHOD3 transcripts are specific RBM20 and PTBP1 targets. Furthermore, we demonstrated that the expression of RBM20 and PTBP1 promoted the alternative shift, from inclusion to exclusion, of selected FHOD3 exons. These results indicate that RBM20 and PTBP1 play a role in the actin filament functional organization mediated by FHOD3 isoforms and suggest their possible involvement in heart diseases.
C1 [Lorenzi, P.; Sangalli, A.; Fochi, S.; Dal Molin, A.; Malerba, G.; Zipeto, D.; Romanelli, M. G.] Univ Verona, Sect Biol & Genet, Dept Neurosci Biomed & Movement Sci, Str Grazie 8, I-37134 Verona, Italy.
C3 University of Verona
RP Romanelli, MG (corresponding author), Univ Verona, Sect Biol & Genet, Dept Neurosci Biomed & Movement Sci, Str Grazie 8, I-37134 Verona, Italy.
EM pamela.lorenzi@univr.it; antonella.sangalli@univr.it;
   stefania.fochi@univr.it; anna.dalmolin.1@gmail.com;
   giovanni.malerba@univr.it; donato.zipeto@univr.it;
   mariagrazia.romanelli@univr.it
RI Zipeto, Donato/P-3041-2019; Malerba, Giovanni/T-3278-2019; Romanelli,
   Maria/AAS-7946-2020
OI Zipeto, Donato/0000-0002-2168-4144; Dal Molin, Anna/0000-0003-1590-0303;
   sangalli, antonella/0000-0001-6359-0149; /0000-0002-7360-1195
FU University of Verona, Italy (FUR Romanelli)
FX This study was supported by grants from University of Verona, Italy (FUR
   Romanelli).
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NR 76
TC 18
Z9 19
U1 1
U2 7
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 1357-2725
EI 1878-5875
J9 INT J BIOCHEM CELL B
JI Int. J. Biochem. Cell Biol.
PD JAN
PY 2019
VL 106
BP 74
EP 83
DI 10.1016/j.biocel.2018.11.009
PG 10
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA HI1RA
UT WOS:000456221500009
PM 30468920
DA 2025-04-10
ER

PT J
AU Ryan, KJ
   Cooper, TA
AF Ryan, KJ
   Cooper, TA
TI Muscle-specific splicing enhancers regulate inclusion of the cardiac
   troponin T alternative exon in embryonic skeletal muscle
SO MOLECULAR AND CELLULAR BIOLOGY
LA English
DT Article
ID PRE-MESSENGER-RNA; COMPLETE NUCLEOTIDE-SEQUENCE; DROSOPHILA DOUBLESEX
   GENE; PREMESSENGER RNA; ADULT ISOFORMS; SITE SELECTION; SR PROTEINS;
   INVITRO; ELEMENTS; DIFFERENTIATION
AB The alternative exon 5 of the striated muscle-specific cardiac troponin T (cTNT) gene is included in mRNA from embryonic skeletal and cardiac muscle and excluded in mRNA from the adult, The embryonic splicing pattern is reproduced in primary skeletal muscle cultures for both the endogenous gene and transiently transfected minigenes, whereas in nonmuscle cell lines, minigenes express a default exon skipping pattern, Using this experimental system, we previously showed that a purine-rich splicing enhancer in the alternative exon functions as a constitutive splicing element but not as a target for factors regulating cell-specific splicing, In this study, we identify four intron elements, one located upstream and three located downstream of the alternative exon, which act in a positive manner to mediate the embryonic splicing pattern of exon inclusion. Synergistic interactions between at least three of the four elements are necessary and sufficient to regulate splicing of a heterologous alternative exon and heterologous splice sites, Mutations in these elements prevent activation of exon inclusion in muscle cells but do not affect the default level of exon inclusion in nonmuscle cells. Therefore, these elements function as muscle specific splicing enhancers (MSEs) and are the first muscle-specific positive-acting splicing elements to be described. One MSE located downstream from the alternative exon is conserved in the rat and chicken cTNT genes, A related sequence is found in a third muscle-specific gene, that encoding skeletal troponin T, downstream from an alternative exon with a developmental pattern of alternative splicing similar to that of rat and chicken cTNT. Therefore, the MSEs identified in the cTNT gene may play a role in developmentally regulated alternative splicing in a number of different genes.
C1 BAYLOR COLL MED,DEPT PATHOL,HOUSTON,TX 77030.
   BAYLOR COLL MED,DEPT CELL BIOL,HOUSTON,TX 77030.
C3 Baylor College of Medicine; Baylor College of Medicine
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NR 64
TC 86
Z9 94
U1 0
U2 6
PU AMER SOC MICROBIOLOGY
PI WASHINGTON
PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171
SN 0270-7306
J9 MOL CELL BIOL
JI Mol. Cell. Biol.
PD AUG
PY 1996
VL 16
IS 8
BP 4014
EP 4023
PG 10
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA UY025
UT WOS:A1996UY02500004
PM 8754799
DA 2025-04-10
ER

PT J
AU Ladd, AN
   Stenberg, MG
   Swanson, MS
   Cooper, TA
AF Ladd, AN
   Stenberg, MG
   Swanson, MS
   Cooper, TA
TI Dynamic balance between activation and repression regulates pre-mRNA
   alternative splicing during heart development
SO DEVELOPMENTAL DYNAMICS
LA English
DT Article
DE CUG-BP; ETR-3; CELF proteins; PTB; MBNL; alternative splicing;
   posttranscriptional regulation; heart development
ID TRACT BINDING-PROTEIN; CARDIAC TROPONIN-T; MYOTONIC-DYSTROPHY;
   SKELETAL-MUSCLE; CANDIDATE GENE; ADULT ISOFORMS; CELF FAMILY;
   EXPRESSION; NUCLEAR; CUGBP2
AB Cardiac troponin T (cTNT) exon 5 splicing is developmentally regulated such that it is included in embryonic but not adult heart. CUG-BP and ETR-3-like factor (CELF) proteins promote exon inclusion, whereas polypyrimidine tract binding protein (PTB) and muscleblind-like (MBNL) proteins repress inclusion. In this study, we addressed what happens to these regulatory proteins during heart development to shift the regulatory balance of cTNT alternative splicing. Using dominant-negative proteins, we found that both CELF and PTB activities are required for appropriate splicing in cardiomyocytes. Two CELF proteins, CUG-BP and ETR-3, are nuclear and cytoplasmic in embryonic heart but are down-regulated in adult heart concomitant with loss of exon inclusion. In contrast, PTB and MBNL1 are expressed throughout heart development. The patterns of cTNT splicing and expression of its regulatory factors are conserved between mouse and chicken. Thus, alternative splicing is determined by a balance between positive and negative regulation, and modulation of expression levels of auxiliary splicing regulators may drive developmental splicing changes. ETR-3 and CUG-BP proteins are also down-regulated in other tissues during development, suggesting that CELF proteins play a broad role in developmental splicing regulation. (c) 2005 Wiley-Liss, Inc.
C1 Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA.
   Univ Florida, Dept Microbiol & Mol Genet, Gainesville, FL USA.
   Univ Florida, Powell Gene Therapy Ctr, Gainesville, FL USA.
C3 Baylor College of Medicine; State University System of Florida;
   University of Florida; State University System of Florida; University of
   Florida
RP Baylor Coll Med, Dept Pathol, 1 Baylor Plaza,Room 268B, Houston, TX 77030 USA.
EM tcooper@bcm.tme.edu
OI Ladd, Andrea/0000-0003-4725-5644; Swanson, Maurice/0000-0001-6245-5367
FU NHLBI NIH HHS [HL045565] Funding Source: Medline; NIAMS NIH HHS
   [AR046799, AR008618] Funding Source: Medline
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NR 45
TC 102
Z9 132
U1 0
U2 12
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1058-8388
EI 1097-0177
J9 DEV DYNAM
JI Dev. Dyn.
PD JUL
PY 2005
VL 233
IS 3
BP 783
EP 793
DI 10.1002/dvdy.20382
PG 11
WC Anatomy & Morphology; Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Anatomy & Morphology; Developmental Biology
GA 936YS
UT WOS:000229892100008
PM 15830352
DA 2025-04-10
ER

PT J
AU Martin, E
   Golunski, E
   Laing, ST
   Estrera, AL
   Sharina, IG
AF Martin, Emil
   Golunski, Eva
   Laing, Susan T.
   Estrera, Anthony L.
   Sharina, Iraida G.
TI Alternative splicing impairs soluble guanylyl cyclase function in aortic
   aneurysm
SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
LA English
DT Article
DE nitric oxide; soluble guanylyl cyclase; alternative splicing; aorta
ID NITRIC-OXIDE RECEPTOR; SPONTANEOUSLY HYPERTENSIVE-RATS; ARTERY
   SMOOTH-MUSCLE; ENDOTHELIAL FUNCTION; DOWN-REGULATION; MESSENGER-RNA;
   EXPRESSION; NO; DYSFUNCTION; PROTEIN
AB Nitric oxide (NO) receptor soluble guanylyl cyclase (sGC) is a key regulator of several important vascular functions and is important for maintaining cardiovascular homeostasis and vascular plasticity. Diminished sGC expression and function contributes to pathogenesis of several cardiovascular diseases. However, the processes that control sGC expression in vascular tissue remain poorly understood. Previous work in animal and cell models revealed the complexity of alternative splicing of sGC genes and demonstrated its importance in modulation of sGC function. The aim of this study was to examine the role of alternative splicing of alpha 1 and beta 1 sGC in healthy and diseased human vascular tissue. Our study found a variety of alpha 1 and beta 1 sGC splice forms expressed in human aorta. Their composition and abundance were different between samples of aortic tissue removed during surgical repair of aortic aneurysm and samples of aortas without aneurysm. Aortas with aneurysm demonstrated decreased sGC activity, which correlated with increased expression of dysfunctional sGC splice variants. In addition, the expression of 55-kDa oxidation-resistant alpha 1 isoform B sGC (alpha 1-IsoB) was significantly lower in aortic samples with aneurysm. The alpha 1-IsoB splice variant was demonstrated to support sGC activity in aortic lysates. Together, our results suggest that alternative splicing contributes to diminished sGC function in vascular dysfunction. Precise understanding of sGC splicing regulation could help to design new therapeutic interventions and to personalize sGC-targeting therapies in treatments of vascular disease.
C1 [Martin, Emil; Golunski, Eva; Laing, Susan T.; Sharina, Iraida G.] Univ Texas Hlth Sci Ctr Houston, Sch Med, Dept Internal Med Cardiol, Houston, TX 77030 USA.
   [Estrera, Anthony L.] Univ Texas Hlth Sci Ctr Houston, Sch Med, Dept Cardiothorac Vasc Surg, Houston, TX 77030 USA.
C3 University of Texas System; University of Texas Health Science Center
   Houston; University of Texas System; University of Texas Health Science
   Center Houston
RP Sharina, IG (corresponding author), Univ Texas Hlth Sci Ctr Houston, Sch Med, Dept Internal Med, Div Cardiol, 1941 East Rd, Houston, TX 77030 USA.
EM Iraida.G.Sharina@uth.tmc.edu
RI Estrera, Anthony/ABG-4175-2021; Sharina, Iraida/C-9888-2014; Martin,
   Emil/HLX-8442-2023
OI Martin, Emil/0000-0002-9094-4165
FU National Institute of Heart, Lung, and Blood Institute [5R01 HL-088128];
   American Heart Association [12GRNT11930007]; American Heart Association
   (AHA) [12GRNT11930007] Funding Source: American Heart Association (AHA)
FX This work was supported by departmental start-up funds (I.G.S.),
   National Institute of Heart, Lung, and Blood Institute (grant 5R01
   HL-088128, E.S.M.), and American Heart Association (grant
   12GRNT11930007, E.S.M.).
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NR 50
TC 20
Z9 21
U1 0
U2 2
PU AMER PHYSIOLOGICAL SOC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0363-6135
EI 1522-1539
J9 AM J PHYSIOL-HEART C
JI Am. J. Physiol.-Heart Circul. Physiol.
PD DEC 1
PY 2014
VL 307
IS 11
BP H1565
EP H1575
DI 10.1152/ajpheart.00222.2014
PG 11
WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Physiology
GA AW0ZM
UT WOS:000346019900004
PM 25239802
OA Green Published
DA 2025-04-10
ER

PT J
AU Sharma, A
   Nguyen, H
   Cai, L
   Lou, H
AF Sharma, Alok
   Nguyen, Hieu
   Cai, Lu
   Lou, Hua
TI Histone hyperacetylation and exon skipping: a calcium-mediated dynamic
   regulation in cardiomyocytes
SO NUCLEUS
LA English
DT Article
DE alternative splicing; CaMK; calcium; class II HDAC; exon skipping;
   histone hyperacetylation; PKD
ID DEPOLARIZATION; TRANSCRIPTION; MECHANISMS; RATES
AB In contrast to cell type-specific pre-mRNA alternative splicing, mechanisms controlling activity-dependent alternative splicing is under-studied and not well understood. In a recent study, we conducted a comprehensive analysis of calcium-mediated mechanism that regulates alternative exon skipping in mouse cardiomyocytes. Our results reveal a strong link between histone hyperacetylation and skipping of cassette exons, and provide support to the kinetic coupling model of the epigenetic regulation of alternative splicing at the chromatin level.
C1 [Sharma, Alok; Nguyen, Hieu; Lou, Hua] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA.
   [Cai, Lu] Inner Mongolia Univ Sci & Technol, Sch Math, Phys & Biol Engn, Baotou, Peoples R China.
   [Lou, Hua] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA.
   [Lou, Hua] Case Western Reserve Univ, Sch Med, Ctr RNA Mol Biol, Cleveland, OH USA.
C3 University System of Ohio; Case Western Reserve University; Inner
   Mongolia University of Science & Technology; University System of Ohio;
   Case Western Reserve University; University System of Ohio; Case Western
   Reserve University
RP Lou, H (corresponding author), Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA.
EM hua.lou@case.edu
FU National Institutes of Health [NS049103, S10RR021228, S10RR024536];
   National Natural Science Foundation of China [61271448]; Vietnam
   Education Foundation
FX This work was supported by the National Institutes of Health (NS049103
   to HL, S10RR021228 and S10RR024536 National Center for Research
   Resources Shared Instrumentation Grants for the Leica DM6000 wide-field
   microscope and the GE Healthcare Typhoon Trio Variable Mode Imager). LC
   was supported by National Natural Science Foundation of China
   (61271448). HN was supported by a fellowship from the Vietnam Education
   Foundation.
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NR 38
TC 7
Z9 8
U1 0
U2 3
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 1949-1034
EI 1949-1042
J9 NUCLEUS-PHILA
JI Nucleus
PD JUL-AUG
PY 2015
VL 6
IS 4
BP 273
EP 278
DI 10.1080/19491034.2015.1081324
PG 6
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA CQ5SM
UT WOS:000360666000005
PM 26325491
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Vajda, NA
   Brimacombe, KR
   LeMasters, KE
   Ladd, AN
AF Vajda, Natalie A.
   Brimacombe, Kyle R.
   LeMasters, Kathryn E.
   Ladd, Andrea N.
TI Muscleblind-like 1 Is a Negative Regulator of TGF-β-Dependent
   Epithelial-Mesenchymal Transition of Atrioventricular Canal Endocardial
   Cells
SO DEVELOPMENTAL DYNAMICS
LA English
DT Article
DE Muscleblind-like 1; alternative splicing, transforming growth factor
   beta; epithelial-mesenchymal transition; cardiac morphogenesis
ID BONE MORPHOGENETIC PROTEIN-2; CUSHION FORMATION; CHICK HEART;
   EXPRESSION; FAMILY; TISSUE; RNA; TRANSFORMATION; REPRESSION; DISEASE
AB The development of the valves and septa of the heart depends on the formation and remodeling of endocardial cushions. Here, we report that the alternative splicing regulator muscleblind-like 1 (MBNL1) exhibits a regionally restricted pattern of expression in canal region endocardium and ventricular myocardium. during endocardial cushion development in chicken. Knockdown of MBNL1 in atrioventricular explants leads to a transforming growth factor V-dependent increase in epithelial-mesenchymal transition (EMT) of endocardial cells. This reveals a novel role for MBNL1 during embryonic development, and represents the first evidence that an alternative splicing regulator is a key player in endocardial cushion development. Developmental Dynamics 238:3266-3272, 2009. (C) 2009 Wiley-Liss, Inc.
C1 [Vajda, Natalie A.; Brimacombe, Kyle R.; LeMasters, Kathryn E.; Ladd, Andrea N.] Cleveland Clin, Lerner Res Inst, Dept Cell Biol, Cleveland, OH 44106 USA.
   [Ladd, Andrea N.] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Dept Mol Med, Cleveland, OH 44106 USA.
C3 Cleveland Clinic Foundation; Cleveland Clinic Foundation; University
   System of Ohio; Case Western Reserve University
RP Ladd, AN (corresponding author), 9500 Euclid Ave,NC10, Cleveland, OH 44195 USA.
EM ladda@ccf.org
OI Ladd, Andrea/0000-0003-4725-5644
FU March of Dimes; American Heart Association; National Institutes of
   Health
FX thank Donna Driscoll for helpful comments on the manuscript. A.N.L was
   funded by the March of Dimes, the American Heart Association, and the
   National Institutes of Health.
CR [Anonymous], 1992, Methods in Lignin Chemistry
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NR 24
TC 18
Z9 20
U1 0
U2 1
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1058-8388
EI 1097-0177
J9 DEV DYNAM
JI Dev. Dyn.
PD DEC
PY 2009
VL 238
IS 12
BP 3266
EP 3272
DI 10.1002/dvdy.22155
PG 7
WC Anatomy & Morphology; Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Anatomy & Morphology; Developmental Biology
GA 529WH
UT WOS:000272549100027
PM 19890912
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Zhou, N
   Chen, X
   Xi, J
   Ma, B
   Leimena, C
   Stoll, S
   Qin, GJ
   Wang, C
   Qiu, HY
AF Zhou, Ning
   Chen, Xin
   Xi, Jing
   Ma, Ben
   Leimena, Christiana
   Stoll, Shaunrick
   Qin, Gangjian
   Wang, Charles
   Qiu, Hongyu
TI Novel genomic targets of valosin-containing protein in protecting
   pathological cardiac hypertrophy
SO SCIENTIFIC REPORTS
LA English
DT Article
AB Pressure overload-induced cardiac hypertrophy, such as that caused by hypertension, is a key risk factor for heart failure. However, the underlying molecular mechanisms remain largely unknown. We previously reported that the valosin-containing protein (VCP), an ATPase-associated protein newly identified in the heart, acts as a significant mediator of cardiac protection against pressure overload-induced pathological cardiac hypertrophy. Still, the underlying molecular basis for the protection is unclear. This study used a cardiac-specific VCP transgenic mouse model to understand the transcriptomic alterations induced by VCP under the cardiac stress caused by pressure overload. Using RNA sequencing and comprehensive bioinformatic analysis, we found that overexpression of the VCP in the heart was able to normalize the pressure overload-stimulated hypertrophic signals by activating G protein-coupled receptors, particularly, the olfactory receptor family, and inhibiting the transcription factor controlling cell proliferation and differentiation. Moreover, VCP overexpression restored pro-survival signaling through regulating alternative splicing alterations of mitochondrial genes. Together, our study revealed a novel molecular regulation mediated by VCP under pressure overload that may bring new insight into the mechanisms involved in protecting against hypertensive heart failure.
C1 [Zhou, Ning; Xi, Jing; Ma, Ben; Leimena, Christiana; Stoll, Shaunrick; Qiu, Hongyu] Loma Linda Univ, Sch Med, Dept Basic Sci, Div Physiol, Loma Linda, CA 92350 USA.
   [Zhou, Ning] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Div Cardiol,Dept Internal Med, Wuhan 430000, Peoples R China.
   [Chen, Xin; Wang, Charles] Loma Linda Univ, Ctr Genom, Sch Med, 11021 Campus St,AH 120-104, Loma Linda, CA 92350 USA.
   [Chen, Xin; Wang, Charles] Loma Linda Univ, Dept Basic Sci, Sch Med, 11021 Campus St,AH 120-104, Loma Linda, CA 92350 USA.
   [Qin, Gangjian] Univ Alabama Birmingham, Sch Med, Dept Biomed Engn, Birmingham, AL 35294 USA.
   [Qin, Gangjian] Univ Alabama Birmingham, Sch Engn, Birmingham, AL 35294 USA.
   [Ma, Ben; Qiu, Hongyu] Georgia State Univ, Ctr Mol & Translat Med, Petit Res Ctr, Inst Biomed Sci, Room 588,100 Piedmont Ave, Atlanta, GA 30303 USA.
C3 Loma Linda University; Huazhong University of Science & Technology; Loma
   Linda University; Loma Linda University; University of Alabama System;
   University of Alabama Birmingham; University of Alabama System;
   University of Alabama Birmingham; University System of Georgia; Georgia
   State University
RP Qiu, HY (corresponding author), Loma Linda Univ, Sch Med, Dept Basic Sci, Div Physiol, Loma Linda, CA 92350 USA.; Wang, C (corresponding author), Loma Linda Univ, Dept Basic Sci, Sch Med, 11021 Campus St,AH 120-104, Loma Linda, CA 92350 USA.; Qiu, HY (corresponding author), Georgia State Univ, Ctr Mol & Translat Med, Petit Res Ctr, Inst Biomed Sci, Room 588,100 Piedmont Ave, Atlanta, GA 30303 USA.
EM chwang@llu.edu; hqiu@gsu.edu
RI Ma, Ben/HMV-0820-2023
OI Xi, Jing/0000-0003-0881-2356
FU NIH [HL115195-01, HL137962, HL 142291]; Ardmore Institute of Health
   (AIH) Grant [2150141]; National Natural Science Foundation of China
   [81570261]
FX This work is supported by NIH Grants HL115195-01 (H.Q.), HL137962
   (H.Q.), and HL 142291(H. Q &. G.Q). We would also like to thank
   partially support from the Ardmore Institute of Health (AIH) Grant
   (2150141, CW), the National Natural Science Foundation of China 81570261
   (N.Z.) and Dr. Charles A. Sims' gift to Loma Linda University (LLU)
   Center for Genomics.
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NR 45
TC 8
Z9 8
U1 0
U2 9
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD OCT 22
PY 2020
VL 10
IS 1
AR 18098
DI 10.1038/s41598-020-75128-z
PG 13
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA QD2UK
UT WOS:000615379800091
PM 33093614
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Freyermuth, F
   Rau, F
   Kokunai, Y
   Linke, T
   Sellier, C
   Nakamori, M
   Kino, Y
   Arandel, L
   Jollet, A
   Thibault, C
   Philipps, M
   Vicaire, S
   Jost, B
   Udd, B
   Day, JW
   Duboc, D
   Wahbi, K
   Matsumura, T
   Fujimura, H
   Mochizuki, H
   Deryckere, F
   Kimura, T
   Nukina, N
   Ishiura, S
   Lacroix, V
   Campan-Fournier, A
   Navratil, V
   Chautard, E
   Auboeuf, D
   Horie, M
   Imoto, K
   Lee, KY
   Swanson, MS
   de Munain, AL
   Inada, S
   Itoh, H
   Nakazawa, K
   Ashihara, T
   Wang, E
   Zimmer, T
   Furling, D
   Takahashi, MP
   Charlet-Berguerand, N
AF Freyermuth, Fernande
   Rau, Frederique
   Kokunai, Yosuke
   Linke, Thomas
   Sellier, Chantal
   Nakamori, Masayuki
   Kino, Yoshihiro
   Arandel, Ludovic
   Jollet, Arnaud
   Thibault, Christelle
   Philipps, Muriel
   Vicaire, Serge
   Jost, Bernard
   Udd, Bjarne
   Day, John W.
   Duboc, Denis
   Wahbi, Karim
   Matsumura, Tsuyoshi
   Fujimura, Harutoshi
   Mochizuki, Hideki
   Deryckere, Francois
   Kimura, Takashi
   Nukina, Nobuyuki
   Ishiura, Shoichi
   Lacroix, Vincent
   Campan-Fournier, Amandine
   Navratil, Vincent
   Chautard, Emilie
   Auboeuf, Didier
   Horie, Minoru
   Imoto, Keiji
   Lee, Kuang-Yung
   Swanson, Maurice S.
   Lopez de Munain, Adolfo
   Inada, Shin
   Itoh, Hideki
   Nakazawa, Kazuo
   Ashihara, Takashi
   Wang, Eric
   Zimmer, Thomas
   Furling, Denis
   Takahashi, Masanori P.
   Charlet-Berguerand, Nicolas
TI Splicing misregulation of SCN5A contributes to cardiac-conduction
   delay and heart arrhythmia in myotonic dystrophy
SO NATURE COMMUNICATIONS
LA English
DT Article
ID PRE-MESSENGER-RNA; BRUGADA-SYNDROME; STRUCTURAL INSIGHTS;
   MUSCULAR-DYSTROPHY; CHLORIDE CHANNEL; SKELETAL-MUSCLE; CTG REPEAT;
   PROTEIN; MODEL; RECEPTOR
AB Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A. We find that MBNL1 regulates alternative splicing of SCN5A mRNA and that the splicing variant of SCN5A produced in DM presents a reduced excitability compared with the control adult isoform. Importantly, reproducing splicing alteration of Scn5a in mice is sufficient to promote heart arrhythmia and cardiac-conduction delay, two predominant features of myotonic dystrophy. In conclusion, misregulation of the alternative splicing of SCN5A may contribute to a subset of the cardiac dysfunctions observed in myotonic dystrophy.
C1 [Freyermuth, Fernande; Sellier, Chantal; Thibault, Christelle; Philipps, Muriel; Vicaire, Serge; Jost, Bernard; Charlet-Berguerand, Nicolas] Univ Strasbourg, INSERM U964, CNRS UMR7104, Dept Translat Med & Neurogenet,IGBMC, F-67400 Illkirch Graffenstaden, France.
   [Rau, Frederique; Arandel, Ludovic; Jollet, Arnaud; Furling, Denis] Univ Paris 06, Sorbonne Univ, INSERM, CNRS,Ctr Rech Myol,UMRS974,FRE3617,Inst Myol,GH P, F-75013 Paris, France.
   [Kokunai, Yosuke; Nakamori, Masayuki; Mochizuki, Hideki; Takahashi, Masanori P.] Osaka Univ, Grad Sch Med, Dept Neurol, Osaka 5650871, Japan.
   [Linke, Thomas; Zimmer, Thomas] Friedrich Schiller Univ Hosp, Dept Physiol, D-07743 Jena, Germany.
   [Kino, Yoshihiro] Meiji Pharmaceut Univ, Dept Bioinformat & Mol Neuropathol, Kiyose 2058588, Japan.
   [Udd, Bjarne] Tampere Univ, Neuromuscular Res Ctr, Tampere 33520, Finland.
   [Udd, Bjarne] Tampere Univ Hosp, Tampere 33520, Finland.
   [Udd, Bjarne] Univ Helsinki, Dept Med Genet, Folkhalsan Inst Genet, Helsinki 00250, Finland.
   [Udd, Bjarne] Vaasa Cent Hosp, Dept Neurol, Vaasa 65130, Finland.
   [Day, John W.] Stanford Univ, Dept Neurol, Stanford, CA 94304 USA.
   [Duboc, Denis; Wahbi, Karim] Univ Paris 05, Hop Cochin, AP HP, Serv Cardiol, F-75014 Paris, France.
   [Matsumura, Tsuyoshi; Fujimura, Harutoshi] Toneyama Natl Hosp, Dept Neurol, Toyonaka, Osaka 5608552, Japan.
   [Deryckere, Francois] Ecole Super Biotechnol Strasbourg, CNRS, UMR7175, F-67400 Illkirch Graffenstaden, France.
   [Kimura, Takashi] Hyogo Coll Med, Div Neurol, Nishinomiya, Hyogo 6638501, Japan.
   [Nukina, Nobuyuki] Doshisha Univ, Grad Sch Brain Sci, Lab Struct Neuropathol, Kyoto 6100394, Japan.
   [Ishiura, Shoichi] Univ Tokyo, Grad Sch Arts & Sci, Tokyo 1538902, Japan.
   [Lacroix, Vincent] Univ Lyon 1, CNRS, LBBE UMR5558, F-69622 Villeurbanne, France.
   [Campan-Fournier, Amandine] Hosp Civils Lyon, Lab Cytogenet Constitut, F-69500 Bron, France.
   [Navratil, Vincent] Univ Lyon 1, Pole Rhone Alpes Bioinformat, Batiment Gregor Mendel, F-69100 Villeurbanne, France.
   [Chautard, Emilie; Auboeuf, Didier] Ctr Rech Cancerol Lyon, F-69373 Lyon, France.
   [Horie, Minoru; Itoh, Hideki; Ashihara, Takashi] Shiga Med Univ, Dept Cardiovasc & Resp Med, Otsu, Shiga 5202192, Japan.
   [Imoto, Keiji] Natl Inst Nat Sci, Natl Inst Physiol Sci, Dept Informat Physiol, 38 Nishigonaka, Okazaki, Aichi 4448585, Japan.
   [Lee, Kuang-Yung] Chang Gung Mem Hosp, Dept Neurol, Keelung 20401, Taiwan.
   [Swanson, Maurice S.; Wang, Eric] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Ctr NeuroGenet, Gainesville, FL 32610 USA.
   [Swanson, Maurice S.; Wang, Eric] Univ Florida, Coll Med, Genet Inst, Gainesville, FL 32610 USA.
   [Lopez de Munain, Adolfo] Hosp Univ DONOSTIA, Inst Biodonostia CIBERNED, Neurosci Area, Dept Neurol, San Sebastian 20014, Spain.
   [Lopez de Munain, Adolfo] Univ Basque Country UPV EHU, San Sebastian 20014, Spain.
   [Inada, Shin; Nakazawa, Kazuo] Natl Cerebral & Cardiovasc Ctr, Res Inst, Lab Biomed Sci & Informat Management, Osaka 5658565, Japan.
   [Freyermuth, Fernande] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA.
C3 Centre National de la Recherche Scientifique (CNRS); CNRS - National
   Institute for Biology (INSB); Universites de Strasbourg Etablissements
   Associes; Universite de Strasbourg; Institut National de la Sante et de
   la Recherche Medicale (Inserm); Centre National de la Recherche
   Scientifique (CNRS); Sorbonne Universite; Institut National de la Sante
   et de la Recherche Medicale (Inserm); The University of Osaka; Friedrich
   Schiller University of Jena; Meiji Pharmaceutical University; Tampere
   University; Tampere University; Tampere University Hospital; University
   of Helsinki; Vaasa Central Hospital; Stanford University; Assistance
   Publique Hopitaux Paris (APHP); Universite Paris Cite; Hopital
   Universitaire Cochin - APHP; Centre National de la Recherche
   Scientifique (CNRS); Hyogo Medical University; Doshisha University;
   University of Tokyo; Centre National de la Recherche Scientifique
   (CNRS); CNRS - Institute of Ecology & Environment (INEE); Universite
   Claude Bernard Lyon 1; CHU Lyon; Universite Claude Bernard Lyon 1;
   UNICANCER; Centre Leon Berard; Universite Claude Bernard Lyon 1;
   Institut National de la Sante et de la Recherche Medicale (Inserm);
   Shiga University of Medical Science; National Institutes of Natural
   Sciences (NINS) - Japan; National Institute for Physiological Sciences
   (NIPS); Chang Gung Memorial Hospital; State University System of
   Florida; University of Florida; State University System of Florida;
   University of Florida; CIBERNED; University of Basque Country; National
   Cerebral & Cardiovascular Center - Japan; Harvard University; Harvard
   University Medical Affiliates; Massachusetts General Hospital
RP Charlet-Berguerand, N (corresponding author), Univ Strasbourg, INSERM U964, CNRS UMR7104, Dept Translat Med & Neurogenet,IGBMC, F-67400 Illkirch Graffenstaden, France.; Furling, D (corresponding author), Univ Paris 06, Sorbonne Univ, INSERM, CNRS,Ctr Rech Myol,UMRS974,FRE3617,Inst Myol,GH P, F-75013 Paris, France.; Takahashi, MP (corresponding author), Osaka Univ, Grad Sch Med, Dept Neurol, Osaka 5650871, Japan.
EM denis.furling@upmc.fr; mtakahas@neurol.med.osaka-u.ac.jp;
   ncharlet@igbmc.fr
RI Takahashi, Masanori/O-8946-2019; Nukina, Nobuyuki/GPP-6265-2022; Udd,
   Bjarne/JBE-3483-2023; Nakamori, Masayuki/ABE-2169-2020; Horie,
   Minoru/ABG-7128-2020; Charlet-Berguerand, Nicolas/GZM-6636-2022; wang,
   eric/LKM-0410-2024; navratil, vincent/C-4193-2008; DE MUNAIN,
   ADOLFO/AAB-1824-2020; Itoh, Hideki/JED-8025-2023; Lacroix,
   Vincent/M-2906-2015; Zimmer, Thomas/ISU-6303-2023; Auboeuf,
   Didier/M-4610-2014; Chautard, Emilie/C-7836-2011; rau,
   frederique/G-6134-2017; Furling, Denis/M-2346-2017; Charlet-Berguerand,
   Nicolas/I-6727-2016
OI Swanson, Maurice/0000-0001-6245-5367; Chautard,
   Emilie/0000-0003-1456-5347; Takahashi, Masanori P/0000-0002-5513-5012;
   Wang, Eric/0000-0003-2655-5525; rau, frederique/0000-0001-7025-8144;
   Auboeuf, Didier/0000-0002-3757-0002; Imoto, Keiji/0000-0002-2861-5985;
   Day, John/0000-0002-0086-9529; Sellier, Chantal/0000-0003-2933-5464;
   Thibault-Carpentier, Christelle/0000-0003-1562-1451; Furling,
   Denis/0000-0001-7912-4409; navratil, vincent/0000-0001-9974-1877; Horie,
   Minoru/0000-0002-9029-2339; Nakamori, Masayuki/0000-0003-4714-3044;
   /0000-0002-9509-4032; Charlet-Berguerand, Nicolas/0000-0002-4423-4920;
   DERYCKERE, Francois/0000-0002-7786-4232; wahbi,
   karim/0000-0001-7682-7387
FU UPMC/INSERM/CNRS/AIM; AFM [18833]; ERC-StG [310659]; MEXT [25136705];
   JSPS [25713034, 15K09314]; Intramural Research Grant of NCNP [26-8];
   AMED;  [ANR-10-LABX-0030-INRT];  [ANR-10-IDEX-0002-02]; 
   [ANR-12-RARE-0005-01]; Grants-in-Aid for Scientific Research [25461106,
   15K09314, 25460406, 15H01801, 15K15339, 25713034, 16K09431] Funding
   Source: KAKEN; European Research Council (ERC) [310659] Funding Source:
   European Research Council (ERC)
FX We thank Tom Cooper (Baylor College of Medicine, Houston, USA) for the
   gift of the DT960 and tgCUGBP1 plasmids, Christiane Branlant (CNRS,
   Nancy, France) for the gift of the pGEX-MBNL1 Delta<SUP>101</SUP>
   vector, the Research Resource Network Japan and the Myobank of the
   Institute of Myology for providing human heart tissue samples, Feriel
   Azibani (UMRS974, Paris, France) and all members of the French DM
   Network for fruitful discussion. We also deeply thank the IGBMC
   Microarray and Sequencing platform, the informatics resources of the
   PRABI, Nathalie Mougenot from the UPMC PECMV-CEF facility, the
   Federation de Recherche en Imagerie Multimodalite
   (www.bichat.inserm.fr), the AAV platform of the Centre de Recherche en
   Myologie, the Penn Vector Core, Gene Therapy Program, University of
   Pennsylvania (Philadelphia) for providing the pAAV2/9 plasmid
   (p5E18-VD29), members of the France Genomique program for RNA sequencing
   and all IGBMC common facilities for assistance. This work was supported
   by UPMC/INSERM/CNRS/AIM (D.F.); ANR-12-RARE-0005-01 E-RARE 'HEART DM'
   (N.C.-B. and D.F.); AFM #18833, ERC-2012-StG #310659 'RNA DISEASES' and
   ANR-10-LABX-0030-INRT and ANR-10-IDEX-0002-02 (N.C.-B.); Research Grants
   for Practical Research Project for Rare / Intractable Diseases and for
   Comprehensive Research on Persons with Disabilities from AMED (H.M.,
   M.P.T.); Grants-in-Aids from MEXT (25136705) (H.I.); Grants-in-Aids from
   JSPS (25713034 (M.N.) and 15K09314 (M.P.T.)); and Intramural Research
   Grant of NCNP 26-8 (M.P.T.).
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NR 73
TC 138
Z9 157
U1 1
U2 32
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD APR
PY 2016
VL 7
AR 11067
DI 10.1038/ncomms11067
PG 14
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA DI9JO
UT WOS:000373819100001
PM 27063795
OA Green Submitted, Green Published, gold
DA 2025-04-10
ER

PT J
AU Sharma, A
   Nguyen, H
   Geng, CY
   Hinman, MN
   Luo, GB
   Lou, H
AF Sharma, Alok
   Nguyen, Hieu
   Geng, Cuiyu
   Hinman, Melissa N.
   Luo, Guangbin
   Lou, Hua
TI Calcium-mediated histone modifications regulate alternative splicing in
   cardiomyocytes
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
   AMERICA
LA English
DT Article
DE alternative splicing; histone hyperacetylation; transcriptional
   elongation rate; calcium; cardiomyocytes
ID CARDIAC TRANSCRIPTION FACTORS; CAM KINASE-II; GENE-EXPRESSION;
   CHROMATIN-STRUCTURE; HYPERTROPHY; DEPOLARIZATION; ACETYLATION;
   CONSEQUENCES; MECHANISMS; PATHWAYS
AB In cardiomyocytes, calcium is known to control gene expression at the level of transcription, whereas its role in regulating alternative splicing has not been explored. Here we report that, in mouse primary or embryonic stem cell-derived cardiomyocytes, increased calcium levels induce robust and reversible skipping of several alternative exons from endogenously expressed genes. Interestingly, we demonstrate a calcium-mediated splicing regulatory mechanism that depends on changes of histone modifications. Specifically, the regulation occurs through changes in calcium-responsive kinase activities that lead to alterations in histone modifications and subsequent changes in the transcriptional elongation rate and exon skipping. We demonstrate that increased intracellular calcium levels lead to histone hyperacetylation along the body of the genes containing calcium-responsive alternative exons by disrupting the histone deacetylase-to-histone acetyltransferase balance in the nucleus. Consequently, the RNA polymerase II elongation rate increases significantly on those genes, resulting in skipping of the alternative exons. These studies reveal a mechanism by which calcium-level changes in cardiomyocytes impact on the output of gene expression through altering alternative pre-mRNA splicing patterns.
C1 [Sharma, Alok; Nguyen, Hieu; Geng, Cuiyu; Hinman, Melissa N.; Luo, Guangbin; Lou, Hua] Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA.
   [Luo, Guangbin; Lou, Hua] Case Western Reserve Univ, Sch Med, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA.
   [Lou, Hua] Case Western Reserve Univ, Sch Med, Ctr RNA Mol Biol, Cleveland, OH 44106 USA.
C3 University System of Ohio; Case Western Reserve University; University
   System of Ohio; Case Western Reserve University; University System of
   Ohio; Case Western Reserve University
RP Lou, H (corresponding author), Case Western Reserve Univ, Sch Med, Dept Genet & Genome Sci, Cleveland, OH 44106 USA.
EM hua.lou@case.edu
OI Hinman, Melissa/0000-0002-0743-646X
FU National Institutes of Health [National Center for Research Resources
   Shared Instrumentation] [NS049103, S10RR021228, S10RR024536]
FX The authors thank Dr. James Stevenin (Institut de Genetique et de
   Biologie Moleculaire et Cellulaire) for the anti-SC35 antibody. We also
   thank Drs. Helen Salz, Saba Valadkhan, and Jo Ann Wise for critical
   reading of the manuscript and members of the H. L. laboratory for
   helpful discussions. We thank Dr. Saptarsi Haldar for stimulating
   discussions. This work was supported by the National Institutes of
   Health [NS049103 (to H. L.), and S10RR021228 and S10RR024536 National
   Center for Research Resources Shared Instrumentation Grants for the
   Leica DM6000 wide-field microscope and the GE Healthcare Typhoon Trio
   Variable Mode Imager].
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Z9 51
U1 0
U2 15
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD NOV 18
PY 2014
VL 111
IS 46
BP E4920
EP E4928
DI 10.1073/pnas.1408964111
PG 9
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA AT7ZL
UT WOS:000345153300006
PM 25368158
OA Green Published, Bronze
DA 2025-04-10
ER

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   Ander, Bradley P.
   Zhan, Xinhua
   Liu, DaZhi
   Hull, Heather
   Orantia, Miles
   Ho, Carolyn
   Stamova, Boryana
TI Intracerebral Hemorrhage and Ischemic Stroke of Different Etiologies
   Have Distinct Alternatively Spliced mRNA Profiles in the Blood: a Pilot
   RNA-seq Study
SO TRANSLATIONAL STROKE RESEARCH
LA English
DT Article
DE Ischemic stroke; Intracerebral hemorrhage; Alternative splicing;
   Biomarkers; RNA-seq; Exon
ID GENE-EXPRESSION; PROGRESSION; PREDICTION; LACUNAR; HUMANS
AB Whole transcriptome studies have used 3'-biased expression microarrays to study genes regulated in the blood of stroke patients. However, alternatively spliced messenger RNA isoforms have not been investigated for ischemic stroke or intracerebral hemorrhage (ICH) in animals or humans. Alternative splicing is the mechanism whereby different combinations of exons of a single gene produce distinct mRNA and protein isoforms. Here, we used RNA sequencing (RNA-seq) to determine if alternative splicing differs for ICH and cardioembolic, large vessel and lacunar causes of ischemic stroke compared to controls. RNA libraries from 20 whole blood samples were sequenced to 200 M 2 x 100 bp reads using Illumina sequencing-by-synthesis technology. Differential alternative splicing was assessed using one-way analysis of variance (ANOVA), and differential exon usage was calculated. Four hundred twelve genes displayed differential alternative splicing among the groups (false discovery rate, FDR; p < 0.05). They were involved in cellular immune response, cell death, and cell survival pathways. Distinct expression signatures based on usage of 308 exons (292 genes) differentiated the groups (p < 0.0005; fold change >|1.2|). This pilot study demonstrates that alternatively spliced genes from whole blood differ in ICH compared to ischemic stroke and differ between different ischemic stroke etiologies. These results require validation in a separate cohort.
C1 [Dykstra-Aiello, Cheryl; Jickling, Glen C.; Ander, Bradley P.; Zhan, Xinhua; Liu, DaZhi; Hull, Heather; Orantia, Miles; Ho, Carolyn; Stamova, Boryana] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA.
   [Stamova, Boryana] MIND Inst Wet Labs, Dept Neurol, Sacramento, CA 95817 USA.
C3 University of California System; University of California Davis
RP Stamova, B (corresponding author), Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA.
EM boryana.stamova@ucdmc.ucdavis.edu
RI Stamova, Boryana/ABA-2981-2020; Dykstra-Aiello, Cheryl/HPF-2368-2023;
   Jickling, Glen/J-8790-2019; Liu, DaZhi/B-6850-2011
OI Dykstra-Aiello, Cheryl/0000-0002-6802-336X; Stamova,
   Boryana/0000-0002-5440-8816; Jickling, Glen/0000-0003-3543-0820
FU NINDS, a division of the National Institutes of Health [RO1NS075035];
   American Heart Association
FX This study was funded by NINDS, a division of the National Institutes of
   Health (RO1NS075035, RO1NS075035) and by a Fellow to Faculty Award from
   the American Heart Association (GCJ).
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NR 25
TC 40
Z9 45
U1 0
U2 15
PU SPRINGER
PI NEW YORK
PA 233 SPRING ST, NEW YORK, NY 10013 USA
SN 1868-4483
EI 1868-601X
J9 TRANSL STROKE RES
JI Transl. Stroke Res.
PD AUG
PY 2015
VL 6
IS 4
BP 284
EP 289
DI 10.1007/s12975-015-0407-9
PG 6
WC Clinical Neurology; Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA CL5YD
UT WOS:000357040400005
PM 25994285
OA Green Submitted, Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Fan, QI
   Vanderpool, KM
   Chung, HS
   Marsh, JD
AF Fan, QI
   Vanderpool, KM
   Chung, HS
   Marsh, JD
TI The L-type calcium channel alpha 1C subunit gene undergoes extensive,
   uncoordinated alternative splicing
SO MOLECULAR AND CELLULAR BIOCHEMISTRY
LA English
DT Article
DE calcium channel; alternative splicing; myocyte; vascular smooth muscle
ID CA2+ CHANNEL; ALPHA(1C) SUBUNIT; SMOOTH-MUSCLE; ALPHA-1 SUBUNIT;
   PROTEIN-KINASE; EXPRESSION; TERMINUS; SITE; SENSITIVITY; VARIANTS
AB The alpha(1C) subunit is the pore-forming protein for the L-type calcium channel. Previous studies indicate that there is possible tissue-specific alternative splicing of this gene. In this study we cloned the entire open reading frame of the alpha(1C) subunit cDNA from adult rat cardiac myocytes in a single piece ( 6.64 kb). Using 75 positive clones that were identified by restriction enzyme mapping, we tested the alternative splicing patterns of the Ca(v)1.2 gene that encodes the alpha(1C) subunit protein and focused on five loci: IS6, post-IS6, IIIS2, IVS3, and the c-terminus. The results indicate that: ( 1) alternative splicing occurs in most of the loci, giving rise to two or three different isoforms at those sites; ( 2) there is a predominant form for each splicing site, ( 3) there does not appear to be consistent coordination of splicing at multiple loci of this gene. Alternative splicing is not tissue-specific in most regions.
C1 Wayne State Univ, Sch Med, Dept Internal Med, Detroit, MI 48201 USA.
C3 Wayne State University
RP Univ Arkansas Med Sci, Dept Internal Med, MS 610,4301 W Markham St, Little Rock, AR 72205 USA.
EM jdmarsh@uams.edu
FU NHLBI NIH HHS [HL54086] Funding Source: Medline
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NR 36
TC 8
Z9 9
U1 0
U2 0
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 0300-8177
EI 1573-4919
J9 MOL CELL BIOCHEM
JI Mol. Cell. Biochem.
PD JAN
PY 2005
VL 269
IS 1-2
BP 153
EP 163
DI 10.1007/s11010-005-3455-8
PG 11
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 899QA
UT WOS:000227158300018
PM 15786728
DA 2025-04-10
ER

PT J
AU Zhang, XH
   Merkler, KA
   McLean, MP
AF Zhang, Xiaohui
   Merkler, Kathleen A.
   McLean, Mark P.
TI Characterization of regulatory intronic and exonic sequences involved in
   alternative splicing of scavenger receptor class B gene
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE scavenger receptor class B; high-density lipoprotein receptor;
   alternative splicing; cis-regulatory element; splicing factor
ID HIGH-DENSITY-LIPOPROTEIN; PRE-MESSENGER-RNA; SR-BII; ENHANCERS;
   PROTEINS; ESTROGEN; SF2/ASF; LIVER
AB Scavenger receptor class B type I (SR-BI) is a major receptor of the high-density lipoprotein that mediates cholesterol efflux and reverse cholesterol transport. Alternative splicing of the scavenger receptor class B (SR-B) gene is observed and different splice forms, SR-BI and scavenger receptor class B type II (SR-BII), have been shown to function and localize in distinct ways. We have previously shown that SR-B alternative splicing regulation is associated with splicing factor ASF/SF2. In this study, using a SR-B minigene as a model, we determined the critical regulatory regions in the upstream intron, intron 11, by serial deletion and mutation analyses. We also further characterized the regulatory elements in intron 11 as well as in the skipped exon, exon 12. Moreover, we studied the interactions of these elements with the splicing factor ASF/SF2. This study provides new insights into the mechanism of SR-B splicing and it is important for further study on the mechanism of SR-B alternative splicing regulation, such as its regulation by estrogen. (C) 2008 Elsevier Inc. All rights reserved.
C1 [Zhang, Xiaohui; Merkler, Kathleen A.; McLean, Mark P.] Univ S Florida, Coll Med, Dept Obstet & Gynecol, Tampa, FL 33612 USA.
   [McLean, Mark P.] Univ S Florida, Coll Med, Dept Mol Pharmacol & Physiol, Tampa, FL 33612 USA.
C3 State University System of Florida; University of South Florida; State
   University System of Florida; University of South Florida
RP McLean, MP (corresponding author), Univ S Florida, Coll Med, Dept Obstet & Gynecol, 12901 Bruce B Downs Blvd,MDC 37, Tampa, FL 33612 USA.
EM mmclean@health.usf.edu
RI McLean, Mark/I-5621-2012
FU NHLBI NIH HHS [HL078817] Funding Source: Medline; NICHD NIH HHS
   [HD35163] Funding Source: Medline
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NR 19
TC 5
Z9 10
U1 0
U2 1
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD JUL 18
PY 2008
VL 372
IS 1
BP 173
EP 178
DI 10.1016/j.bbrc.2008.05.007
PG 6
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA 315JJ
UT WOS:000256874400031
PM 18477479
DA 2025-04-10
ER

PT J
AU Gan, PH
   Wang, ZN
   Bezprozvannaya, S
   McAnally, JR
   Tan, W
   Li, H
   Bassel-Duby, R
   Liu, N
   Olson, EN
AF Gan, Peiheng
   Wang, Zhaoning
   Bezprozvannaya, Svetlana
   McAnally, John R.
   Tan, Wei
   Li, Hui
   Bassel-Duby, Rhonda
   Liu, Ning
   Olson, Eric N.
TI RBPMS regulates cardiomyocyte contraction and cardiac function through
   RNA alternative splicing
SO CARDIOVASCULAR RESEARCH
LA English
DT Article
DE RNA binding protein; Cardiomyocyte contraction; Dilated cardiomyopathy;
   Titin; Pdlim5
ID BINDING PROTEIN; ENIGMA HOMOLOG; TITIN; MYOCARDIUM; EXPRESSION;
   STIFFNESS; NEXILIN; PROMOTE; FAMILY; RBM20
AB Aims RNA binding proteins play essential roles in mediating RNA splicing and are key post-transcriptional regulators in the heart. Our recent study demonstrated that RBPMS (RNA binding protein with multiple splicing) is crucial for cardiac development through modulating mRNA splicing, but little is known about its functions in the adult heart. In this study, we aim to characterize the post-natal cardiac function of Rbpms and its mechanism of action.Methods and results We generated a cardiac-specific knockout mouse line and found that cardiac-specific loss of Rbpms caused severe cardiomyocyte contractile defects, leading to dilated cardiomyopathy and early lethality in adult mice. We showed by proximity-dependent biotin identification assay and mass spectrometry that RBPMS associates with spliceosome factors and other RNA binding proteins, such as RBM20, that are important in cardiac function. We performed paired-end RNA sequencing and RT-PCR and found that RBPMS regulates mRNA alternative splicing of genes associated with sarcomere structure and function, such as Ttn, Pdlim5, and Nexn, generating new protein isoforms. Using a minigene splicing reporter assay, we determined that RBPMS regulates target gene splicing through recognizing tandem intronic CAC motifs. We also showed that RBPMS knockdown in human induced pluripotent stem cell-derived cardiomyocytes impaired cardiomyocyte contraction.Conclusion This study identifies RBPMS as an important regulator of cardiomyocyte contraction and cardiac function by modulating sarcomeric gene alternative splicing.
   Graphical Abstract
C1 [Gan, Peiheng; Wang, Zhaoning; Bezprozvannaya, Svetlana; McAnally, John R.; Tan, Wei; Li, Hui; Bassel-Duby, Rhonda; Liu, Ning; Olson, Eric N.] Univ Texas Southwestern Med Ctr Dallas, Hamon Ctr Regenerat Sci & Med, Dept Mol Biol, 6000 Harry Hines Blvd, Dallas, TX 75390 USA.
   [Wang, Zhaoning] Univ Calif San Diego, San Diego Sch Med, Dept Cellular & Mol Med, La Jolla, CA 92093 USA.
C3 University of Texas System; University of Texas Southwestern Medical
   Center Dallas; University of California System; University of California
   San Diego
RP Liu, N; Olson, EN (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Hamon Ctr Regenerat Sci & Med, Dept Mol Biol, 6000 Harry Hines Blvd, Dallas, TX 75390 USA.
EM Ning.Liu@utsouthwestern.edu; eric.olson@utsouthwestern.edu
RI Tan, Wei/KBB-7333-2024; LI, HUI/G-1227-2011; Gan, Peiheng/ABC-7490-2020;
   Wang, Zhaoning/AAB-5893-2021
OI Gan, Peiheng/0000-0001-8617-0606; Li, Hui/0000-0002-4114-8349; Liu,
   Ning/0000-0003-0257-1889; mcanally, john/0000-0001-6938-2703
FU National Institutes of Health (NIH) [HL-130253, AR-071980, HD-087351];
   Fondation Leducq Transatlantic Networks of Excellence in Cardiovascular
   Research; Robert A. Welch Foundation [1-0025]; American Heart
   Association [825635]; American Heart Association (AHA) [825635] Funding
   Source: American Heart Association (AHA)
FX This work was supported by grants from the National Institutes of Health
   (NIH) (HL-130253, AR-071980, and HD-087351), the Fondation Leducq
   Transatlantic Networks of Excellence in Cardiovascular Research, and the
   Robert A. Welch Foundation (grant 1-0025 to E.N.O.). P.G. was supported
   by a post-doctoral fellowship from the American Heart Association
   (825635). Z.W. is a DDBrown Awardee of the Life Sciences Research
   Foundation.
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NR 44
TC 14
Z9 14
U1 2
U2 6
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0008-6363
EI 1755-3245
J9 CARDIOVASC RES
JI Cardiovasc. Res.
PD FEB 27
PY 2024
VL 120
IS 1
BP 56
EP 68
DI 10.1093/cvr/cvad166
EA NOV 2023
PG 13
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA JN3K5
UT WOS:001108890000001
PM 37890031
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Schroeter, A
   Walzik, S
   Blechschmidt, S
   Haufe, V
   Benndorf, K
   Zimmer, T
AF Schroeter, Annett
   Walzik, Stefan
   Blechschmidt, Steve
   Haufe, Volker
   Benndorf, Klaus
   Zimmer, Thomas
TI Structure and function of splice variants of the cardiac voltage-gated
   sodium channel Nav1.5
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Review
DE Sodium channel; SCN5A; Cellular electrophysiology; Arrhythmias;
   Alternative splicing
ID SMOOTH-MUSCLE CELLS; DORSAL-ROOT GANGLIA; ALPHA-SUBUNIT GENES;
   BREAST-CANCER CELLS; NA+ CHANNEL; MESSENGER-RNA; RAT-BRAIN;
   SKELETAL-MUSCLE; LUNG-CANCER; MOUSE HEART
AB Voltage-gated sodium channels mediate the rapid upstroke of the action potential in excitable tissues The tetrodotoxin (TTX) resistant isoform Na(v)1.5, encoded by the SCN5A gene, is the predominant isoform in the heart. This channel plays a key role for excitability of atrial and ventricular cardiomyocytes and for rapid Impulse propagation through the specific conduction system During recent years, strong evidence has been accumulated in support of the expression of several Na(v)1.5 splice variants in the heart, and in various other tissues and cell lines including brain, dorsal root ganglia, breast cancer cells and neuronal stem cell lines This review summarizes our knowledge on the structure and putative function of nine Na(v)1.5 splice variants detected so far. Attention will be paid to the distinct biophysical properties of the four functional splice variants, to the pronounced tissue- and species-specific expression, and to the developmental regulation of Na(v)1.5 splicing The implications of alternative splicing for SCN5A channelopathies, and for a better understanding of genotype-phenotype correlations, are discussed (C) 2010 Elsevier Ltd. All rights reserved
C1 [Schroeter, Annett; Walzik, Stefan; Blechschmidt, Steve; Haufe, Volker; Benndorf, Klaus; Zimmer, Thomas] Univ Jena, Inst Physiol 2, Univ Clin, D-07743 Jena, Germany.
C3 Friedrich Schiller University of Jena
RP Zimmer, T (corresponding author), Univ Jena, Inst Physiol 2, Univ Clin, Kollegiengasse 9, D-07743 Jena, Germany.
RI Zimmer, Thomas/ISU-6303-2023
OI Benndorf, Klaus/0000-0002-0707-4083
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NR 72
TC 53
Z9 65
U1 0
U2 8
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD JUL
PY 2010
VL 49
IS 1
BP 16
EP 24
DI 10.1016/j.yjmcc.2010.04.004
PG 9
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA 610QW
UT WOS:000278750300003
PM 20398673
DA 2025-04-10
ER

PT J
AU Cornelius, VA
   Fulton, JR
   Margariti, A
AF Cornelius, Victoria A.
   Fulton, Jenna R.
   Margariti, Andriana
TI Alternative Splicing: A Key Mediator of Diabetic Vasculopathy
SO GENES
LA English
DT Review
DE alternative splicing; cardiovascular disease; diabetic vasculopathy;
   atherosclerosis; isoforms; quaking; QKI; therapeutic strategies
ID ENDOTHELIAL GROWTH-FACTOR; VEGF-A; CARDIOVASCULAR-DISEASE; IN-VIVO;
   ANGIOGENESIS; ISOFORM; MUTATIONS; QUAKING; DYSFUNCTION; EXPRESSION
AB Cardiovascular disease is the leading cause of death amongst diabetic individuals. Atherosclerosis is the prominent driver of diabetic vascular complications, which is triggered by the detrimental effects of hyperglycemia and oxidative stress on the vasculature. Research has extensively shown diabetes to result in the malfunction of the endothelium, the main component of blood vessels, causing severe vascular complications. The pathogenic mechanism in which diabetes induces vascular dysfunction, however, remains largely unclear. Alternative splicing of protein coding pre-mRNAs is an essential regulatory mechanism of gene expression and is accepted to be intertwined with cellular physiology. Recently, a role for alternative splicing has arisen within vascular health, with aberrant mis-splicing having a critical role in disease development, including in atherosclerosis. This review focuses on the current knowledge of alternative splicing and the roles of alternatively spliced isoforms within the vasculature, with a particular focus on disease states. Furthermore, we explore the recent elucidation of the alternatively spliced QKI gene within vascular cell physiology and the onset of diabetic vasculopathy. Potential therapeutic strategies to restore aberrant splicing are also discussed.
C1 [Cornelius, Victoria A.; Fulton, Jenna R.; Margariti, Andriana] Wellcome Wolfson Inst Expt Med, Belfast BT9 7BL, Antrim, North Ireland.
RP Margariti, A (corresponding author), Wellcome Wolfson Inst Expt Med, Belfast BT9 7BL, Antrim, North Ireland.
EM vcornelius01@qub.ac.uk; jfulton07@qub.ac.uk; a.margariti@qub.ac.uk
FU British Heart Foundation; Department for the Economy studentships NI;
   MRC [MC_PC_19050] Funding Source: UKRI
FX This work was supported by grants from the British Heart Foundation and
   the Department for the Economy studentships NI.
CR American Heart Association, 2021, CARD DIS DIAB
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NR 79
TC 7
Z9 7
U1 0
U2 7
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2073-4425
J9 GENES-BASEL
JI Genes
PD SEP
PY 2021
VL 12
IS 9
AR 1332
DI 10.3390/genes12091332
PG 13
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA UV4ZU
UT WOS:000699489300001
PM 34573314
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Liao, P
   Yong, TF
   Liang, MC
   Yue, DT
   Soong, TW
AF Liao, P
   Yong, TF
   Liang, MC
   Yue, DT
   Soong, TW
TI Splicing for alternative structures of Cav1.2 Ca<SUP>2+</SUP>
   channels in cardiac and smooth muscles
SO CARDIOVASCULAR RESEARCH
LA English
DT Review
ID EPISODIC ATAXIA TYPE-2; GATED CALCIUM-CHANNEL; PRE-MESSENGER-RNA;
   PROTEIN-KINASE-C; ALPHA(1C) SUBUNIT; N-TERMINUS; CA2+-DEPENDENT
   INACTIVATION; BETA(4) SUBUNIT; ALPHA-1 SUBUNIT; CURRENT-DENSITY
AB An estimate of up to 60% of genes are subjected to alternative splicing, and 15% of human genetic diseases are associated with mutation of the splice sites [Krawczak M, Reiss J, and Cooper DN. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 1992; 90: 41-54; Cooper TA, and Mattox W. The regulation of splice-site selection, and its role in human disease. Am J Hum Genet 1997; 61: 259-66; Modrek B and Lee CJ. Alternative splicing in the human, mouse and rat genomes is associated with an increased frequency of exon creation and/or loss. Nat Genet 2003; 34: 177-80; Modrek B, Resch A, Grasso C, and Lee C. Genome-wide detection of alternative splicing in expressed sequences of human genes. Nucleic Acids Res 2001; 29: 2850-9; Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature 2001; 409: 860-921] [1-5]. The molecular diversity of alternatively spliced transcripts provides templates for a myriad of protein structures that are potentially crucial to sustaining the complexity of human physiology. The extensive alternative splicing of the alpha(1)1.2-subunit of the L-type Ca(v)l.2 channel, producing splice variants with distinct electrophysiological and pharmacological properties, would impact directly on the function of the cardiovascular system. Cell-selective expression of Ca(v)1.2 channels containing a specific alternatively spliced exon increases the functional variations for specific cellular activities in response to changing physiological signals. However, the regulation or control of the a I 1.2-subunit alternative splicing machinery is unknown, and the role of numerous splice variants expressed in a cell is a mystery. A systematic and concerted effort is required to determine all the possible combinations of alternatively spliced exons in alpha(1)1.2-subunits in smooth and cardiac muscles. This will provide useful information to monitor changes on the usage of the entire suite of alternatively spliced exons to help relate altered Ca(v)1.2 channel function to physiology and disease. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
C1 Natl Univ Singapore, Fac Med, Dept Physiol, Singapore 117597, Singapore.
   Natl Inst Neurosci, Singapore 308433, Singapore.
   Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA.
   Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA.
C3 National University of Singapore; National Neuroscience Institute (NNI);
   Johns Hopkins University; Johns Hopkins University
RP Natl Univ Singapore, Fac Med, Dept Physiol, Blk MD9,2 Med Dr, Singapore 117597, Singapore.
EM tuck_wah_soong@nni.com.sg
RI Liao, Ping/LBI-1504-2024
OI Liang, Mui Cheng/0000-0003-1208-0733; Liao, Ping/0000-0002-6205-4042;
   Soong, Tuck Wah/0000-0002-0876-0325
FU NHLBI NIH HHS [P01HL52307-10] Funding Source: Medline
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NR 76
TC 100
Z9 116
U1 0
U2 15
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0008-6363
EI 1755-3245
J9 CARDIOVASC RES
JI Cardiovasc. Res.
PD NOV 1
PY 2005
VL 68
IS 2
BP 197
EP 203
DI 10.1016/j.cardiores.2005.06.024
PG 7
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 978VI
UT WOS:000232900700007
PM 16051206
DA 2025-04-10
ER

PT J
AU Vandecaetsbeek, I
   Raeymaekers, L
   Wuytack, F
   Vangheluwe, P
AF Vandecaetsbeek, Ilse
   Raeymaekers, Luc
   Wuytack, Frank
   Vangheluwe, Peter
TI Factors controlling the activity of the SERCA2a pump in the normal and
   failing heart
SO BIOFACTORS
LA English
DT Review
DE SERCA; Ca2+ affinity; heart disease; splicing; phospholamban; sarcolipin
ID SARCOPLASMIC-RETICULUM CA2+-ATPASE; CARDIAC-SPECIFIC OVEREXPRESSION;
   CALCIUM-BINDING PROTEIN; MESSENGER-RNA STABILITY; ENDOPLASMIC-RETICULUM;
   CA2+ HOMEOSTASIS; INSULIN-RECEPTOR; HISTIDINE-RICH; DILATED
   CARDIOMYOPATHY; GENE-TRANSFER
AB Heart failure is the leading cause of death in western countries and is often associated with impaired Ca2+ handling in the cardiomyocyte. In fact, cardiomyocyte relaxation and contraction are tightly controlled by the activity of the cardiac sarco(endo)plasmic reticulum(ER/SR) Ca2+ pump SERCA2a, pumping Ca2+ from the cytosol into the lumen of the ER/SR. This review addresses three important facets that control the SERCA2 activity in the heart. First, we focus on the alternative splicing of the SERCA2 messenger, which is strictly regulated in the developing heart. This splicing controls the formation of three SERCA2 splice variants with different enzymatic of properties. Second, we will discuss the role and regulation of SERCA2a activity in the normal and failing heart. The two well-studied Ca2+ affinity modulators phospholamban and sarcolipin control the activity of SERCA2a within a narrow window. An aberrantly high or low Ca2+ affinity is often observed in and may even trigger cardiac failure. Correcting SERCA2a activity might therefore constitute a therapeutic approach to improve the contractility of the failing heart. Finally, we address the controversies and unanswered questions of other putative regulators of the cardiac Ca2+ pump, such as sarcalumenin, HRC, S100A1, Bcl-2, HAX-1, calreticulin, calnexin, ERP57, IRS-1, and -2. (C) 2009 International Union of Biochemistry and Molecular Biology, Inc.
C1 [Vandecaetsbeek, Ilse; Raeymaekers, Luc; Wuytack, Frank; Vangheluwe, Peter] Katholieke Univ Leuven, Dept Mol Cell Biol, Lab Ca2 Transport ATPases, B-3000 Louvain, Belgium.
C3 KU Leuven
RP Wuytack, F (corresponding author), Katholieke Univ Leuven, Dept Mol Cell Biol, Lab Ca2 Transport ATPases, O&N1 Campus Gasthuisberg,Herestr 49,Bus 802, B-3000 Louvain, Belgium.
EM frank.wuytack@med.kuleuven.be
RI Vangheluwe, Peter/P-5476-2017
OI Vangheluwe, Peter/0000-0002-7822-2944
FU Research Foundation Flanders (FWO-Vlaanderen); FWO-Vlaanderen
   [G.0646.08]; Interuniversity Attraction Poles Program Belgium [P6/28]
FX P.V. is funded by the Research Foundation Flanders (FWO-Vlaanderen).
   This work was supported by the FWO-Vlaanderen (G.0646.08) and by the
   Interuniversity Attraction Poles Program Belgium (P6/28).
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NR 199
TC 37
Z9 49
U1 0
U2 16
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0951-6433
EI 1872-8081
J9 BIOFACTORS
JI Biofactors
PD NOV-DEC
PY 2009
VL 35
IS 6
BP 484
EP 499
DI 10.1002/biof.63
PG 16
WC Biochemistry & Molecular Biology; Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Endocrinology & Metabolism
GA 535NF
UT WOS:000272975200003
PM 19904717
DA 2025-04-10
ER

PT J
AU van den Homberg, DAL
   van der Kwast, RVCT
   Quax, PHA
   Nossent, AY
AF van den Homberg, Daphne A. L.
   van der Kwast, Reginald V. C. T.
   Quax, Paul H. A.
   Nossent, A. Yael
TI N-6-Methyladenosine in Vasoactive microRNAs during Hypoxia; A Novel Role
   for METTL4
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Article
DE N-6-methyladenosine; m6A; microRNAs; vascular; fibroblasts; hypoxia;
   ischemia; METTL4; METTL3
ID NUCLEAR-RNA; CARDIOVASCULAR-DISEASE; N6-METHYLADENOSINE; INHIBITION;
   NEOVASCULARIZATION; METHYLATION; SUBSTRATE; MIR-329; ALTERS
AB N-6-methyladenosine (m6A) is the most prevalent post-transcriptional RNA modification in eukaryotic cells. The modification is reversible and can be dynamically regulated by writer and eraser enzymes. Alteration in the levels of these enzymes can lead to changes in mRNA stability, alternative splicing or microRNA processing, depending on the m6A-binding proteins. Dynamic regulation of mRNA m6A methylation after ischemia and hypoxia influences mRNA stability, alternative splicing and translation, contributing to heart failure. In this study, we studied vasoactive microRNA m6A methylation in fibroblasts and examined the effect of hypoxia on microRNAs methylation using m6A immunoprecipitation. Of the 19 microRNAs investigated, at least 16 contained m6A in both primary human fibroblasts and a human fibroblast cell line, suggesting vasoactive microRNAs are commonly m6A methylated in fibroblasts. More importantly, we found that mature microRNA m6A levels increased upon subjecting cells to hypoxia. By silencing different m6A writer and eraser enzymes followed by m6A immunoprecipitation, we identified METTL4, an snRNA m6A methyltransferase, to be predominantly responsible for the increase in m6A modification. Moreover, by using m6A-methylated microRNA mimics, we found that microRNA m6A directly affects downstream target mRNA repression efficacy. Our findings highlight the regulatory potential of the emerging field of microRNA modifications.
C1 [van den Homberg, Daphne A. L.; van der Kwast, Reginald V. C. T.; Quax, Paul H. A.; Nossent, A. Yael] Leiden Univ, Med Ctr, Dept Surg, NL-2300 RC Leiden, Netherlands.
   [van den Homberg, Daphne A. L.; van der Kwast, Reginald V. C. T.; Quax, Paul H. A.; Nossent, A. Yael] Leiden Univ, Med Ctr, Einthoven Lab Expt Vasc Med, NL-2300 RC Leiden, Netherlands.
   [Nossent, A. Yael] Med Univ Vienna, Dept Lab Med, AT-1090 Vienna, Austria.
   [Nossent, A. Yael] Med Univ Vienna, Dept Internal Med 2, AT-1090 Vienna, Austria.
C3 Leiden University - Excl LUMC; Leiden University; Leiden University
   Medical Center (LUMC); Leiden University; Leiden University Medical
   Center (LUMC); Leiden University - Excl LUMC; Medical University of
   Vienna; Medical University of Vienna
RP Nossent, AY (corresponding author), Leiden Univ, Med Ctr, Dept Surg, NL-2300 RC Leiden, Netherlands.; Nossent, AY (corresponding author), Leiden Univ, Med Ctr, Einthoven Lab Expt Vasc Med, NL-2300 RC Leiden, Netherlands.; Nossent, AY (corresponding author), Med Univ Vienna, Dept Lab Med, AT-1090 Vienna, Austria.; Nossent, AY (corresponding author), Med Univ Vienna, Dept Internal Med 2, AT-1090 Vienna, Austria.
EM d.a.l.van_den_homberg@lumc.nl; regi.vd.kwast@tum.de; p.h.a.quax@lumc.nl;
   a.y.nossent@lumc.nl
RI Quax, Paul/W-8520-2019
OI Nossent, Anne Yael/0000-0002-2155-4286; Van den Homberg,
   Daphne/0000-0001-7359-9470; Quax, Paul/0000-0002-6853-5760
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NR 56
TC 25
Z9 25
U1 0
U2 37
PU MDPI
PI BASEL
PA MDPI AG, Grosspeteranlage 5, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD FEB
PY 2022
VL 23
IS 3
AR 1057
DI 10.3390/ijms23031057
PG 16
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA YZ8DM
UT WOS:000755701800001
PM 35162982
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Tao, LA
   Valdimarsson, G
AF Tao, Liang
   Valdimarsson, Gunnar
TI Tandem alternative splicing of zebrafish connexin45.6
SO GENOMICS
LA English
DT Article
DE Connexin; Gap junction; Tandem alternative splicing; Alternative
   promoter; Genomic structure; Zebrafish
ID TIME RT-PCR; GAP-JUNCTIONS; CARDIOVASCULAR DEVELOPMENT;
   MOLECULAR-CLONING; PROMOTER USAGE; CDNA ENDS; GENE; MOUSE; EXPRESSION;
   HEART
AB Early studies suggested that most connexin genes share a relatively simple structure with a single intron of variable length interrupting the 5' untranslated region (UTR). Here we report that zebrafish cx45.6 shows six isoforms of alternative 5'UTRs which are generated from multiple promoter usage and alternative pre-mRNA splicing. Interestingly, cx45.6 undergoes tandem alternative splicing, which produces transcripts only differing by 3 nucleotides. This is the first study that has demonstrated tandem alternative pre-mRNA splicing in the connexin gene family. Expression patterns of cx45.6 alternative transcripts were demonstrated by real-time RT-PCR during zebrafish embryonic development and in adult tissues. The complexity of 5'UTR diversity suggests complicated regulatory mechanisms for cx45.6 gene expression at both transcriptional and post-transcriptional levels, and we propose that tandem alternative splicing in cx45.6 5'UTRs could play a role in translational control. These results lay groundwork for further investigations on the regulation and function of cx45.6 gene expression. (C) 2010 Elsevier Inc. All rights reserved.
C1 [Tao, Liang; Valdimarsson, Gunnar] Univ Manitoba, Dept Biol Sci, Winnipeg, MB R3T 2N2, Canada.
   [Valdimarsson, Gunnar] Univ Manitoba, Dept Biochem & Med Genet, Winnipeg, MB, Canada.
C3 University of Manitoba; University of Manitoba
RP Tao, LA (corresponding author), Univ Manitoba, Manitoba Ctr Prote & Syst Biol, Winnipeg, MB R3E 3P4, Canada.
EM tao@cc.umanitoba.ca
FU Natural Sciences and Engineering Research Council of Canada (NSERC);
   Manitoba Health Research Council (MHRC)
FX This work was supported by a Natural Sciences and Engineering Research
   Council of Canada (NSERC) grant and a Manitoba Health Research Council
   (MHRC) grant awarded to CV. LT was financially supported by a MHRC
   fellowship.
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NR 63
TC 1
Z9 1
U1 0
U2 1
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0888-7543
EI 1089-8646
J9 GENOMICS
JI Genomics
PD AUG
PY 2010
VL 96
IS 2
BP 112
EP 118
DI 10.1016/j.ygeno.2010.05.001
PG 7
WC Biotechnology & Applied Microbiology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Genetics & Heredity
GA 632RA
UT WOS:000280443800006
PM 20466054
DA 2025-04-10
ER

PT J
AU Morinaga, A
   Ito, J
   Niimi, T
   Maturana, AD
AF Morinaga, Akihito
   Ito, Jumpei
   Niimi, Tomoaki
   Maturana, Andres D.
TI RBM20 Regulates CaV1.2 Surface Expression by Promoting Exon 9*Inclusion
   of CACNA1C in Neonatal Rat Cardiomyocytes
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Article
DE l-type voltage-gated calcium channels; alternative splicing;
   cardiomyocytes; RBM20
ID CALCIUM-CHANNEL; BETA-SUBUNITS
AB The CACNA1C gene encodes for the CaV1.2 protein, which is the pore subunit of cardiac l-type voltage-gated calcium (Ca2+) channels (l-channels). Through alternative splicing, CACNA1C encodes for various CaV1.2 isoforms with different electrophysiological properties. Splice variants of CaV1.2 are differentially expressed during heart development or pathologies. The molecular mechanisms of CACNA1C alternative splicing still remain incompletely understood. RNA sequencing analysis has suggested that CACNA1C is a potential target of the splicing factor RNA-binding protein motif 20 (RBM20). Here, we aimed at elucidating the role of RBM20 in the regulation of CACNA1C alternative splicing. We found that in neonatal rat cardiomyocytes (NRCMs), RBM20 overexpression promoted the inclusion of CACNA1C's exon 9*, whereas the skipping of exon 9* occurred upon RBM20 siRNA knockdown. The splicing of other known alternative exons was not altered by RBM20. RNA immunoprecipitation suggested that RBM20 binds to introns flanking exon 9*. Functionally, in NRCMs, RBM20 overexpression decreased l-type Ca2+ currents, whereas RBM20 siRNA knockdown increased l-type Ca2+ currents. Finally, we found that RBM20 overexpression reduced CaV1.2 membrane surface expression in NRCMs. Taken together, our results suggest that RBM20 specifically regulates the inclusion of exon 9* in CACNA1C mRNA, resulting in reduced cell-surface membrane expression of l-channels in cardiomyocytes.
C1 [Morinaga, Akihito; Niimi, Tomoaki; Maturana, Andres D.] Nagoya Univ, Grad Sch Bioagr Sci, Lab Anim Cell Physiol, Nagoya, Aichi 4648601, Japan.
   [Ito, Jumpei] Kings Coll London, British Heart Fdn Ctr Excellence, Sch Cardiovasc Med & Sci, London SE5 9NU, England.
C3 Nagoya University; University of London; King's College London
RP Maturana, AD (corresponding author), Nagoya Univ, Grad Sch Bioagr Sci, Lab Anim Cell Physiol, Nagoya, Aichi 4648601, Japan.
EM nago.akihito89@gmail.com; jumpei.ito@kcl.ac.uk;
   tniimi@agr.nagoya-u.ac.jp; maturana@agr.nagoya-u.ac.jp
OI Ito, Jumpei/0000-0001-5149-9962
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NR 18
TC 6
Z9 7
U1 1
U2 2
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD NOV
PY 2019
VL 20
IS 22
AR 5591
DI 10.3390/ijms20225591
PG 12
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA JW0YW
UT WOS:000502786800073
PM 31717392
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Ruano, CSM
   Apicella, C
   Jacques, S
   Gascoin, G
   Gaspar, C
   Miralles, F
   Méhats, C
   Vaiman, D
AF Ruano, Camino S. M.
   Apicella, Clara
   Jacques, Sebastien
   Gascoin, Geraldine
   Gaspar, Cassandra
   Miralles, Francisco
   Mehats, Celine
   Vaiman, Daniel
TI Alternative splicing in normal and pathological human placentas is
   correlated to genetic variants
SO HUMAN GENETICS
LA English
DT Article
ID INTRAUTERINE GROWTH RESTRICTION; PREECLAMPSIA; EXPRESSION; RNA; GENOME;
   STOX1; TRANSCRIPTOME; FEATURES; NUCLEAR; BRAIN
AB Two major obstetric diseases, preeclampsia (PE), a pregnancy-induced endothelial dysfunction leading to hypertension and proteinuria, and intra-uterine growth-restriction (IUGR), a failure of the fetus to acquire its normal growth, are generally triggered by placental dysfunction. Many studies have evaluated gene expression deregulations in these diseases, but none has tackled systematically the role of alternative splicing. In the present study, we show that alternative splicing is an essential feature of placental diseases, affecting 1060 and 1409 genes in PE vs controls and IUGR vs controls, respectively, many of those involved in placental function. While in IUGR placentas, alternative splicing affects genes specifically related to pregnancy, in preeclamptic placentas, it impacts a mix of genes related to pregnancy and brain diseases. Also, alternative splicing variations can be detected at the individual level as sharp splicing differences between different placentas. We correlate these variations with genetic variants to define splicing Quantitative Trait Loci (sQTL) in the subset of the 48 genes the most strongly alternatively spliced in placental diseases. We show that alternative splicing is at least partly piloted by genetic variants located either in cis (52 QTL identified) or in trans (52 QTL identified). In particular, we found four chromosomal regions that impact the splicing of genes in the placenta. The present work provides a new vision of placental gene expression regulation that warrants further studies.
C1 [Ruano, Camino S. M.; Apicella, Clara; Jacques, Sebastien; Miralles, Francisco; Mehats, Celine; Vaiman, Daniel] Univ Paris, CNRS, Inst Cochin, Inserm,U1016, 24 Rue Faubourg St Jacques, F-75014 Paris, France.
   [Gascoin, Geraldine] Univ Angers, CNRS 6015, Unite Mixte Rech MITOVASC, Equipe Mitolab,INSERM,U1083, Angers, France.
   [Gascoin, Geraldine] Ctr Hosp Univ, Reanimat & Med Neonatales, Angers, France.
   [Gaspar, Cassandra] Sorbonne Univ, Inserm, UMS Prod & Anal Donnees Sci Vie & Sante, PASS,Plateforme Postgenom Pitie Salpetriere,P3S, F-75013 Paris, France.
C3 Universite Paris Cite; Centre National de la Recherche Scientifique
   (CNRS); Institut National de la Sante et de la Recherche Medicale
   (Inserm); Universite d'Angers; Institut National de la Sante et de la
   Recherche Medicale (Inserm); CHU de Toulouse; Universite d'Angers;
   Centre Hospitalier Universitaire d'Angers; Sorbonne Universite; Institut
   National de la Sante et de la Recherche Medicale (Inserm)
RP Vaiman, D (corresponding author), Univ Paris, CNRS, Inst Cochin, Inserm,U1016, 24 Rue Faubourg St Jacques, F-75014 Paris, France.
EM daniel.vaiman@inserm.fr
RI Gascoin, Geraldine/ABE-4950-2020; Jacques, Sebastien/ITT-3046-2023;
   Mehats, Celine/D-8650-2017; Vaiman, Daniel/O-6030-2015
OI Apicella, Clara/0009-0008-9564-3039; Mehats, Celine/0000-0002-3677-2024;
   Vaiman, Daniel/0000-0002-1915-0717; GASPAR,
   Cassandra/0000-0002-6358-6657; Ruano, Camino/0000-0002-4003-2117;
   Gascoin, Geraldine/0009-0001-6317-4871
FU European Union's Horizon 2020 research and innovation program under
   Marie Sklodowska-Curie Actions Innovative Training Network
   (H2020-MSCA-ITN 2017) [765274]; INSERM; Angers University Hospital,
   France
FX The PhD projects of CRSM and CA is funded by the European Union's
   Horizon 2020 research and innovation program under Marie
   Sklodowska-Curie Actions Innovative Training Network (H2020-MSCA-ITN
   2017), Grant No. 765274, acronym iPLACENTA (http://www.iplacenta.eu); in
   addition, recurrent funding was obtained from INSERM. The Angers
   University Hospital Cohort was funded by a grant from the Angers
   University Hospital, France.
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NR 65
TC 12
Z9 12
U1 2
U2 11
PU SPRINGER
PI NEW YORK
PA ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES
SN 0340-6717
EI 1432-1203
J9 HUM GENET
JI Hum. Genet.
PD MAY
PY 2021
VL 140
IS 5
SI SI
BP 827
EP 848
DI 10.1007/s00439-020-02248-x
EA JAN 2021
PG 22
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA RO1FB
UT WOS:000607359700002
PM 33433680
OA hybrid, Green Published
DA 2025-04-10
ER

PT J
AU DeBenedittis, P
   Jiao, K
AF DeBenedittis, Paige
   Jiao, Kai
TI Alternative splicing of T-box transcription factor genes
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Review
DE Alternative splicing; T-box; TBX3; TBX5; TBX20
ID ULNAR-MAMMARY SYNDROME; CELL-PROLIFERATION; EPITHELIAL-CELLS; HUMAN
   TBX3; MUTATIONS; EXPRESSION; MUSKELIN; LIMB; SPECIFICATION; COMPLEX
AB T-box (TBX) transcription factors are an ancient gene family with critical roles in embryogenesis. Currently, TBX3, TBX5, and TBX20 are TBX genes defined to have multiple protein isoforms created by alternative splicing and characterized by expression and functional studies. These proteins are important for development as mutations lead to severe developmental disorders in humans and mice. Cumulative studies suggest that alternative splicing of these genes can regulate TBX activities during multiple biological processes including cardiogenesis, limb development, and cancer mechanisms. This mini-review focuses on how alternative splicing adds complexity to transcriptional regulation of target genes controlled by TBX transcription factors. (C) 2011 Elsevier Inc. All rights reserved.
C1 [DeBenedittis, Paige; Jiao, Kai] Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA.
C3 University of Alabama System; University of Alabama Birmingham
RP Jiao, K (corresponding author), Kaul 768,720 20th St S, Birmingham, AL 35294 USA.
EM kjiao@uab.edu
OI Jiao, Kai/0000-0002-5415-9020
FU UAB Faculty; NHLBI [HL095783-01A1]
FX We regret that we could not reference all studies in this area due to
   space limitations. The work in KJ's lab is supported by a UAB Faculty
   Development Grant and a NHLBI R01 Grant (HL095783-01A1) awarded to KJ.
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NR 46
TC 18
Z9 23
U1 1
U2 17
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD SEP 9
PY 2011
VL 412
IS 4
BP 513
EP 517
DI 10.1016/j.bbrc.2011.08.010
PG 5
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA 823TD
UT WOS:000295148500001
PM 21856288
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Beqqali, A
   Bollen, IAE
   Rasmussen, TB
   van den Hoogenhof, MM
   van Deutekom, HWM
   Schafer, S
   Haas, J
   Meder, B
   Sorensen, KE
   van Oort, RJ
   Mogensen, J
   Hubner, N
   Creemers, EE
   van der Velden, J
   Pinto, YM
AF Beqqali, Abdelaziz
   Bollen, Ilse A. E.
   Rasmussen, Torsten B.
   van den Hoogenhof, Maarten M.
   van Deutekom, Hanneke W. M.
   Schafer, Sebastian
   Haas, Jan
   Meder, Benjamin
   Sorensen, Keld E.
   van Oort, Ralph J.
   Mogensen, Jens
   Hubner, Norbert
   Creemers, Esther E.
   van der Velden, Jolanda
   Pinto, Yigal M.
TI A mutation in the glutamate-rich region of RNA-binding motif protein 20
   causes dilated cardiomyopathy through missplicing of titin and impaired
   Frank-Starling mechanism
SO CARDIOVASCULAR RESEARCH
LA English
DT Article
DE Sarcomere; Cardiomyopathy; Dilated cardiomyopathy; Heart failure;
   Alternative splicing; RBM20
ID LENGTH-DEPENDENT ACTIVATION; CALCIUM HOMEOSTASIS; TROPONIN-I; RBM20;
   EXPRESSION; GENE; MYOCARDIUM; STIFFNESS; REVEALS; TENSION
AB Mutations in the RS-domain of RNA-binding motif protein 20 (RBM20) have recently been identified to segregate with aggressive forms of familial dilated cardiomyopathy (DCM). Loss of RBM20 in rats results in missplicing of the sarcomeric gene titin (TTN). The functional and physiological consequences of RBM20 mutations outside the mutational hotspot of RBM20 have not been explored to date. In this study, we investigated the pathomechanism of DCM caused by a novel RBM20 mutation in human cardiomyocytes.
   We identified a family with DCM carrying a mutation (RBM20(E913K/+)) in a glutamate-rich region of RBM20. Western blot analysis of endogenous RBM20 protein revealed strongly reduced protein levels in the heart of an RBM20(E913K/+) carrier. RNA deep-sequencing demonstrated massive inclusion of exons coding for the spring region of titin in the RBM20(E913K/+) carrier. Titin isoform analysis revealed a dramatic shift from the less compliant N2B towards the highly compliant N2BA isoforms in RBM20(E913K/+) heart. Moreover, an increased sarcomere resting-length was observed in single cardiomyocytes and isometric force measurements revealed an attenuated Frank-Starling mechanism (FSM), which was rescued by protein kinase A treatment.
   A mutation outside the mutational hotspot of RBM20 results in haploinsufficiency of RBM20. This leads to disturbed alternative splicing of TTN, resulting in a dramatic shift to highly compliant titin isoforms and an impaired FSM. These effects may contribute to the early onset, and malignant course of DCM caused by RBM20 mutations. Altogether, our results demonstrate that heterozygous loss of RBM20 suffices to profoundly impair myocyte biomechanics by its disturbance of TTN splicing.
C1 [Beqqali, Abdelaziz; van den Hoogenhof, Maarten M.; van Deutekom, Hanneke W. M.; van Oort, Ralph J.; Creemers, Esther E.; Pinto, Yigal M.] Acad Med Ctr, Dept Expt Cardiol, Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands.
   [Bollen, Ilse A. E.; van der Velden, Jolanda] Vrije Univ Amsterdam, Med Ctr, Inst Cardiovasc Res ICaR VU, Dept Physiol, Boechorststr 7, NL-1081 BT Amsterdam, Netherlands.
   [Rasmussen, Torsten B.; Sorensen, Keld E.] Aarhus Univ Hosp, Dept Cardiol, Norrebrogade 44, DK-8000 Aarhus, Denmark.
   [Schafer, Sebastian] Natl Heart Ctr Singapore, Natl Heart Res Inst Singapore, 5 Hosp Dr, Singapore 169609, Singapore.
   [Schafer, Sebastian] Duke Natl Univ Singapore, Div Cardiovasc & Metab Disorders, 8 Coll Rd, Singapore 169857, Singapore.
   [Haas, Jan; Meder, Benjamin] Univ Heidelberg Hosp, Cardiol, Dept Internal Med 3, D-69120 Heidelberg, Germany.
   [Haas, Jan; Meder, Benjamin; Hubner, Norbert] DZHK German Ctr Cardiovasc Res, Oudenarder Str 16, D-13347 Berlin, Germany.
   [Mogensen, Jens] Odense Univ Hosp, Dept Cardiol, Sdr Blvd 29, DK-5000 Odense, Denmark.
   [Hubner, Norbert] Charite Univ Med Berlin, Charitepl 1, D-10117 Berlin, Germany.
   [Hubner, Norbert] Max Delbruck Ctr Mol Med MDC, Cardiovasc & Metab Sci, Robert Rossle Str 10, D-13125 Berlin, Germany.
C3 University of Amsterdam; Academic Medical Center Amsterdam; Vrije
   Universiteit Amsterdam; Aarhus University; National Heart Centre
   Singapore; National University of Singapore; Ruprecht Karls University
   Heidelberg; German Centre for Cardiovascular Research; University of
   Southern Denmark; Odense University Hospital; Berlin Institute of
   Health; Free University of Berlin; Humboldt University of Berlin;
   Charite Universitatsmedizin Berlin; Helmholtz Association; Max Delbruck
   Center for Molecular Medicine
RP Beqqali, A (corresponding author), Acad Med Ctr, Dept Expt Cardiol, Meibergdreef 15, NL-1105 AZ Amsterdam, Netherlands.
EM a.beqqali@icloud.com
RI van der Velden, J/D-1925-2016; van Deutekom, Hanneke/H-9140-2013; van
   Heesch, Sebastiaan/AAT-6595-2020; van Oort, Ralph/C-5713-2011; Beqqali,
   Abdelaziz/F-8568-2013
OI van den Hoogenhof, Maarten/0000-0003-2768-3457; Creemers,
   Esther/0000-0002-9001-3854; Rasmussen, Torsten
   Bloch/0000-0003-1468-7248; Mogensen, Jens/0000-0002-8813-573X; ,
   yigal/0000-0002-2836-571X; van Deutekom, Hanneke W.
   M./0000-0002-2429-1098; Beqqali, Abdelaziz/0000-0003-1390-5821; Schafer,
   Sebastian/0000-0002-6909-8275; van der Velden,
   Jolanda/0000-0001-5224-5788
FU Netherlands Organisation for Scientific Research (NWO) [825.13.007,
   836.12.002]; Netherlands Cardiovascular Research Initiative [CVON
   2011-11]; CVON young talent programme; EU FP7 project INHERITANCE
   [241924]; Lundbeck Foundation; Rembrandt grant; Arvid Nilsson's
   Foundation
FX This work was supported by grants from the Netherlands Organisation for
   Scientific Research (NWO) (grants 825.13.007 and 836.12.002), the
   Netherlands Cardiovascular Research Initiative (CVON 2011-11), CVON
   young talent programme, EU FP7 project INHERITANCE 241924, the Lundbeck
   Foundation, Rembrandt grant 2013, and Arvid Nilsson's Foundation.
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NR 32
TC 83
Z9 90
U1 0
U2 5
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0008-6363
EI 1755-3245
J9 CARDIOVASC RES
JI Cardiovasc. Res.
PD OCT 1
PY 2016
VL 112
IS 1
BP 452
EP 463
DI 10.1093/cvr/cvw192
PG 12
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA EB7PC
UT WOS:000387579900005
PM 27496873
OA Bronze
DA 2025-04-10
ER

PT J
AU Natua, S
   Ashok, C
   Shukla, S
AF Natua, Subhashis
   Ashok, Cheemala
   Shukla, Sanjeev
TI Hypoxia-induced alternative splicing in human diseases: the pledge, the
   turn, and the prestige
SO CELLULAR AND MOLECULAR LIFE SCIENCES
LA English
DT Review
DE Hypoxia; Alternative splicing; Hallmarks of cancer; Cardiovascular
   disease; Neurodegenerative diseases; Splicing therapeutics
ID PRE-MESSENGER-RNA; INDUCIBLE FACTOR-I; GROWTH-FACTOR-I; K-RAS 4A; BCL-X;
   ANTISENSE OLIGONUCLEOTIDES; GLUTAMATE TRANSPORTERS; ERYTHROPOIETIN GENE;
   BREAST-CANCER; UP-REGULATION
AB Maintenance of oxygen homeostasis is an indispensable criterion for the existence of multicellular life-forms. Disruption of this homeostasis due to inadequate oxygenation of the respiring tissues leads to pathological hypoxia, which acts as a significant stressor in several pathophysiological conditions including cancer, cardiovascular defects, bacterial infections, and neurological disorders. Consequently, the hypoxic tissues develop necessary adaptations both at the tissue and cellular level. The cellular adaptations involve a dramatic alteration in gene expression, post-transcriptional and post-translational modification of gene products, bioenergetics, and metabolism. Among the key responses to oxygen-deprivation is the skewing of cellular alternative splicing program. Herein, we discuss the current concepts of oxygen tension-dependent alternative splicing relevant to various pathophysiological conditions. Following a brief description of cellular response to hypoxia and the pre-mRNA splicing mechanism, we outline the impressive number of hypoxia-elicited alternative splicing events associated with maladies like cancer, cardiovascular diseases, and neurological disorders. Furthermore, we discuss how manipulation of hypoxia-induced alternative splicing may pose promising strategies for novel translational diagnosis and therapeutic interventions.
C1 [Natua, Subhashis; Ashok, Cheemala; Shukla, Sanjeev] Indian Inst Sci Educ & Res Bhopal, Dept Biol Sci, Bhopal 462066, Madhya Pradesh, India.
C3 Indian Institute of Science Education & Research (IISER) - Bhopal
RP Shukla, S (corresponding author), Indian Inst Sci Educ & Res Bhopal, Dept Biol Sci, Bhopal 462066, Madhya Pradesh, India.
EM sanjeevs@iiserb.ac.in
RI Natua, Subhashis/AAT-2710-2021; Shukla, Sanjeev/L-8391-2018
OI Cheemala, Ashok/0000-0003-2259-2839; Natua,
   Subhashis/0000-0003-3973-2842; Shukla, Sanjeev/0000-0003-3361-0588
FU DBT/Wellcome Trust India Alliance Fellowship [IA/I/16/2/502719];
   Department of Science and Technology, Ministry of Science and
   Technology; Indian Institute of Science Education and Research Bhopal
FX This work is supported by DBT/Wellcome Trust India Alliance Fellowship
   Grant IA/I/16/2/502719 [to S.S.]. S.N. was supported by the Department
   of Science and Technology, Ministry of Science and Technology. C.A. was
   supported by Indian Institute of Science Education and Research Bhopal.
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NR 174
TC 14
Z9 16
U1 0
U2 10
PU SPRINGER BASEL AG
PI BASEL
PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND
SN 1420-682X
EI 1420-9071
J9 CELL MOL LIFE SCI
JI Cell. Mol. Life Sci.
PD MAR
PY 2021
VL 78
IS 6
BP 2729
EP 2747
DI 10.1007/s00018-020-03727-0
EA JAN 2021
PG 19
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA RD9SZ
UT WOS:000604199500001
PM 33386889
OA Green Published
DA 2025-04-10
ER

PT J
AU Qiu, HY
   Dai, HC
   Jain, K
   Shah, R
   Hong, C
   Pain, J
   Tian, B
   Vatner, DE
   Vatner, SF
   Depre, C
AF Qiu, Hongyu
   Dai, Huacheng
   Jain, Komal
   Shah, Rina
   Hong, Chull
   Pain, Jayashree
   Tian, Bin
   Vatner, Dorothy E.
   Vatner, Stephen F.
   Depre, Christophe
TI Characterization of a novel cardiac isoform of the cell cycle-related
   kinase that is regulated during heart failure
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID MYOCARDIAL-INFARCTION; ACTIVATING KINASE; GENE-EXPRESSION; H11 KINASE;
   APOPTOSIS; SURVIVAL; MECHANISMS; MYOCYTES; PROGRAM; COMPLEX
AB Myocardial infarction (MI) is often followed by heart failure (HF), but the mechanisms precipitating the transition to HF remain largely unknown. A genomic profile was performed in a monkey model of MI, from the myocardium adjacent to chronic (2-month) MI followed by 3 weeks of pacing to develop HF. The transcript of the gene encoding the cell cycle-related kinase (CCRK) was down-regulated by 50% in HF heart compared with control ( p < 0.05), which was confirmed by quantitative PCR. The CCRK sequence cloned from a heart library showed a conservation of the N-terminal kinase domain when compared with the "generic" isoform cloned previously but a different C-terminal half due to alternative splicing with frameshift. The homology of the cardiac sequence was 100% between mice and humans. Expression of the corresponding protein, measured upon generation of a monoclonal antibody, was limited to heart, liver, and kidney. Upon overexpression in cardiac myocytes, both isoforms promote cell growth and reduce apoptosis by chelerythrine (p < 0.05 versus control). Using a yeast two-hybrid screening, we found an interaction of the generic but not the cardiac CCRK with cyclin H and casein kinase 2. In addition, only the generic CCRK phosphorylates the cyclin-dependent kinase 2, which was accompanied by a doubling of myocytes in the S and G(2) phases of the cell cycle (p < 0.05 versus control). Therefore, the heart expresses a splice variant of CCRK, which promotes cardiac cell growth and survival; differs from the generic isoform in terms of protein-protein interactions, substrate specificity and regulation of the cell cycle; and is downregulated significantly in HF.
C1 [Jain, Komal; Tian, Bin] Univ Med & Dent New Jersey, Sch Med, Dept Biochem, Newark, NJ 07103 USA.
   [Qiu, Hongyu; Dai, Huacheng; Shah, Rina; Hong, Chull; Pain, Jayashree; Vatner, Dorothy E.; Vatner, Stephen F.; Depre, Christophe] Univ Med & Dent New Jersey, Sch Med, Dept Cell Biol & Mol Med, Cardiovasc Res Inst, Newark, NJ 07103 USA.
C3 Rutgers University System; Rutgers University New Brunswick; Rutgers
   University Biomedical & Health Sciences; Rutgers University System;
   Rutgers University New Brunswick; Rutgers University Biomedical & Health
   Sciences
RP Depre, C (corresponding author), Univ Med & Dent New Jersey, Sch Med, Dept Cell Biol & Mol Med, Cardiovasc Res Inst, MSB G609,185 S Orange Ave, Newark, NJ 07103 USA.
EM deprech@umdnj.edu
OI Tian, Bin/0000-0001-8903-8256
FU NHLBI NIH HHS [HL069020, HL059139, HL069752, HL033107] Funding Source:
   Medline; NIA NIH HHS [AG014121, AG027211, AG023137] Funding Source:
   Medline
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NR 36
TC 19
Z9 23
U1 0
U2 4
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
SN 0021-9258
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD AUG 8
PY 2008
VL 283
IS 32
BP 22157
EP 22165
DI 10.1074/jbc.M710459200
PG 9
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 332WV
UT WOS:000258114700035
PM 18508765
OA hybrid, Green Published
DA 2025-04-10
ER

PT J
AU Suhy, A
   Hartmann, K
   Newman, L
   Papp, A
   Toneff, T
   Hook, V
   Sadee, W
AF Suhy, Adam
   Hartmann, Katherine
   Newman, Leslie
   Papp, Audrey
   Toneff, Thomas
   Hook, Vivian
   Sadee, Wolfgang
TI Genetic variants affecting alternative splicing of human cholesteryl
   ester transfer protein
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE Cholesteryl ester transfer protein; Coronary artery disease; Statin;
   Alternative splicing; CETP levels in liver and plasma
ID DENSITY-LIPOPROTEIN CHOLESTEROL; HEART-DISEASE; CETP GENE; ASSOCIATION;
   POLYMORPHISMS
AB Cholesteryl ester transfer protein (CETP) plays an important role in reverse cholesterol transport, with decreased CETP activity increasing HDL levels. Formation of an alternative splice form lacking exon 9 (Delta 9-CETP) has been associated with two single nucleotide polymorphisms (SNPs) in high linkage disequilibrium with each other, namely rs9930761 T>C located in intron 8 in a putative splicing branch site and rs5883 C>T in a possible exonic splicing enhancer (ESE) site in exon 9. To assess the relative effect of rs9930761 and rs5883 on splicing, mini-gene constructs spanning CETP exons 8 to 10, carrying all four possible allele combinations, were transfected into HEK293 and HepG2 cells. The minor T allele of rs5883 enhanced splicing significantly in both cell lines whereas the minor C allele of rs9930761 did not. In combination, the two alleles did not yield greater splicing than the rs5883 T allele alone in HepG2 cells. These results indicate that the genetic effect on CETP splicing is largely attributable to rs5883. We also confirm that Delta 9-CETP protein is expressed in the liver but fails to circulate in the blood. (C) 2014 Elsevier Inc. All rights reserved.
C1 [Suhy, Adam; Hartmann, Katherine; Newman, Leslie; Papp, Audrey; Sadee, Wolfgang] Ohio State Univ, Wexner Med Ctr, Coll Med, Ctr Pharmacogen,Dept Pharmacol, Columbus, OH 43210 USA.
   [Hook, Vivian] Univ Calif San Diego, Sch Med, Skaggs Sch Pharm & Pharmaceut Sci, Dept Neurosci, La Jolla, CA 92093 USA.
   [Hook, Vivian] Univ Calif San Diego, Sch Med, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmacol, La Jolla, CA 92093 USA.
C3 University System of Ohio; Ohio State University; University of
   California System; University of California San Diego; University of
   California System; University of California San Diego
RP Suhy, A (corresponding author), 5168 Graves Hall,333 West 10th Ave, Columbus, OH 43210 USA.
EM suhy.2@osu.edu
RI Hartmann, Katherine/T-8874-2019
OI Suhy, Adam/0000-0003-1282-6339; Hartmann, Katherine/0000-0002-7051-8185;
   Newman, Leslie/0000-0002-0522-0278
FU NIH, part of the NIH Pharmacogenomics Research Network [U01 GM092655]
FX We acknowledge the advice of Dr. Dawn Chandler for designing the
   mini-genes. This study was supported NIH grant U01 GM092655, part of the
   NIH Pharmacogenomics Research Network.
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Z9 11
U1 1
U2 7
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD JAN 24
PY 2014
VL 443
IS 4
BP 1270
EP 1274
DI 10.1016/j.bbrc.2013.12.127
PG 5
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA AB6TD
UT WOS:000331921500023
PM 24393849
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Tijsen, AJ
   Ortega, LC
   Reckman, YJ
   Zhang, XL
   van der Made, I
   Aufiero, S
   Li, JR
   Kamps, SC
   van den Bout, A
   Devalla, HD
   van Spaendonck-Zwarts, KY
   Engelhardt, S
   Gepstein, L
   Ware, JS
   Pinto, YM
AF Tijsen, Anke J.
   Cocera Ortega, Lucia
   Reckman, Yolan J.
   Zhang, Xiaolei
   van der Made, Ingeborg
   Aufiero, Simona
   Li, Jiuru
   Kamps, Selina C.
   van den Bout, Anouk
   Devalla, Harsha D.
   van Spaendonck-Zwarts, Karin Y.
   Engelhardt, Stefan
   Gepstein, Lior
   Ware, James S.
   Pinto, Yigal M.
TI Titin Circular RNAs Create a Back-Splice Motif Essential for SRSF10
   Splicing
SO CIRCULATION
LA English
DT Article
DE alternative splicing; cardiomyopathies; induced pluripotent stem cells;
   RNA; circular; RNA; untranslated; SRSF10 protein; human
AB Background:
   TTN (Titin), the largest protein in humans, forms the molecular spring that spans half of the sarcomere to provide passive elasticity to the cardiomyocyte. Mutations that disrupt the TTN transcript are the most frequent cause of hereditary heart failure. We showed before that TTN produces a class of circular RNAs (circRNAs) that depend on RBM20 to be formed. In this study, we show that the back-splice junction formed by this class of circRNAs creates a unique motif that binds SRSF10 to enable it to regulate splicing. Furthermore, we show that one of these circRNAs (cTTN1) distorts both localization of and splicing by RBM20.
   Methods:
   We calculated genetic constraint of the identified motif in 125 748 exomes collected from the gnomAD database. Furthermore, we focused on the highest expressed RBM20-dependent circRNA in the human heart, which we named cTTN1. We used shRNAs directed to the back-splice junction to induce selective loss of cTTN1 in human induced pluripotent stem cell-derived cardiomyocytes.
   Results:
   Human genetics suggests reduced genetic tolerance of the generated motif, indicating that mutations in this motif might lead to disease. RNA immunoprecipitation confirmed binding of circRNAs with this motif to SRSF10. Selective loss of cTTN1 in human induced pluripotent stem cell-derived cardiomyocytes induced structural abnormalities, apoptosis, and reduced contractile force in engineered heart tissue. In line with its SRSF10 binding, loss of cTTN1 caused abnormal splicing of important cardiomyocyte SRSF10 targets such as MEF2A and CASQ2. Strikingly, loss of cTTN1 also caused abnormal splicing of TTN itself. Mechanistically, we show that loss of cTTN1 distorts both localization of and splicing by RBM20.
   Conclusions:
   We demonstrate that circRNAs formed from the TTN transcript are essential for normal splicing of key muscle genes by enabling splice regulators RBM20 and SRSF10. This shows that the TTN transcript also has regulatory roles, besides its well-known signaling and structural function. In addition, we demonstrate that the specific sequence created by the back-splice junction of these circRNAs has important functions. This highlights the existence of functionally important sequences that cannot be recognized as such in the human genome but provides an as-yet unrecognized source for functional sequence variation.
C1 [Tijsen, Anke J.; Cocera Ortega, Lucia; Reckman, Yolan J.; van der Made, Ingeborg; Aufiero, Simona; Kamps, Selina C.; van den Bout, Anouk; Pinto, Yigal M.] Univ Amsterdam, Amsterdam UMC, Dept Expt Cardiol, Amsterdam Cardiovasc Sci, Amsterdam, Netherlands.
   [Li, Jiuru; Devalla, Harsha D.] Univ Amsterdam, Amsterdam UMC, Dept Med Biol, Amsterdam Cardiovasc Sci, Amsterdam, Netherlands.
   [van Spaendonck-Zwarts, Karin Y.] Univ Amsterdam, Amsterdam UMC, Dept Clin Genet, Amsterdam, Netherlands.
   [Zhang, Xiaolei; Ware, James S.] Imperial Coll London, South Kensington Campus, London, England.
   [Engelhardt, Stefan] Partner Site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany.
   [Engelhardt, Stefan] Tech Univ Munich, Inst Pharmakol & Toxikol, Munich, Germany.
   [Gepstein, Lior] Technion Israel Inst Technol, Rappaport Fac Med & Res Inst, Sohnis Family Lab Cardiac Electrophysiol & Regene, Haifa, Israel.
C3 University of Amsterdam; University of Amsterdam; University of
   Amsterdam; Imperial College London; Munich Heart Alliance; German Centre
   for Cardiovascular Research; Technical University of Munich; Technion
   Israel Institute of Technology
RP Tijsen, AJ (corresponding author), Univ Amsterdam, Amsterdam UMC, Dept Expt Cardiol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands.
EM a.j.tijsen@amsterdamumc.nl; y.j.reckman@amc.uva.nl;
   xiaolei.zhang@imperial.ac.uk; i.vandermade@amsterdamumc.nl;
   s.aufiero@amsterdamumc.nl; J.Li1@amsterdamumc.nl;
   s.c.kamps@amsterdamumc.nl; anoukvdbout@gmail.com;
   h.d.devalla@amsterdamumc.nl;
   Karin.VanSpaendonck-Zwarts@health.qld.gov.au; stefan.engelhardt@tum.de;
   mdlior@technion.ac.il; j.ware@imperial.ac.uk; y.pinto@amsterdamumc.nl
RI van Spaendonck-Zwarts, Karin/AAY-1506-2021; Zhang,
   Xiaolei/AAQ-5284-2021; Gepstein, Lior/HOC-9949-2023; Engelhardt,
   Stefan/HJH-5744-2023; Ware, James/G-5139-2012; Devalla, Harsha
   D./GRF-0685-2022
OI Cocera Ortega, Lucia/0000-0002-5788-1617; Devalla, Harsha
   D./0000-0001-5343-1021; Ware, James/0000-0002-6110-5880; Li,
   Jiuru/0000-0003-3022-6361; Engelhardt, Stefan/0000-0001-5378-8661;
   Zhang, Xiaolei/0000-0003-2369-2719; Tijsen, Anke/0000-0002-8030-8894
FU ZonMw [Veni 91616150]; Netherlands Cardiovascular Research Initiative;
   Wellcome Trust [107469/Z/15/Z]; Medical Research Council (UK); British
   Heart Foundation [RE/18/4/34215]; NIHR Imperial College Biomedical
   Research Centre; MRC [MC_UP_1102/20] Funding Source: UKRI
FX This work was supported by grants from ZonMw to Dr Tijsen (Veni
   91616150), the Netherlands Cardiovascular Research Initiative to Dr
   Pinto (CVON-ARENAPRIME), the Wellcome Trust (107469/Z/15/Z), Medical
   Research Council (UK), British Heart Foundation (RE/18/4/34215), and the
   NIHR Imperial College Biomedical Research Centre to Dr Ware.
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NR 44
TC 25
Z9 28
U1 1
U2 9
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7322
EI 1524-4539
J9 CIRCULATION
JI Circulation
PD APR 13
PY 2021
VL 143
IS 15
BP 1502
EP 1512
DI 10.1161/CIRCULATIONAHA.120.050455
PG 11
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA RM3VO
UT WOS:000639592100012
PM 33583186
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Ye, JQ
   Beetz, N
   O'Keeffe, S
   Tapia, JC
   Macpherson, L
   Chen, WV
   Bassel-Duby, R
   Olson, EN
   Maniatis, T
AF Ye, Junqiang
   Beetz, Nadine
   O'Keeffe, Sean
   Tapia, Juan Carlos
   Macpherson, Lindsey
   Chen, Weisheng V.
   Bassel-Duby, Rhonda
   Olson, Eric N.
   Maniatis, Tom
TI hnRNP U protein is required for normal pre-mRNA splicing and postnatal
   heart development and function
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
   AMERICA
LA English
DT Article
DE heart development; alternative splicing; RNA-seq; dilated
   cardiomyopathy; N-glycosylation
ID BINDING PROTEINS; IN-VIVO; SAF-A; ENDOPLASMIC-RETICULUM; JUNCTIN;
   CARDIOMYOPATHY; IDENTIFICATION; EXPRESSION; MUSCLE; SEQ
AB We report that mice lacking the heterogeneous nuclear ribonucleoprotein U (hnRNP U) in the heart develop lethal dilated cardiomyopathy and display numerous defects in cardiac pre-mRNA splicing. Mutant hearts have disorganized cardiomyocytes, impaired contractility, and abnormal excitation-contraction coupling activities. RNA-seq analyses of Hnrnpu mutant hearts revealed extensive defects in alternative splicing of pre-mRNAs encoding proteins known to be critical for normal heart development and function, including Titin and calcium/calmodulin-dependent protein kinase II delta (Camk2d). Loss of hnRNP U expression in cardiomyocytes also leads to aberrant splicing of the pre-mRNA encoding the excitation-contraction coupling component Junctin. We found that the protein product of an alternatively spliced Junctin isoform is N-glycosylated at a specific asparagine site that is required for interactions with specific protein partners. Our findings provide conclusive evidence for the essential role of hnRNP U in heart development and function and in the regulation of alternative splicing.
C1 [Ye, Junqiang; O'Keeffe, Sean; Tapia, Juan Carlos; Macpherson, Lindsey; Chen, Weisheng V.; Maniatis, Tom] Columbia Univ, Coll Phys & Surg, Dept Biochem & Mol Biophys, New York, NY 10032 USA.
   [Beetz, Nadine; Bassel-Duby, Rhonda; Olson, Eric N.] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA.
   [Beetz, Nadine] Univ Freiburg, Inst Expt & Clin Pharmacol & Toxicol, D-79104 Freiburg, Germany.
C3 Columbia University; University of Texas System; University of Texas
   Southwestern Medical Center Dallas; University of Freiburg
RP Maniatis, T (corresponding author), Columbia Univ, Coll Phys & Surg, Dept Biochem & Mol Biophys, New York, NY 10032 USA.
EM tm2472@columbia.edu
RI Lorkowski, Stefan/B-9689-2008; Bassel-Duby, Rhonda/HJP-5742-2023;
   Macpherson, Lindsey/IYS-3873-2023; Olson, Eric/B-4391-2013
OI Macpherson, Lindsey/0000-0002-1089-3733; Olson, Eric
   N./0000-0003-1151-8262; Bassel-Duby, Rhonda/0000-0001-7568-410X; Ye,
   Junqiang/0000-0002-4529-0713
FU National Institutes of Health (NIH) Pioneer Grant [8DP1NS082099];
   Columbia University Medical Center; NIH [HL-077439, HL-111665,
   HL-093039, DK-099653, U01-HL-100401]; Foundation Leducq Networks of
   Excellence; Cancer Prevention and Research Institute of Texas; Robert A.
   Welch Foundation Grant [1-0025]; Marie Curie International Outgoing
   Fellowship within the 7th European Community Framework Program
FX We thank Wei Tan for performing TAC and MI surgeries. We also thank
   members of the T.M. laboratory for discussions and comments on the
   manuscript. This work was supported by US National Institutes of Health
   (NIH) Pioneer Grant 8DP1NS082099 (to T.M.) and startup funds from the
   Columbia University Medical Center. E.N.O. was supported by NIH Grants
   HL-077439, HL-111665, HL-093039, DK-099653, and U01-HL-100401; the
   Foundation Leducq Networks of Excellence; the Cancer Prevention and
   Research Institute of Texas; and Robert A. Welch Foundation Grant
   1-0025. N.B. was supported by a Marie Curie International Outgoing
   Fellowship within the 7th European Community Framework Program.
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NR 56
TC 93
Z9 108
U1 1
U2 16
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD JUN 9
PY 2015
VL 112
IS 23
BP E3020
EP E3029
DI 10.1073/pnas.1508461112
PG 10
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA CJ9LG
UT WOS:000355823200010
PM 26039991
OA Green Published
DA 2025-04-10
ER

PT J
AU Tang, ZZ
   Hong, X
   Wang, J
   Soong, TW
AF Tang, Zhen Zhi
   Hong, Xin
   Wang, Jing
   Soong, Tuck Wah
TI Signature combinatorial splicing profiles of rat cardiac- and
   smooth-muscle Cav1.2 channels with distinct biophysical
   properties
SO CELL CALCIUM
LA English
DT Article
DE calcium channel; L-type calcium channel; Ca(v)1.2; alternative splicing;
   splice variant
ID CALCIUM-CHANNEL; CA2+ CHANNEL; MOLECULAR DIVERSITY; ALPHA(1C) SUBUNIT;
   FUNCTIONAL EXPRESSION; GENE-EXPRESSION; TRANSCRIPTS; INHIBITION;
   DIHYDROPYRIDINES; SENSITIVITY
AB L-type (Ca(v)1.2) voltage-gated calcium channels play an essential role in muscle contraction in the cardiovascular system. Alternative splicing of the pore-forming Ca-v 1.2 subunit provides potent means to enrich the functional diversity of the channels. There are 11 alternatively spliced exons identified in rat Ca(v)1.2 gene and random rearrangements may generate up to hundreds of combinatorial splicing profiles. Due to such complexity, the real combinatorial splicing profiles of Ca(v)1.2 have not been solved. This study investigated whether the 11 alternatively spliced exons are spliced randomly or linked and if linked, how many combinatorial splicing profiles can be arranged in cardiac- and smooth-muscle cells. By examining three full-length cDNA libraries of the Ca(v)1.2 transcripts isolated from rat heart and aorta, our results showed that the arrangements of some of the alternatively spliced exons are tissue-specific and tightly linked, giving rise to only 41 alternative combinatorial profiles, of which 29 have not been reported. Interestingly, the 41 combinatorial profiles were distinctively distributed in the three Ca(v)1.2 libraries and the one named "heart 1-50" contained unexpected splice variants. Significantly, the tissue-specific cardiac- and smooth-muscle combinatorial splicing profiles of Ca(v)1.2 channels demonstrated distinct electrophysiological properties that may help rationalize the differences observed in native currents. The unique sequences in these tissue-specific splice variants may provide the potential targets for drug design and screening. (c) 2006 Elsevier Ltd. All rights reserved.
C1 Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore.
   Natl Inst Neurosci, Singapore 308433, Singapore.
   Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA.
C3 National University of Singapore; National Neuroscience Institute (NNI);
   Johns Hopkins University
RP Soong, TW (corresponding author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Blk MD9,2 Med Dr, Singapore 117597, Singapore.
EM phsstw@nus.edu.sg
RI HONG, XIN/AAI-5177-2020
OI HONG, XIN/0000-0002-9671-0116
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NR 51
TC 43
Z9 46
U1 0
U2 0
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 0143-4160
EI 1532-1991
J9 CELL CALCIUM
JI Cell Calcium
PD MAY
PY 2007
VL 41
IS 5
BP 417
EP 428
DI 10.1016/j.ceca.2006.08.002
PG 12
WC Cell Biology; Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Physiology
GA 165RY
UT WOS:000246324400002
PM 16979758
DA 2025-04-10
ER

PT J
AU Dykstra-Aiello, C
   Sharp, FR
   Jickling, GC
   Hull, H
   Hamade, F
   Shroff, N
   Durocher, M
   Cheng, XY
   Zhan, XH
   Liu, DZ
   Ander, BP
   Stamova, BS
AF Dykstra-Aiello, Cheryl
   Sharp, Frank R.
   Jickling, Glen C.
   Hull, Heather
   Hamade, Farah
   Shroff, Natasha
   Durocher, Marc
   Cheng, Xiyuan
   Zhan, Xinhua
   Liu, DaZhi
   Ander, Bradley P.
   Stamova, Boryana S.
TI Alternative Splicing of Putative Stroke/Vascular Risk Factor Genes
   Expressed in Blood Following Ischemic Stroke Is Sexually Dimorphic and
   Cause-Specific
SO FRONTIERS IN NEUROLOGY
LA English
DT Article
DE gene; exon; stroke; sex; etiology; array
ID POLYMORPHISM; ASSOCIATION; VARIANTS; DISEASE; GENDER; SUSCEPTIBILITY;
   INFLAMMATION; METAANALYSIS; COAGULATION; WOMEN
AB Genome-wide association studies have identified putative ischemic stroke risk genes, yet, their expression after stroke is unexplored in spite of growing interest in elucidating their specific role and identifying candidate genes for stroke treatment. Thus, we took an exploratory approach to investigate sexual dimorphism, alternative splicing, and etiology in putative risk gene expression in blood following cardioembolic, atherosclerotic large vessel disease and small vessel disease/lacunar causes of ischemic stroke in each sex compared to controls. Whole transcriptome arrays assessed 71 putative stroke/vascular risk factor genes for blood RNA expression at gene-, exon-, and alternative splicing-levels. Male (n = 122) and female (n = 123) stroke and control volunteers from three university medical centers were matched for race, age, vascular risk factors, and blood draw time since stroke onset. Exclusion criteria included: previous stroke, drug abuse, subarachnoid or intracerebral hemorrhage, hemorrhagic transformation, infection, dialysis, cancer, hematological abnormalities, thrombolytics, anticoagulants or immunosuppressants. Significant differential gene expression (fold change > |1.2|, p < 0.05, partial correlation > |0.4|) and alternative splicing (false discovery rate p < 0.3) were assessed. At gene level, few were differentially expressed: ALDH2, ALOX5AP, F13A1, and IMPA2 (males, all stroke); ITGB3 (females, cardioembolic); ADD1 (males, atherosclerotic); F13A1, IMPA2 (males, lacunar); and WNK1 (females, lacunar). GP1BA and ITGA2B were alternatively spliced in both sexes (all patients vs. controls). Six genes in males, five in females, were alternatively spliced in all stroke compared to controls. Alternative splicing and exon-level analyses associated many genes with specific etiology in either sex. Of 71 genes, 70 had differential exon-level expression in stroke patients compared to control subjects. Among stroke patients, 24 genes represented by differentially expressed exons were male-specific, six were common between sexes, and two were female-specific. In lacunar stroke, expression of 19 differentially expressed exons representing six genes (ADD1, NINJ2, PCSK9, PEMT, SMARCA4, WNK1) decreased in males and increased in females. Results demonstrate alternative splicing and sexually dimorphic expression of most putative risk genes in stroke patients' blood. Since expression was also often cause-specific, sex, and etiology are factors to consider in stroke treatment trials and genetic association studies as society trends toward more personalized medicine.
C1 [Dykstra-Aiello, Cheryl; Sharp, Frank R.; Jickling, Glen C.; Hull, Heather; Hamade, Farah; Shroff, Natasha; Durocher, Marc; Cheng, Xiyuan; Zhan, Xinhua; Liu, DaZhi; Ander, Bradley P.; Stamova, Boryana S.] Univ Calif Davis, Med Invest Neurodevelopmental Disorders MIND Inst, Dept Neurol, Sacramento, CA 95817 USA.
C3 University of California System; University of California Davis
RP Stamova, BS (corresponding author), Univ Calif Davis, Med Invest Neurodevelopmental Disorders MIND Inst, Dept Neurol, Sacramento, CA 95817 USA.
EM bsstamova@ucdavis.edu
RI Jickling, Glen/J-8790-2019; Stamova, Boryana/ABA-2981-2020; Liu,
   DaZhi/B-6850-2011; Dykstra-Aiello, Cheryl/HPF-2368-2023
OI Jickling, Glen/0000-0003-3543-0820; Dykstra-Aiello,
   Cheryl/0000-0002-6802-336X; Stamova, Boryana/0000-0002-5440-8816
FU American Heart Association; NIH/NINDS [NS079153, NS075035, NS097000]
FX These studies were supported by an AHA Fellow to Faculty award to GJ,
   American Heart Association grants to BS and DL, and NIH/NINDS grants to
   FS, GJ, and BS (NS079153, NS075035, and NS097000).
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NR 55
TC 9
Z9 9
U1 0
U2 3
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 1664-2295
J9 FRONT NEUROL
JI Front. Neurol.
PD OCT 22
PY 2020
VL 11
AR 584695
DI 10.3389/fneur.2020.584695
PG 20
WC Clinical Neurology; Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA OL3UX
UT WOS:000585269800001
PM 33193047
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Huang, C
   Cao, WW
   Liao, RJ
   Wang, J
   Wang, YZ
   Tong, LJ
   Chen, XF
   Zhu, WZ
   Zhang, W
AF Huang, Chao
   Cao, Wenwen
   Liao, Rujia
   Wang, Jia
   Wang, Yuzhe
   Tong, Lijuan
   Chen, Xiangfan
   Zhu, Weizhong
   Zhang, Wei
TI PP1γ functionally augments the alternative splicing of CaMKIIδ through
   interaction with ASF
SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
LA English
DT Article
DE protein phosphatase 1 gamma; alternative splicing factor; CaMKII delta
   C; splicing; cardiomyocytes
ID PROTEIN PHOSPHATASE 1; DILATED CARDIOMYOPATHY; CARDIAC-HYPERTROPHY; BAX
   ACTIVATION; KINASE; PHOSPHORYLATION; EXPRESSION; ISOFORM; APOPTOSIS;
   ASF/SF2
AB Protein phosphatase 1 (PP1) and Ca2+/calmodulin-dependent protein kinase delta (CaMKII delta) are upregulated in heart disorders. Alternative splicing factor (ASF), a major splice factor for CaMKII delta splicing, can be regulated by both protein kinase and phosphatase. Here we determine the role of PP1 isoforms in ASF-mediated splicing of CaMKII delta in cells. We found that 1) PP1 gamma, but not alpha or beta isoform, enhanced the splicing of CaMKII delta in HEK293T cells; 2) PP1 gamma promoted the function of ASF, evidenced by the existence of ASF-PP1 gamma association as well as the PP1 gamma overexpression- or silencing-mediated change in CaMKII delta splicing in ASF-transfected HEK293T cells; 3) CaMKII delta splicing was promoted by overexpression of PP1 gamma and impaired by application of PP1 inhibitor 1 (I1PP1) or pharmacological inhibitor tautomycetin in primary cardiomyocytes; 4) CaMKII delta splicing and enhancement of ASF-PP1 gamma association induced by oxygen-glucose deprivation followed by reperfusion (OGD/R) were potentiated by overexpression of PP1 gamma and suppressed by inhibition of PP1 gamma with I1PP1 or tautomycetin in primary cardiomyocytes; 5) functionally, overexpression and inhibition of PP1 gamma, respectively, potentiated or suppressed the apoptosis and Bax/Bcl-2 ratio, which were associated with the enhanced activity of CaMKII in OGD/R-stimulated cardiomyocytes; and 6) CaMKII was required for the OGD/R induced-and PP1 gamma exacerbated-apoptosis of cardiomyocytes, evidenced by a specific inhibitor of CaMKII KN93, but not its structural analog KN92, attenuating the apoptosis and Bax/Bcl-2 ratio in OGD/R and PP1 gamma-treated cells. In conclusion, our results show that PP1 gamma promotes the alternative splicing of CaMKII delta ary cardiomyocytes.
C1 [Huang, Chao; Cao, Wenwen; Liao, Rujia; Wang, Jia; Wang, Yuzhe; Tong, Lijuan; Chen, Xiangfan; Zhang, Wei] Nantong Univ, Sch Med, Dept Pharmacol, Nantong 226001, Peoples R China.
   [Zhu, Weizhong] Temple Univ, Sch Med, Cardiovasc Res Ctr, Philadelphia, PA 19122 USA.
C3 Nantong University; Pennsylvania Commonwealth System of Higher Education
   (PCSHE); Temple University
RP Zhang, W (corresponding author), Nantong Univ, Sch Med, Dept Pharmacol, Rm 613,19 Qixiu Rd, Nantong 226001, Peoples R China.
EM asicampa@aliyun.com
RI Chen, Xiangfan/M-3719-2016; Tsai, Ming/ABA-9806-2020
OI liao, ru-jia/0000-0001-6928-4003
FU National Natural Science Foundation of China [81070197, 81102428];
   Priority Academic Program Development of Jiangsu Higher Education
   Institutions
FX This work was supported by the National Natural Science Foundation of
   China to W. Zhang (No. 81070197) and C. Huang (No. 81102428) and the
   Priority Academic Program Development of Jiangsu Higher Education
   Institutions.
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NR 41
TC 13
Z9 13
U1 1
U2 13
PU AMER PHYSIOLOGICAL SOC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0363-6143
EI 1522-1563
J9 AM J PHYSIOL-CELL PH
JI Am. J. Physiol.-Cell Physiol.
PD JAN
PY 2014
VL 306
IS 2
BP C167
EP C177
DI 10.1152/ajpcell.00145.2013
PG 11
WC Cell Biology; Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Physiology
GA 291WK
UT WOS:000329862400012
PM 24196533
DA 2025-04-10
ER

PT J
AU Dori, A
   Cohen, J
   Silverman, WF
   Pollack, Y
   Soreq, H
AF Dori, A
   Cohen, J
   Silverman, WF
   Pollack, Y
   Soreq, H
TI Functional manipulations of acetylcholinesterase splice variants
   highlight alternative splicing contributions to murine neocortical
   development
SO CEREBRAL CORTEX
LA English
DT Article
DE alternative splicing; neurogenesis; neuronal migration; radial glia;
   readthrough acetylcholinesterase
ID RADIAL GLIAL-CELLS; READTHROUGH ACETYLCHOLINESTERASE; VENTRICULAR ZONE;
   GENE-EXPRESSION; CHICKEN BRAIN; BETA-TUBULIN; NEURONS; GROWTH; CYCLE;
   DIFFERENTIATION
AB Proliferation and differentiation of mammalian central nervous system progenitor cells involve concertedly controlled transcriptional and alternative splicing modulations. Searching for the developmental implications of this programming, we manipulated specific acetylcholinesterase (AChE) splice variants in the embryonic mouse brain. In wild type mice, 'synaptic' AChE-S appeared in migrating neurons, whereas the C-terminus cleaved off the stress-induced AChE-R variant associated with migratory radial glial fibers. Antisense suppression of AChE-R reduced neuronal migration, allowing increased proliferation of progenitor cells. In contrast, transgenic overexpression of AChE-R was ineffective, whereas transgenic excess of enzymatically active AChE-S or inactive AChE-Sin suppressed progenitors proliferation alone or both proliferation and neuronal migration, respectively. Our findings attribute to alternative splicing events an interactive major role in neocortical development.
C1 Hebrew Univ Jerusalem, Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel.
   Soroka Univ, Med Ctr, Dept Neurosurg, Beer Sheva, Israel.
   Ben Gurion Univ Negev, Fac Hlth Sci, Zlotowski Ctr Neurosci, Dept Morphol, Beer Sheva, Israel.
   Ben Gurion Univ Negev, Fac Hlth Sci, Dept Microbiol & Immunol, IL-84105 Beer Sheva, Israel.
C3 Hebrew University of Jerusalem; Ben Gurion University; Soroka Medical
   Center; Ben Gurion University; Ben Gurion University
RP Hebrew Univ Jerusalem, Inst Life Sci, Dept Biol Chem, Edmond J Safra Campus, IL-91904 Jerusalem, Israel.
EM soreq@cc.huji.ac.il
RI Dori, Amir/JCD-7507-2023; Soreq, Hermona/AFM-0869-2022
OI Dori, Amir/0000-0003-4633-1481; Soreq, Hermona/0000-0002-0955-526X;
   Cohen, Jonathan/0000-0001-8120-3827
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NR 75
TC 69
Z9 74
U1 0
U2 6
PU OXFORD UNIV PRESS INC
PI CARY
PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA
SN 1047-3211
EI 1460-2199
J9 CEREB CORTEX
JI Cereb. Cortex
PD APR
PY 2005
VL 15
IS 4
BP 419
EP 430
DI 10.1093/cercor/bhh145
PG 12
WC Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 905JL
UT WOS:000227564300008
PM 15749986
OA Bronze, Green Submitted
DA 2025-04-10
ER

PT J
AU Li, S
   Yang, P
AF Li, Shuai
   Yang, Ping
TI Relationship between HSPA1A-regulated gene expression and alternative
   splicing in mouse cardiomyocytes and cardiac hypertrophy
SO JOURNAL OF THORACIC DISEASE
LA English
DT Article
DE HSPA1A; RNA-seq; non-coding RNA; cardiac hypertrophy; inflammation and
   immune response
ID DIASTOLIC DYSFUNCTION; MYOCARDIAL FIBROSIS; HSP70 CHAPERONES;
   INFLAMMATION; REGULATOR; PROTECTS; AUF1; CELL
AB Background: Cardiac hypertrophy may be classified as either physiological or pathological. Pathological hypertrophy has a complex etiology and is genetically regulated. In this study, we used a mouse model of cardiac hypertrophy to explore the mechanisms of gene regulation, in particular, modulation of the expression of target genes through transcription factor activity, regulation of immune and inflammation-associated genes and regulation of the alternative splicing of transcription factors. Methods: Mouse models of pathological cardiac hypertrophy were established by transverse aortic constriction (TAC). We overexpressed HSPA1A in mouse cardiac HL-1 cells. GO and KEGG pathway annotation database was used to analyze all DEGs. Results: The expression of HSPA1A differed significantly between TAC + dantrolene vs. sham + dantrolene (Sham was the non-TAC group, and DMSO was the contrast agent), and TAC + DMSO vs. sham + DMSO. The RNA-binding protein Zfp36 was found to be differentially expressed between both TAC + dantrolene vs. sham + dantrolene and TAC + DMSO vs. sham + DMSO. The expression of mki67 and gm5619 was significantly different between TAC + dantrolene and TAC + DMSO. HSPA1A was found to selectively regulate the expression of non-coding RNAs related to cardiac hypertrophy, including Rn7sk and RMRP. The downregulated genes were mainly related to inflammation and the immune response. HSPA1A negatively regulated alternative splicing of Asxl2 and positively regulated alternative splicing of Runx1. Conclusions: HSPA1A was closely related to cardiac hypertrophy. Zfp36 was also related to cardiac hypertrophy. Dantrolene may delay cardiac hypertrophy and ventricular remodeling by regulating the expression of the RNA-binding protein genes mki67 and gm5619. HSPA1A positively regulated the expression of the non-coding RNAs RN7SK and RMRP while negatively regulating the expression of inflammation-and immune response-related genes. HSPA1A can play a role in cardiac hypertrophy by regulating the alternative splicing of asxl2 and runx1.
C1 [Li, Shuai; Yang, Ping] Jilin Univ, China Japan Union Hosp, Dept Cardiol, Jilin Prov Precis Med Key Lab Cardiovasc Genet Di, Changchun, Peoples R China.
C3 Jilin University
RP Yang, P (corresponding author), Jilin Univ, China Japan Union Hosp, Dept Cardiol, 126 Xiantai St, Changchun 130033, Peoples R China.
EM pyang@jlu.edu.cn
FU National Natural Science Foundation of China [81970209]
FX This study was supported by grants provided by the National Natural
   Science Foundation of China (81970209) .
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NR 50
TC 2
Z9 2
U1 0
U2 7
PU AME PUBL CO
PI SHATIN
PA FLAT-RM C 16F, KINGS WING PLAZA 1, NO 3 KWAN ST, SHATIN, HONG KONG
   00000, PEOPLES R CHINA
SN 2072-1439
EI 2077-6624
J9 J THORAC DIS
JI J. Thorac. Dis.
PD SEP
PY 2021
VL 13
IS 9
BP 5517
EP 5533
DI 10.21037/jtd-21-1222
EA AUG 2021
PG 17
WC Respiratory System
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Respiratory System
GA WD6CS
UT WOS:000696975400001
PM 34659818
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Ho, TH
   Charlet-B, N
   Poulos, MG
   Singh, G
   Swanson, MS
   Cooper, TA
AF Ho, TH
   Charlet-B, N
   Poulos, MG
   Singh, G
   Swanson, MS
   Cooper, TA
TI Muscleblind proteins regulate alternative splicing
SO EMBO JOURNAL
LA English
DT Article
DE alternative splicing; CELF proteins; CUG-BP1; muscleblind; myotonic
   dystrophy
ID TRACT-BINDING-PROTEIN; PRE-MESSENGER-RNA; 3 UNTRANSLATED REGION;
   MYOTONIC-DYSTROPHY; TRINUCLEOTIDE REPEAT; NUCLEAR FOCI; CELF FAMILY; CTG
   REPEAT; IN-VIVO; EXON
AB Although the muscleblind (MBNL) protein family has been implicated in myotonic dystrophy (DM), a specific function for these proteins has not been reported. A key feature of the RNA-mediated pathogenesis model for DM is the disrupted splicing of specific pre-mRNA targets. Here we demonstrate that MBNL proteins regulate alternative splicing of two pre-mRNAs that are misregulated in DM, cardiac troponin T (cTNT) and insulin receptor (IR). Alternative cTNT and IR exons are also regulated by CELF proteins, which were previously implicated in DM pathogenesis. MBNL proteins promote opposite splicing patterns for cTNT and IR alternative exons, both of which are antagonized by CELF proteins. CELF- and MBNL-binding sites are distinct and regulation by MBNL does not require the CELF- binding site. The results are consistent with a mechanism for DM pathogenesis in which expanded repeats cause a loss of MBNL and/or gain of CELF activities, leading to misregulation of alternative splicing of specific pre-mRNA targets.
C1 Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA.
   Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
   Univ Florida, Coll Med, Powell Gene Therapy Ctr, Dept Mol Genet & Microbiol, Gainesville, FL USA.
C3 Baylor College of Medicine; Baylor College of Medicine; State University
   System of Florida; University of Florida
RP Baylor Coll Med, Dept Pathol, Room 268B,1 Baylor Plaza, Houston, TX 77030 USA.
EM tcooper@bcm.tmc.edu
RI Charlet-Berguerand, Nicolas/GZM-6636-2022; Charlet-Berguerand,
   Nicolas/I-6727-2016
OI Poulos, Michael/0000-0002-7622-9966; Swanson,
   Maurice/0000-0001-6245-5367; Ho, Thai/0000-0003-0023-2939;
   Charlet-Berguerand, Nicolas/0000-0002-4423-4920
FU NHLBI NIH HHS [HL45565, R01 HL045565] Funding Source: Medline; NIAMS NIH
   HHS [R01 AR045653, R01 AR046799, AR46799, AR45653] Funding Source:
   Medline; NINDS NIH HHS [NS48843, U54 NS048843, P50 NS048843] Funding
   Source: Medline
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NR 54
TC 380
Z9 450
U1 0
U2 18
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0261-4189
EI 1460-2075
J9 EMBO J
JI Embo J.
PD AUG 4
PY 2004
VL 23
IS 15
BP 3103
EP 3112
DI 10.1038/sj.emboj.7600300
PG 10
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 852BE
UT WOS:000223729400020
PM 15257297
OA Green Published
DA 2025-04-10
ER

PT J
AU Li, N
   Li, Y
   Han, XW
   Zhang, J
   Han, JX
   Jiang, XH
   Wang, WZ
   Xu, Y
   Xu, YN
   Fu, Y
   Si, SY
AF Li, Ni
   Li, Yan
   Han, Xiaowan
   Zhang, Jing
   Han, Jiangxue
   Jiang, Xinhai
   Wang, Weizhi
   Xu, Yang
   Xu, Yanni
   Fu, Yu
   Si, Shuyi
TI LXR agonist inhibits inflammation through regulating MyD88 mRNA
   alternative splicing
SO FRONTIERS IN PHARMACOLOGY
LA English
DT Article
DE LXR; inflammation; MyD88; alternative splicing; multi-target; TLR4
ID LIVER X-RECEPTOR; NF-KAPPA-B; NUCLEAR RECEPTORS; ACTIVATION; PATHWAYS;
   ATHEROSCLEROSIS; IDENTIFICATION; MACROPHAGE
AB Liver X receptors (LXRs) are important regulators of cholesterol metabolism and inflammatory responses. LXR agonists exhibit potently anti-inflammatory effects in macrophages, which make them beneficial to anti-atherogenic therapy. In addition to transrepressive regulation by SUMOylation, LXRs can inhibit inflammation by various mechanisms through affecting multiple targets. In this study, we found that the classic LXR agonist T0901317 mediated numerous genes containing alternative splice sites, including myeloid differentiation factor 88 (MyD88), that contribute to inflammatory inhibition in RAW264.7 macrophages. Furthermore, T0901317 increased level of alternative splice short form of MyD88 mRNA by down-regulating expression of splicing factor SF3A1, leading to nuclear factor kappa B-mediated inhibition of inflammation. In conclusion, our results suggest for the first time that the LXR agonist T0901317 inhibits lipopolysaccharide-induced inflammation through regulating MyD88 mRNA alternative splicing involved in TLR4 signaling pathway.
C1 [Li, Ni; Han, Xiaowan] Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing, Peoples R China.
   [Li, Ni; Zhang, Jing; Han, Jiangxue; Jiang, Xinhai; Wang, Weizhi; Xu, Yang; Xu, Yanni; Si, Shuyi] Chinese Acad Med Sci & Peking Union Med Coll, Inst Med Biotechnol, NHC Key Lab Biotechnol Antibiot, Beijing, Peoples R China.
   [Li, Yan; Fu, Yu] Hebei Univ Sci & Technol, Coll Food Sci & Biol, Shijiazhuang, Hebei, Peoples R China.
C3 Chinese Academy of Medical Sciences - Peking Union Medical College;
   Institute of Materia Medica - CAMS; Chinese Academy of Medical Sciences
   - Peking Union Medical College; Peking Union Medical College; Hebei
   University of Science & Technology
RP Li, N (corresponding author), Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing, Peoples R China.; Li, N; Si, SY (corresponding author), Chinese Acad Med Sci & Peking Union Med Coll, Inst Med Biotechnol, NHC Key Lab Biotechnol Antibiot, Beijing, Peoples R China.; Fu, Y (corresponding author), Hebei Univ Sci & Technol, Coll Food Sci & Biol, Shijiazhuang, Hebei, Peoples R China.
EM linineon@126.com; fuyu@hebust.edu.cn; sisyimb@hotmail.com
RI Wang, Weizhi/JJC-2093-2023; LIU, Yandong/KVZ-1066-2024
OI Li, Yan/0009-0009-6675-8096
FU National Natural Science Foundation of China; Natural Science Foundation
   of Hebei Province; Fundamental Research Funds for CAMS of China; CAMS
   Innovation Fund for Medical Sciences;  [81503065];  [H2020208002]; 
   [2018RC350001];  [2021-1-I2M-030]
FX Funding This work was supported by the National Natural Science
   Foundation of China (grant NO. 81503065), Natural Science Foundation of
   Hebei Province (Grant No. H2020208002), Fundamental Research Funds for
   CAMS of China (Grant NO. 2018RC350001), CAMS Innovation Fund for Medical
   Sciences (Grant NO. 2021-1-I2M-030).
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NR 41
TC 9
Z9 9
U1 0
U2 5
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
EI 1663-9812
J9 FRONT PHARMACOL
JI Front. Pharmacol.
PD OCT 14
PY 2022
VL 13
AR 973612
DI 10.3389/fphar.2022.973612
PG 14
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA 5V0TX
UT WOS:000876952000001
PM 36313296
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Han, ELY
   Han, Y
   Williams, DR
   Thomas, CT
   Shrestha, R
   Wu, JC
   Lam, MPY
AF Han, Edward Lau Yu
   Han, Yu
   Williams, Damon R.
   Thomas, Cody T.
   Shrestha, Rajani
   Wu, Joseph C.
   Lam, Maggie P. Y.
TI Splice-Junction-Based Mapping of Alternative Isoforms in the Human
   Proteome
SO CELL REPORTS
LA English
DT Article
ID PROTEOGENOMICS; LANDSCAPE; DISCOVERY; IDENTIFICATION; TRANSCRIPTOME;
   EXPRESSION; PEPTIDES; PROTEINS; ACCURACY; ENABLES
AB The protein-level translational status and function of many alternative splicing events remain poorly understood. We use an RNA sequencing (RNA-seq)-guided proteomics method to identify protein alternative splicing isoforms in the human proteome by constructing tissue-specific protein databases that prioritize transcript splice junction pairs with high translational potential. Using the custom databases to reanalyze similar to 80 million mass spectra in public proteomics datasets, we identify more than 1,500 noncanonical protein isoforms across 12 human tissues, including similar to 400 sequences undocumented on TrEMBL and RefSeq databases. We apply the method to original quantitative mass spectrometry experiments and observe widespread isoform regulation during human induced pluripotent stem cell cardiomyocyte differentiation. On a proteome scale, alternative isoform regions overlap frequently with disordered sequences and post-translational modification sites, suggesting that alternative splicing may regulate protein function through modulating intrinsically disordered regions. The described approach may help elucidate functional consequences of alternative splicing and expand the scope of proteomics investigations in various systems.
C1 [Han, Edward Lau Yu; Williams, Damon R.; Shrestha, Rajani; Wu, Joseph C.] Stanford Univ, Dept Med, Stanford Cardiovasc Inst, Palo Alto, CA 94304 USA.
   [Wu, Joseph C.] Stanford Univ, Sch Med, Dept Radiol, Palo Alto, CA 94304 USA.
   [Han, Yu; Lam, Maggie P. Y.] Univ Colorado, Consortium Fibrosis Res & Translat, Anschutz Med Campus, Aurora, CO 80045 USA.
   [Han, Yu; Thomas, Cody T.; Lam, Maggie P. Y.] Univ Colorado, Dept Med Cardiol, Anschutz Med Campus, Aurora, CO 80045 USA.
   [Lam, Maggie P. Y.] Univ Colorado, Dept Biochem & Mol Genet, Anschutz Med Campus, Aurora, CO 80045 USA.
C3 Stanford University; Stanford University; University of Colorado System;
   University of Colorado Anschutz Medical Campus; University of Colorado
   System; University of Colorado Anschutz Medical Campus; University of
   Colorado System; University of Colorado Anschutz Medical Campus
RP Lam, MPY (corresponding author), Univ Colorado, Consortium Fibrosis Res & Translat, Anschutz Med Campus, Aurora, CO 80045 USA.; Lam, MPY (corresponding author), Univ Colorado, Dept Med Cardiol, Anschutz Med Campus, Aurora, CO 80045 USA.; Lam, MPY (corresponding author), Univ Colorado, Dept Biochem & Mol Genet, Anschutz Med Campus, Aurora, CO 80045 USA.
EM maggie.lam@cuanschutz.edu
RI Wu, Joseph/H-1067-2013
OI Wu, Joseph/0000-0002-6068-8041
FU NIH [F32 HL139045, K99 HL144829, F32 HL149191, R01 HL113006, R01
   HL145676, R01 HL141371, R01 HL146690, R01 GM117624, R01 HL141278, T32
   HL007822]; CU Consortium for Fibrosis Research and Translation Pilot
   Grant
FX This work was supported, in part, by NIH research grants F32 HL139045
   and K99 HL144829 to E.L.; T32 HL007822 (CU AMC) and F32 HL149191 to
   Y.H.; R01 HL113006, R01 HL145676, R01 HL141371, and R01 HL146690 to
   J.C.W.; and R01 GM117624, R01 HL141278, and The CU Consortium for
   Fibrosis Research and Translation Pilot Grant to M.P.Y.L.
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NR 88
TC 46
Z9 56
U1 0
U2 10
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
SN 2211-1247
J9 CELL REP
JI Cell Reports
PD DEC 10
PY 2019
VL 29
IS 11
BP 3751
EP +
DI 10.1016/j.celrep.2019.11.026
PG 20
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA JV1FS
UT WOS:000502113400031
PM 31825849
OA gold, Green Accepted, Green Submitted
DA 2025-04-10
ER

PT J
AU Gao, C
   Wang, YB
AF Gao, Chen
   Wang, Yibin
TI Global impact of RNA splicing on transcriptome remodeling in the heart
SO JOURNAL OF ZHEJIANG UNIVERSITY-SCIENCE B
LA English
DT Article
DE Alternative RNA splicing; Transcriptome; Gene regulation; Heart; RNA-seq
ID CARDIAC TROPONIN-T; MESSENGER-RNA; DILATED CARDIOMYOPATHY;
   MYOTONIC-DYSTROPHY; GENE; PROTEINS; SEQ; EXPRESSION; EXON; COMPLEXITY
AB In the eukaryotic transcriptome, both the numbers of genes and different RNA species produced by each gene contribute to the overall complexity. These RNA species are generated by the utilization of different transcriptional initiation or termination sites, or more commonly, from different messenger RNA (mRNA) splicing events. Among the 30 000+ genes in human genome, it is estimated that more than 95% of them can generate more than one gene product via alternative RNA splicing. The protein products generated from different RNA splicing variants can have different intracellular localization, activity, or tissue-distribution. Therefore, alternative RNA splicing is an important molecular process that contributes to the overall complexity of the genome and the functional specificity and diversity among different cell types. In this review, we will discuss current efforts to unravel the full complexity of the cardiac transcriptome using a deep-sequencing approach, and highlight the potential of this technology to uncover the global impact of RNA splicing on the transcriptome during development and diseases of the heart.
C1 [Gao, Chen; Wang, Yibin] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA.
C3 University of California System; University of California Los Angeles
RP Wang, YB (corresponding author), Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA.
EM yibinwang@mednet.ucla.edu
RI Yimei, Wang/AAE-4083-2019; Gao, Chen/KZU-1046-2024; Wang,
   Yibin/AES-4559-2022
OI Wang, Yibin/0000-0003-0852-0767
FU Broad Stem Cell Research Center (BSCRC); National Institutes of Health,
   USA
FX Project supported partially by Broad Stem Cell Research Center (BSCRC)
   Pre-doctoral Fellowship in UCLA, and the National Institutes of Health,
   USA
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NR 40
TC 1
Z9 3
U1 0
U2 13
PU ZHEJIANG UNIV
PI HANGZHOU
PA EDITORIAL BOARD, 20 YUGU RD, HANGZHOU, 310027, PEOPLES R CHINA
SN 1673-1581
J9 J ZHEJIANG UNIV-SC B
JI J. Zhejiang Univ.-SCI. B
PD AUG
PY 2012
VL 13
IS 8
BP 603
EP 608
DI 10.1631/jzus.B1201006
PG 6
WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology;
   Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology;
   Research & Experimental Medicine
GA 987EC
UT WOS:000307398300003
PM 22843179
OA Green Published
DA 2025-04-10
ER

PT J
AU Luo, HQ
   Song, S
   Chen, Y
   Xu, MT
   Sun, LL
   Meng, GL
   Zhang, W
AF Luo, Huiqin
   Song, Shu
   Chen, Yun
   Xu, Mengting
   Sun, Linlin
   Meng, Guoliang
   Zhang, Wei
TI Inhibitor 1 of Protein Phosphatase 1 Regulates
   Ca<SUP>2+</SUP>/Calmodulin-Dependent Protein Kinase II to Alleviate
   Oxidative Stress in Hypoxia-Reoxygenation Injury of Cardiomyocytes
SO OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
LA English
DT Article
ID NF-KAPPA-B; CELL-DEATH; MYOCARDIAL-ISCHEMIA; REPERFUSION INJURY;
   CAMKII-DELTA; ISCHEMIA/REPERFUSION INJURY; MITOCHONDRIAL DYNAMICS;
   CARDIAC-HYPERTROPHY; INDUCED APOPTOSIS; PATHWAYS
AB Ca2+/calmodulin-dependent protein kinase II (CaMKII), regulated by inhibitor 1 of protein phosphatase 1 (I1PP1), is vital for maintaining cardiovascular homeostasis. However, the role and mechanism of I1PP1 against hypoxia-reoxygenation (H/R) injury in cardiomyocytes remain a question. In our study, after I1PP1 overexpression by adenovirus infection in the neonatal cardiomyocytes followed by hypoxia for 4 h and reoxygenation for 12 h, the CaMKII delta alternative splicing subtype, ATP content, and lactate dehydrogenase (LDH) release were determined. CaMKII activity was evaluated by phosphoprotein phosphorylation at Thr17 (p-PLB Thr17), CaMKII phosphorylation (p-CaMKII), and CaMKII oxidation (ox-CaMKII). Reactive oxygen species (ROS), mitochondrial membrane potential, dynamin-related protein 1 (DRP1), and optic atrophy 1 (OPA1) expressions were assessed. Our study verified that I1PP1 overexpression attenuated the CaMKII delta alternative splicing disorder; suppressed PLB phosphorylation at Thr17, p-CaMKII, and ox-CaMKII; decreased cell LDH release; increased ATP content; attenuated ROS production; increased mitochondrial membrane potential; and decreased DRP1 expression but increased OPA1 expression in the cardiomyocytes after H/R. Contrarily, CaMKII delta alternative splicing disorder, LDH release, ATP reduction, and ROS accumulation were aggravated after H/R injury with the I1PP1 knockdown. Collectively, I1PP1 overexpression corrected disorders of CaMKII delta alternative splicing, inhibited CaMKII phosphorylation, repressed CaMKII oxidation, suppressed ROS production, and attenuated cardiomyocyte H/R injury.
C1 [Luo, Huiqin; Song, Shu; Chen, Yun; Xu, Mengting; Sun, Linlin; Meng, Guoliang; Zhang, Wei] Nantong Univ, Sch Pharm, Dept Pharmacol, Key Lab Inflammat & Mol Drug Target Jiangsu Prov, Nantong, Jiangsu, Peoples R China.
   [Chen, Yun; Meng, Guoliang; Zhang, Wei] Nantong Univ, Sch Med, Nantong, Jiangsu, Peoples R China.
C3 Nantong University; Nantong University
RP Meng, GL; Zhang, W (corresponding author), Nantong Univ, Sch Pharm, Dept Pharmacol, Key Lab Inflammat & Mol Drug Target Jiangsu Prov, Nantong, Jiangsu, Peoples R China.; Meng, GL; Zhang, W (corresponding author), Nantong Univ, Sch Med, Nantong, Jiangsu, Peoples R China.
EM mengguoliang@ntu.edu.cn; zhangw@ntu.edu.cn
RI Xu, Meng/HJY-7139-2023
FU National Natural Science Foundation of China [81670243, 81873470,
   81770279]; Natural Science Foundation of Jiangsu Province [BK20151276];
   major project of the Natural Science Research of Jiangsu Higher
   Education Institutions of China [18KJA310005]; Six Talent Peaks Project
   in Jiangsu Province [2018-WSN-062]; China Postdoctoral Science
   Foundation [2017M610342, 2019T120449]; Jiangsu Planned Projects for
   Postdoctoral Research Funds [1701050A]; Graduate Research and Innovation
   Projects of Jiangsu Province [KYCX18_ 2401]; Nantong University
   Cooperative Innovation Program of Small Molecular Compound RD
   [NTU2016-1]
FX The work was funded by grants 81670243, 81873470, and 81770279 from the
   National Natural Science Foundation of China, grant BK20151276 from the
   Natural Science Foundation of Jiangsu Province, a major project of the
   Natural Science Research of Jiangsu Higher Education Institutions of
   China (18KJA310005), the Six Talent Peaks Project in Jiangsu Province
   (2018-WSN-062), grants from the China Postdoctoral Science Foundation
   (2017M610342 and 2019T120449), the Jiangsu Planned Projects for
   Postdoctoral Research Funds (1701050A), the Graduate Research and
   Innovation Projects of Jiangsu Province (KYCX18_ 2401), and the Nantong
   University Cooperative Innovation Program of Small Molecular Compound
   R&D (NTU2016-1).
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NR 79
TC 17
Z9 17
U1 0
U2 9
PU HINDAWI LTD
PI LONDON
PA ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, W1T 5HF, ENGLAND
SN 1942-0900
EI 1942-0994
J9 OXID MED CELL LONGEV
JI Oxidative Med. Cell. Longev.
PD DEC 7
PY 2019
VL 2019
AR 2193019
DI 10.1155/2019/2193019
PG 19
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA JX5NM
UT WOS:000503781500002
PM 31885777
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Marcucci, R
   Baralle, FE
   Romano, M
AF Marcucci, Roberto
   Baralle, Francisco E.
   Romano, Maurizio
TI Complex splicing control of the human thrombopoietin gene by intronic G
   runs
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID PRE-MESSENGER-RNA; HNRNP-H; REGULATORY ELEMENTS; MENTAL-RETARDATION;
   ALTERNATIVE EXON; BINDING; PROTEINS; ENHANCER; VARIANT; LOCALIZATION
AB The human thrombopoietin (THPO) gene displays a series of alternative splicing events that provide valuable models for studying splicing mechanisms. The THPO region spanning exon 1-4 presents both alternative splicing of exon 2 and partial intron 2 (IVS2) retention following the activation of a cryptic 3' splice site 85 nt upstream of the authentic acceptor site. IVS2 is particularly rich in stretches of 3-5 guanosines (namely, G1-G10) and we have characterized the role of these elements in the processing of this intron. In vivo studies show that runs G7-G10 work in a combinatorial way to control the selection of the proper 3' splice site. In particular, the G7 element behaves as the splicing hub of intron 2 and its interaction with hnRNP H1 is critical for the splicing process. Removal of hnRNP H1 by RNA interference promoted the usage of the cryptic 3' splice site so providing functional evidence that this factor is involved in the selection of the authentic 3' splice site of THPO IVS2.
C1 Int Ctr Genet Engn & Biotechnol, I-34012 Trieste, Italy.
   Univ Trieste, Dept Physiol & Pathol, I-34127 Trieste, Italy.
C3 International Center for Genetic Engineering & Biotechnology (ICGEB);
   University of Trieste
RP Baralle, FE (corresponding author), Int Ctr Genet Engn & Biotechnol, Padriciano 99, I-34012 Trieste, Italy.
EM baralle@icgeb.org
RI Romano, Maurizio/G-9431-2012
OI Romano, Maurizio/0000-0002-4820-2897
FU Telethon [GGP02453] Funding Source: Medline
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NR 39
TC 27
Z9 32
U1 0
U2 2
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0305-1048
J9 NUCLEIC ACIDS RES
JI Nucleic Acids Res.
PD JAN
PY 2007
VL 35
IS 1
BP 132
EP 142
DI 10.1093/nar/gkl965
PG 11
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 130NH
UT WOS:000243805800020
PM 17158158
OA Green Submitted, Green Published
DA 2025-04-10
ER

PT J
AU Savarese, M
   Jonson, PH
   Huovinen, S
   Paulin, L
   Auvinen, P
   Udd, B
   Hackman, P
AF Savarese, Marco
   Jonson, Per Harald
   Huovinen, Sanna
   Paulin, Lars
   Auvinen, Petri
   Udd, Bjarne
   Hackman, Peter
TI The complexity of titin splicing pattern in human adult skeletal muscles
SO SKELETAL MUSCLE
LA English
DT Article
DE Titin; Titinopathies; RNA-sequencing; Exon usage; Alternative splicing
   events; Splicing pattern
ID TISSUE-SPECIFIC EXPRESSION; RNA-SEQ; ISOFORMS; NEBULIN; GENE;
   CARDIOMYOPATHY; INVOLVEMENT; SEQUENCE; MUTATION; BINDING
AB Background: Mutations in the titin gene (TTN) cause a large spectrum of diseases affecting skeletal and/or cardiac muscle. TTN includes 363 coding exons, a repeated region with a high degree of complexity, isoform-specific elements, and metatranscript-only exons thought to be expressed only during fetal development. Although three main classes of isoforms have been described so far, alternative splicing events (ASEs) in different tissues or in different developmental and physiological states have been reported.
   Methods: To achieve a comprehensive view of titin ASEs in adult human skeletal muscles, we performed a RNA-Sequencing experiment on 42 human biopsies collected from 12 anatomically different skeletal muscles of 11 individuals without any skeletal-muscle disorders.
   Results: We confirmed that the skeletal muscle N2A isoforms are highly prevalent, but we found an elevated number of alternative splicing events, some at a very high level. These include previously unknown exon skipping events and alternative 5' and 3' splice sites. Our data suggests the partial inclusion in the TTN transcript of some metatranscript-only exons and the partial exclusion of canonical N2A exons.
   Conclusions: This study provides an extensive picture of the complex TTN splicing pattern in human adult skeletal muscle, which is crucial for a proper clinical interpretation of TTN variants.
C1 [Savarese, Marco; Jonson, Per Harald; Udd, Bjarne; Hackman, Peter] Univ Helsinki, Folkhalsan Res Ctr, Helsinki, Finland.
   [Huovinen, Sanna; Udd, Bjarne] Tampere Univ Hosp, Fimlab Labs, Dept Pathol, Tampere, Finland.
   [Paulin, Lars; Auvinen, Petri] Univ Helsinki, Inst Biotechnol, Helsinki, Finland.
   [Udd, Bjarne] Vaasa Cent Hosp, Vaasa, Finland.
   [Savarese, Marco] Univ Helsinki, Dept Med Genet, Folkhalsan Inst Genet, Haartmaninkatu 8,Pb 63, Helsinki 00014, Finland.
C3 University of Helsinki; Folkhalsan Research Center; Tampere University;
   Tampere University Hospital; University of Helsinki; Vaasa Central
   Hospital; University of Helsinki
RP Savarese, M (corresponding author), Univ Helsinki, Folkhalsan Res Ctr, Helsinki, Finland.; Savarese, M (corresponding author), Univ Helsinki, Dept Med Genet, Folkhalsan Inst Genet, Haartmaninkatu 8,Pb 63, Helsinki 00014, Finland.
EM marco.savarese@helsinki.fi
RI Udd, Bjarne/JBE-3483-2023; Jonson, pH/GPX-1306-2022; Auvinen,
   Petri/D-5044-2009; Savarese, Marco/J-8307-2016
OI Jonson, Per Harald/0000-0003-2423-359X; Savarese,
   Marco/0000-0002-2591-244X; Huovinen, Sanna/0000-0001-7659-7921
FU Finnish Academy; Juselius Research Foundation; Association Francaise
   contre les Myopathies; Orion Research Foundation
FX This study was supported by Finnish Academy, Juselius Research
   Foundation, Association Francaise contre les Myopathies and Orion
   Research Foundation. The funders had no role in the study design, data
   collection and analysis, decision to publish, or preparation of the
   manuscript.
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NR 37
TC 51
Z9 58
U1 0
U2 0
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 2044-5040
J9 SKELET MUSCLE
JI Skeletal Muscle
PD MAR 29
PY 2018
VL 8
AR 11
DI 10.1186/s13395-018-0156-z
PG 9
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA GB2PB
UT WOS:000428894800001
PM 29598826
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Granzier, H
   Labeit, S
AF Granzier, Henk
   Labeit, Siegfried
TI Structure-function relations of the giant elastic protein titin in
   striated and smooth muscle cells
SO MUSCLE & NERVE
LA English
DT Review
DE alpha B-crystallin; gap filaments; myofilament; sarcomere; titin
ID ALPHA-B-CRYSTALLIN; ATOMIC-FORCE MICROSCOPY; HUMAN DILATED
   CARDIOMYOPATHY; DIASTOLIC HEART-FAILURE; SKELETAL-MUSCLE; CARDIAC TITIN;
   PASSIVE STIFFNESS; Z-DISC; IMMUNOGLOBULIN DOMAINS; ISOFORM EXPRESSION
AB The striated muscle sarcomere contains, in addition to thin and thick filaments, a third myofilament comprised of titin. The extensible region of titin spans the I-band region of the sarcomere and develops passive force in stretched sarcomeres. This force positions the A-bands in the middle of the sarcomere, maintains sarcomere length homogeneity and, importantly, is responsible for myocardial passive tension that determines diastolic filling. Recent work suggests that smooth muscle expresses a truncated titin isoform with a short extensible region that is predicted to develop high passive force levels. Several mechanisms for tuning the titin-based passive tension have been discovered that involve alternative splicing as well as posttranslational modification, mechanisms that are at play both during normal muscle function as well as during disease.
C1 Univ Arizona, Dept Mol & Cellular Biol, Tucson, AZ 85724 USA.
   Washington State Univ, Dept Vet & Comparat Anat Pharmacol & Physiol, Pullman, WA USA.
   Univ Mannheim, Dept Anesthesiol, Mannheim, Germany.
C3 University of Arizona; Washington State University; University of
   Mannheim
RP Granzier, H (corresponding author), Univ Arizona, Dept Mol & Cellular Biol, Med Res Bldg 325,1656 E Mabel St, Tucson, AZ 85724 USA.
EM granzier@email.arizona.edu
FU NHLBI NIH HHS [HL084579, HL062881] Funding Source: Medline
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NR 139
TC 100
Z9 120
U1 1
U2 20
PU WILEY-BLACKWELL
PI MALDEN
PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA
SN 0148-639X
J9 MUSCLE NERVE
JI Muscle Nerve
PD DEC
PY 2007
VL 36
IS 6
BP 740
EP 755
DI 10.1002/mus.20886
PG 16
WC Clinical Neurology; Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 238SW
UT WOS:000251468900003
PM 17763461
DA 2025-04-10
ER

PT J
AU Lundberg, AK
   Jonasson, L
   Hansson, GK
   Mailer, RKW
AF Lundberg, Anna K.
   Jonasson, Lena
   Hansson, Goran K.
   Mailer, Reiner K. W.
TI Activation-induced FOXP3 isoform profile in peripheral CD4+T cells is
   associated with coronary artery disease
SO ATHEROSCLEROSIS
LA English
DT Article
DE FOXP3 isoforms; Treg cells; Coronary artery disease; Alternative
   splicing
ID REGULATORY T-CELLS; CHOLESTEROL; IL-17; ATHEROSCLEROSIS;
   DIFFERENTIATION; INTERLEUKIN-17; TRANSCRIPTION; SIMVASTATIN; INHIBITION;
   EXPRESSION
AB Background and aims: The expression of FOXP3 isoforms affects regulatory T (Treg) cell function. Reduced Treg cell function has been associated with coronary artery disease (CAD). However, alternative splicing of FOXP3 in CAD has not been investigated.
   Methods: FOXP3 splice variants and IL17A transcripts in peripheral blood mononuclear cells from stable CAD patients and healthy controls were quantified, and FOXP3 isoform expression in response to T cell receptor (TCR) stimulation or LDL was analyzed by flow cytometry.
   Results: Compared to healthy controls, CAD patients expressed significantly more FOXP3 transcripts that included exon 2, whereas alternative splicing of exon 7 in correlation with IL17A expression was reduced. Moreover, TCR stimulation, as well as exposure to LDL, decreased alternative splicing of FOXP3 in CD4+ T cells in vitro.
   Conclusions: Our results demonstrate that blood mononuclear cells in stable CAD patients express a ratio of FOXP3 isoforms that is characteristic for activated CD4+ T cells. (C) 2017 Elsevier B.V. All rights reserved.
C1 [Lundberg, Anna K.; Jonasson, Lena] Linkoping Univ, Dept Med & Hlth Sci, Div Cardiovasc Med, Linkoping, Sweden.
   [Hansson, Goran K.; Mailer, Reiner K. W.] Karolinska Univ Hosp, Karolinska Inst, Dept Med, Cardiovasc Med Unit, SE-17176 Stockholm, Sweden.
C3 Linkoping University; Karolinska Institutet; Karolinska University
   Hospital
RP Mailer, RKW (corresponding author), Karolinska Inst, Ctr Mol Med, Dept Med, L8-03, Stockholm, Sweden.
EM reiner.mailer@ki.se
RI Hansson, Goran/B-7423-2012; Mailer, Reiner/AAC-1991-2022
OI Hansson, Goran/0000-0003-4148-5190; Mailer, Reiner/0000-0001-8279-3355
FU Swedish Research Council [349-2007-8703]; Swedish Heart-Lung Foundation;
   Foundation for Strategic Research (SSF); Vinnova Foundation; Stockholm
   County Council; European Commission (project Athero-Flux); European
   Commission (project VIA);  [06816]
FX This work was supported by project grant 06816 and Linnaeus support
   349-2007-8703 from the Swedish Research Council, and by grants from the
   Swedish Heart-Lung Foundation, the Foundation for Strategic Research
   (SSF), Vinnova Foundation, Stockholm County Council, and the European
   Commission (FP7 projects Athero-Flux and VIA).
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NR 47
TC 18
Z9 22
U1 0
U2 7
PU ELSEVIER IRELAND LTD
PI CLARE
PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000,
   IRELAND
SN 0021-9150
EI 1879-1484
J9 ATHEROSCLEROSIS
JI Atherosclerosis
PD DEC
PY 2017
VL 267
BP 27
EP 33
DI 10.1016/j.atherosclerosis.2017.10.026
PG 7
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA FN5FU
UT WOS:000416032800004
PM 29100058
DA 2025-04-10
ER

PT J
AU Qiao, B
   Liu, XH
   Wang, BL
   Wei, SJ
AF Qiao, Bao
   Liu, Xuehao
   Wang, Bailu
   Wei, Shujian
TI The role of periostin in cardiac fibrosis
SO HEART FAILURE REVIEWS
LA English
DT Article
DE Periostin; Alternative splicing; ECM protein; Cardiac remodeling;
   Cardiac fibrosis; Mechanical stress
ID TRANSFORMING-GROWTH-FACTOR; ACUTE MYOCARDIAL-INFARCTION;
   OSTEOBLAST-SPECIFIC FACTOR; EXTRACELLULAR-MATRIX; PERIODONTAL-LIGAMENT;
   TENASCIN-C; MATRICELLULAR PROTEINS; HEART REGENERATION; EARLY
   DEGRADATION; MOUSE HEART
AB Cardiac fibrosis, which is the buildup of proteins in the connective tissues of the heart, can lead to end-stage extracellular matrix (ECM) remodeling and ultimately heart failure. Cardiac remodeling involves changes in gene expression in cardiac cells and ECM, which significantly leads to the morbidity and mortality in heart failure. However, despite extensive research, the elusive intricacies underlying cardiac fibrosis remain unidentified. Periostin, an extracellular matrix (ECM) protein of the fasciclin superfamily, acts as a scaffold for building complex architectures in the ECM, which improves intermolecular interactions and augments the mechanical properties of connective tissues. Recent research has shown that periostin not only contributes to normal ECM homeostasis in a healthy heart but also serves as a potent inducible regulator of cellular reorganization in cardiac fibrosis. Here, we reviewed the constitutive domain of periostin and its interaction with other ECM proteins. We have also discussed the critical pathophysiological functions of periostin in cardiac remodeling mechanisms, including two distinct yet potentially intertwined mechanisms. Furthermore, we will focus on the intrinsic complexities within periostin research, particularly surrounding the contentious issues observed in experimental findings.
C1 [Qiao, Bao; Liu, Xuehao; Wei, Shujian] Shandong Univ, Qilu Hosp, Dept Emergency, Jinan 250012, Shandong, Peoples R China.
   [Qiao, Bao; Liu, Xuehao; Wei, Shujian] Shandong Univ, Chest Pain Ctr, Qilu Hosp, Jinan 250012, Shandong, Peoples R China.
   [Qiao, Bao; Liu, Xuehao; Wei, Shujian] Shandong Univ, Clin Res Ctr Emergency & Crit Care Med Shandong Pr, Qilu Hosp, Jinan 250012, Shandong, Peoples R China.
   [Qiao, Bao; Liu, Xuehao; Wei, Shujian] Shandong Univ, Key Lab Emergency & Crit Care Med Shandong Prov, Key Lab Cardiopulm Cerebral Resuscitat Res Shandon, Qilu Hosp, Jinan 250012, Shandong, Peoples R China.
   [Wang, Bailu] Shandong Univ, Clin Trial Ctr, Qilu Hosp, Jinan 250012, Shandong, Peoples R China.
C3 Shandong University; Shandong University; Shandong University; Shandong
   University; Shandong University
RP Wei, SJ (corresponding author), Shandong Univ, Qilu Hosp, Dept Emergency, Jinan 250012, Shandong, Peoples R China.; Wei, SJ (corresponding author), Shandong Univ, Chest Pain Ctr, Qilu Hosp, Jinan 250012, Shandong, Peoples R China.; Wei, SJ (corresponding author), Shandong Univ, Clin Res Ctr Emergency & Crit Care Med Shandong Pr, Qilu Hosp, Jinan 250012, Shandong, Peoples R China.; Wei, SJ (corresponding author), Shandong Univ, Key Lab Emergency & Crit Care Med Shandong Prov, Key Lab Cardiopulm Cerebral Resuscitat Res Shandon, Qilu Hosp, Jinan 250012, Shandong, Peoples R China.
EM weishujian@sdu.edu.cn
RI qiao, bao/GZB-2758-2022
OI Wei, Shujian/0000-0002-0896-6032
FU National Natural Science Foundation of China [82072141, 82202376];
   Natural Science Foundation of Shandong Province [ZR2020MH030,
   ZR2022QH225]; Clinical Research Foundation of Shandong University
   [2020SDUCRCC014]
FX This research was funded by the National Natural Science Foundation of
   China, 82072141 and 82202376; Natural Science Foundation of Shandong
   Province, ZR2020MH030 and ZR2022QH225, and Clinical Research Foundation
   of Shandong University, 2020SDUCRCC014.
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NR 143
TC 1
Z9 1
U1 4
U2 6
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 1382-4147
EI 1573-7322
J9 HEART FAIL REV
JI Heart Fail. Rev.
PD JAN
PY 2024
VL 29
IS 1
BP 191
EP 206
DI 10.1007/s10741-023-10361-y
EA OCT 2023
PG 16
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA JC2C6
UT WOS:001090500300002
PM 37870704
DA 2025-04-10
ER

PT J
AU Wang, SB
   Venkatraman, V
   Crowgey, EL
   Liu, T
   Fu, ZM
   Holewinski, R
   Ranek, M
   Kass, DA
   O'Rourke, B
   Van Eyk, JE
AF Wang, Sheng-Bing
   Venkatraman, Vidya
   Crowgey, Erin L.
   Liu, Ting
   Fu, Zongming
   Holewinski, Ronald
   Ranek, Mark
   Kass, David A.
   O'Rourke, Brian
   Van Eyk, Jennifer E.
TI Protein S-Nitrosylation Controls Glycogen Synthase Kinase 3β Function
   Independent of Its Phosphorylation State
SO CIRCULATION RESEARCH
LA English
DT Article
DE glycogen synthase kinase 3 beta; kinase-substrates interactome; nuclear
   translocation; redox regulation; S-nitrosylation
ID NITRIC-OXIDE; SUBCELLULAR-LOCALIZATION; HEART-FAILURE; KINASE-3-BETA;
   INACTIVATION; GSK3; INSULIN; HYPERTROPHY; INHIBITORS; GSK-3-BETA
AB Rationale: GSK-3 beta (glycogen synthase kinase 3 beta) is a multifunctional and constitutively active kinase known to regulate a myriad of cellular processes. The primary mechanism to regulate its function is through phosphorylation-dependent inhibition at serine-9 residue. Emerging evidence indicates that there may be alternative mechanisms that control GSK-3 beta for certain functions.
   Objectives: Here, we sought to understand the role of protein S-nitrosylation (SNO) on the function of GSK-3 beta. SNO-dependent modulation of the localization of GSK- 3 beta and its ability to phosphorylate downstream targets was investigated in vitro, and the network of proteins differentially impacted by phospho- or SNO-dependent GSK-3 beta regulation and in vivo SNO modification of key signaling kinases during the development of heart failure was also studied.
   Methods and Results: We found that GSK-3 beta undergoes site-specific SNO both in vitro, in HEK293 cells, H9C2 myoblasts, and primary neonatal rat ventricular myocytes, as well as in vivo, in hearts from an animal model of heart failure and sudden cardiac death. S-nitrosylation of GSK-3 beta significantly inhibits its kinase activity independent of the canonical phospho-inhibition pathway. S-nitrosylation of GSK-3 beta promotes its nuclear translocation and access to novel downstream phosphosubstrates which are enriched for a novel amino acid consensus sequence motif. Quantitative phosphoproteomics pathway analysis reveals that nuclear GSK-3 beta plays a central role in cell cycle control, RNA splicing, and DNA damage response.
   Conclusions: The results indicate that SNO has a differential effect on the location and activity of GSK-3 beta in the cytoplasm versus the nucleus. SNO modification of GSK-3 beta occurs in vivo and could contribute to the pathobiology of heart failure and sudden cardiac death.
C1 [Wang, Sheng-Bing; Venkatraman, Vidya; Liu, Ting; Holewinski, Ronald; Ranek, Mark; Kass, David A.; O'Rourke, Brian; Van Eyk, Jennifer E.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA.
   [Fu, Zongming] Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA.
   [Venkatraman, Vidya; Holewinski, Ronald; Van Eyk, Jennifer E.] Cedars Sinai Med Ctr, Heart Inst, Adv Clin Biosyst Res Inst, Dept Med, Los Angeles, CA 90048 USA.
   [Crowgey, Erin L.] Nemours Alfred I duPont Hosp, Dept Nemours Biomed Res, Wilmington, DE USA.
C3 Johns Hopkins University; Johns Hopkins University; Cedars Sinai Medical
   Center; Nemours Alfred I. duPont Hospital for Children
RP Van Eyk, JE (corresponding author), Cedars Sinai Med Ctr, Smidt Heart Inst, Dept Med, Adv Hlth Sci Pavil Room A9307, Los Angeles, CA 90048 USA.; Wang, SB (corresponding author), Johns Hopkins Univ, Dept Med, Div Cardiol, Ross Res Bldg,720 Rutland Ave, Baltimore, MD 21205 USA.
EM swang86@jhmi.edu; Jennifer.VanEyk@cshs.org
RI Ranek, Mark/GYA-1420-2022
OI Crowgey, Erin/0000-0002-2037-0389; Liu, Ting/0000-0002-8304-5751;
   O'Rourke, Brian/0000-0002-5548-4853; Van Eyk,
   Jennifer/0000-0001-9050-148X
FU National Institutes of Health (NIH)-National Heart, Lung, and Blood
   Institute (NHLBI) Program Project Grants on Pathology of Cardiac
   Dysynchrony and Resynchronization [P01HL77189-01]; NIH-NHLBI
   [NHLBI-HV-10-05 (2)]; Barbara Streisand Women's Heart Center; Smidt
   Heart Institute at Cedars-Sinai Medical Center; Erika Glazer Endowed
   Chair in Women's Heart Health
FX This study was funded by National Institutes of Health (NIH)-National
   Heart, Lung, and Blood Institute (NHLBI) Program Project Grants on
   Pathology of Cardiac Dysynchrony and Resynchronization, P01HL77189-01,
   to J.E. Van Eyk, B. O'Rourke, and D.A. Kass. NIH-NHLBI contract on The
   Johns Hopkins Innovation Proteomics Center in Heart Failure,
   NHLBI-HV-10-05 (2), to J.E. Van Eyk, B. O'Rourke, and D.A. Kass. We also
   acknowledge the Barbara Streisand Women's Heart Center (to J.E. Van
   Eyk), The Smidt Heart Institute at Cedars-Sinai Medical Center (to J.E.
   Van Eyk), and The Erika Glazer Endowed Chair in Women's Heart Health (to
   J.E. Van Eyk) to support this study.
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NR 59
TC 35
Z9 39
U1 0
U2 3
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7330
EI 1524-4571
J9 CIRC RES
JI Circ.Res.
PD MAY 25
PY 2018
VL 122
IS 11
BP 1517
EP 1531
DI 10.1161/CIRCRESAHA.118.312789
PG 15
WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Hematology
GA GJ5GM
UT WOS:000435409500011
PM 29563102
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Sharma, A
   Markey, M
   Torres-Muñoz, K
   Varia, S
   Kadakia, M
   Bubulya, A
   Bubulya, PA
AF Sharma, Alok
   Markey, Michael
   Torres-Munoz, Keshia
   Varia, Sapna
   Kadakia, Madhavi
   Bubulya, Athanasios
   Bubulya, Paula A.
TI Son maintains accurate splicing for a subset of human pre-mRNAs
SO JOURNAL OF CELL SCIENCE
LA English
DT Article
DE Son; NREBP; pre-mRNA; Alternative splicing; SR proteins; Nuclear
   speckles
ID POLYMERASE-II; GENE-EXPRESSION; PROTEIN; TRANSCRIPTION; ORGANIZATION;
   RECRUITMENT; EXON; DEACETYLASE; MECHANISMS; COMPLEXES
AB Serine-arginine-rich (SR) proteins play a key role in alternative pre-mRNA splicing in eukaryotes. We recently showed that a large SR protein called Son has unique repeat motifs that are essential for maintaining the subnuclear organization of pre-mRNA processing factors in nuclear speckles. Motif analysis of Son highlights putative RNA interaction domains that suggest a direct role for Son in pre-mRNA splicing. Here, we used in situ approaches to show that Son localizes to a reporter minigene transcription site, and that RNAi-mediated Son depletion causes exon skipping on reporter transcripts at this transcription site. A genome-wide exon microarray analysis was performed to identify human transcription and splicing targets of Son. Our data show that Son-regulated splicing encompasses all known types of alternative splicing, the most common being alternative splicing of cassette exons. We confirmed that knockdown of Son leads to exon skipping in pre-mRNAs for chromatin-modifying enzymes, including ADA, HDAC6 and SetD8. This study reports a comprehensive view of human transcription and splicing targets for Son in fundamental cellular pathways such as integrin-mediated cell adhesion, cell cycle regulation, cholesterol biosynthesis, apoptosis and epigenetic regulation of gene expression.
C1 [Sharma, Alok; Torres-Munoz, Keshia; Varia, Sapna; Bubulya, Athanasios; Bubulya, Paula A.] Wright State Univ, Dept Biol Sci, Dayton, OH 45435 USA.
   [Sharma, Alok; Varia, Sapna] Wright State Univ, Biomed Sci Ph D Program, Dayton, OH 45435 USA.
   [Markey, Michael; Kadakia, Madhavi] Wright State Univ, Dept Biochem & Mol Biol, Dayton, OH 45435 USA.
   [Torres-Munoz, Keshia] Wright State Univ, Master Sci Program Biol Sci, Dayton, OH 45435 USA.
C3 University System of Ohio; Wright State University Dayton; University
   System of Ohio; Wright State University Dayton; University System of
   Ohio; Wright State University Dayton; University System of Ohio; Wright
   State University Dayton
RP Bubulya, PA (corresponding author), Wright State Univ, Dept Biol Sci, Dayton, OH 45435 USA.
EM paula.bubulya@wright.edu
OI Markey, Michael/0000-0002-8593-2290
FU National Institutes of Health [R15GM084407]; Wright State University
   start-up funds; State of Ohio Research Incentive funds [666435, 262143,
   666768, 667129, 668371]; Center for Genomic Research Seed Grant; H2020 -
   Industrial Leadership [666435] Funding Source: H2020 - Industrial
   Leadership
FX This work was supported by the National Institutes of Health [grant
   number R15GM084407]; Wright State University start-up funds; State of
   Ohio Research Incentive funds [grant numbers 666435, 262143, 666768,
   667129, 668371]; and the Center for Genomic Research Seed Grant (WSU)
   awarded to P.A.B. Deposited in PMC for immediate release.
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NR 68
TC 42
Z9 46
U1 0
U2 19
PU COMPANY BIOLOGISTS LTD
PI CAMBRIDGE
PA BIDDER BUILDING, STATION RD, HISTON, CAMBRIDGE CB24 9LF, ENGLAND
SN 0021-9533
EI 1477-9137
J9 J CELL SCI
JI J. Cell Sci.
PD DEC 15
PY 2011
VL 124
IS 24
BP 4286
EP 4298
DI 10.1242/jcs.092239
PG 13
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 879FD
UT WOS:000299314200018
PM 22193954
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Rogalska, ME
   Vafiadaki, E
   Erpapazoglou, Z
   Haghighi, K
   Green, L
   Mantzoros, CS
   Hajjar, RJ
   Tranter, M
   Karakikes, I
   Kranias, EG
   Stillitano, F
   Kafasla, P
   Sanoudou, D
AF Rogalska, Malgorzata E.
   Vafiadaki, Elizabeth
   Erpapazoglou, Zoi
   Haghighi, Kobra
   Green, Lisa
   Mantzoros, Christos S.
   Hajjar, Roger J.
   Tranter, Michael
   Karakikes, Ioannis
   Kranias, Evangelia G.
   Stillitano, Francesca
   Kafasla, Panagiota
   Sanoudou, Despina
TI Isoform changes of action potential regulators in the ventricles of
   arrhythmogenic phospholamban-R14del humanized mouse hearts
SO METABOLISM-CLINICAL AND EXPERIMENTAL
LA English
DT Article
DE Arrhythmia; Cardiomyopathy; Genomics; Alternative splicing; Microexons
ID SPINAL MUSCULAR-ATROPHY; DILATED CARDIOMYOPATHY; CARDIAC-HYPERTROPHY;
   KINASE-II; MUTATION; PROTEIN; FAILURE; GENE; DYSREGULATION; MODULATION
AB Arrhythmogenic cardiomyopathy (ACM) is characterized by life-threatening ventricular arrhythmias and sudden cardiac death and affects hundreds of thousands of patients worldwide. The deletion of Arginine 14 (p.R14del) in the phospholamban (PLN) gene has been implicated in the pathogenesis of ACM. PLN is a key regulator of sarcoplasmic reticulum (SR) Ca2+ cycling and cardiac contractility. Despite global gene and protein expression studies, the molecular mechanisms of PLN-R14del ACM pathogenesis remain unclear. Using a humanized PLNR14del mouse model and human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs), we investigated the transcriptome-wide mRNA splicing changes associated with the R14del mutation. We identified >200 significant alternative splicing (AS) events and distinct AS profiles were observed in the right (RV) and left (LV) ventricles in PLN-R14del compared to WT mouse hearts. Enrichment analysis of the AS events showed that the most affected biological process was associated with "cardiac cell action potential", specifically in the RV. We found that splicing of 2 key genes, Trpm4 and Camk2d, which encode proteins regulating calcium homeostasis in the heart, were altered in PLN-R14del mouse hearts and human iPSC-CMs. Bioinformatical analysis pointed to the tissue-specific splicing factors Srrm4 and Nova1 as likely upstream regulators of the observed splicing changes in the PLN-R14del cardiomyocytes. Our findings suggest that aberrant splicing may affect Ca2+-homeostasis in the heart, contributing to the increased risk of arrythmogenesis in PLN-R14del ACM.
C1 [Rogalska, Malgorzata E.] Barcelona Inst Sci & Technol, Ctr Genom Regulat CRG, Barcelona 08003, Spain.
   [Vafiadaki, Elizabeth; Sanoudou, Despina] Acad Athens, Mol Biol Div, Biomed Res Fdn, Athens 11527, Greece.
   [Erpapazoglou, Zoi; Kafasla, Panagiota] BSRC Alexander Fleming, Inst Fundamental Biomed Res, Athens 16672, Greece.
   [Haghighi, Kobra; Kranias, Evangelia G.] Univ Cincinnati, Dept Pharmacol & Syst Physiol, Coll Med, Cincinnati, OH 45267 USA.
   [Green, Lisa; Tranter, Michael] Univ Cincinnati, Dept Med, Coll Med, Cincinnati, OH 45267 USA.
   [Mantzoros, Christos S.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02215 USA.
   [Mantzoros, Christos S.] Harvard Med Sch, Sect Endocrinol, Boston VA Healthcare Syst, Boston, MA 02215 USA.
   [Hajjar, Roger J.] Flagship Pioneering, Cambridge, MA 02142 USA.
   [Karakikes, Ioannis] Stanford Univ, Dept Cardiothorac Surg, Sch Med, 240 Pasteur Dr, Stanford, CA 94304 USA.
   [Karakikes, Ioannis] Stanford Univ, Cardiovasc Inst, Sch Med, 240 Pasteur Dr, Stanford, CA 94304 USA.
   [Stillitano, Francesca] Univ Med Ctr Utrecht, Div Heart & Lung, Dept Cardiol, NL-3584 CX Utrecht, Netherlands.
   [Sanoudou, Despina] Natl & Kapodistrian Univ Athens, Attikon Hosp, Dept Internal Med 4, Clin Genom & Pharmacogen Unit,Med Sch, Athens 11527, Greece.
   [Sanoudou, Despina] Natl & Kapodistrian Univ Athens, Ctr New Biotechnol & Precis Med, Med Sch, Athens 11527, Greece.
C3 Barcelona Institute of Science & Technology; Pompeu Fabra University;
   Centre de Regulacio Genomica (CRG); Academy of Athens; Alexander Fleming
   Biomedical Sciences Research Center; University System of Ohio;
   University of Cincinnati; University System of Ohio; University of
   Cincinnati; Harvard University; Harvard University Medical Affiliates;
   Beth Israel Deaconess Medical Center; Harvard Medical School; Harvard
   University; Harvard University Medical Affiliates; US Department of
   Veterans Affairs; Veterans Health Administration (VHA); VA Boston
   Healthcare System; Harvard Medical School; Stanford University; Stanford
   University; Utrecht University; Utrecht University Medical Center;
   National & Kapodistrian University of Athens; University Hospital
   Attikon; National & Kapodistrian University of Athens
RP Sanoudou, D (corresponding author), Natl & Kapodistrian Univ Athens, Attikon Hosp, Dept Internal Med 4, Clin Genom & Pharmacogen Unit,Med Sch, Athens 11527, Greece.
EM dsanoudou@med.uoa.gr
RI Kafasla, Panagiota/B-9187-2009; Tranter, Michael/D-2855-2013; Mantzoros,
   Christos/Y-2902-2019; Vafiadaki, Elizabeth/K-1171-2019; Rogalska,
   Malgorzata/ABF-1334-2020; Stillitano, Francesca/KDP-0830-2024; Sanoudou,
   Despina/AAD-8139-2019
FU Leducq Foundation for Cardiovascular Research; American Heart
   Association;  [18CVD01];  [18TPA34230062]
FX Funding This work was supported by CUREPLaN, a grant from the Leducq
   Foundation for Cardiovascular Research (18CVD01 to D.S., E.G.K. and F.
   S.) , and the American Heart Association (18TPA34230062 to F.S.)
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NR 104
TC 6
Z9 6
U1 1
U2 10
PU W B SAUNDERS CO-ELSEVIER INC
PI PHILADELPHIA
PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA
SN 0026-0495
EI 1532-8600
J9 METABOLISM
JI Metab.-Clin. Exp.
PD JAN
PY 2023
VL 138
AR 155344
DI 10.1016/j.metabol.2022.155344
EA NOV 2022
PG 15
WC Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Endocrinology & Metabolism
GA 6Y1UF
UT WOS:000896886700006
PM 36375644
DA 2025-04-10
ER

PT J
AU Chen, ZL
   Maimaiti, R
   Zhu, CQ
   Cai, HF
   Stern, A
   Mozdziak, P
   Ge, Y
   Ford, SP
   Nathanielsz, PW
   Guo, W
AF Chen, Zhilong
   Maimaiti, Rexiati
   Zhu, Chaoqun
   Cai, Hanfang
   Stern, Allysa
   Mozdziak, Paul
   Ge, Ying
   Ford, Stephen P.
   Nathanielsz, Peter W.
   Guo, Wei
TI Z-band and M-band titin splicing and regulation by RNA binding motif 20
   in striated muscles
SO JOURNAL OF CELLULAR BIOCHEMISTRY
LA English
DT Article
DE alternative splicing; heart disease; M-band; RNA binding motif 20
   (RBM20); titin (TTN); Z-band
ID TISSUE-SPECIFIC EXPRESSION; GIANT PROTEIN TITIN; Z-DISC; CARDIAC TITIN;
   Z-LINE; ISOFORM; CARDIOMYOPATHY; REGION; GENE; ORGANIZATION
AB Titin (TTN) has multifunctional roles in sarcomere assembly, mechanosignaling transduction, and muscle stiffness. TTN splicing generates variable protein sizes with different functions. Therefore, understanding TTN splicing is important to develop a novel treatment for TTN-based diseases. The I-band TTN splicing regulated by RNA binding motif 20 (RBM20) has been extensively studied. However, the Z- and M-band splicing and regulation remain poorly understood. Herein, we aimed to define the Z- and M-band splicing in striated muscles and determined whether RBM20 regulates the Z- and M-band splicing. We discovered four new Z-band TTN splicing variants, and one of them dominates in mouse, rat, sheep, and human hearts. But only one form can be detected in frog and chicken hearts. In skeletal muscles, three new Z repeats (Zr) were detected, and Zr4 to 6 exclusion dominates in the fast muscles, whereas Zr4 skipping dominates in the slow muscle. No developmental changes were detected in the Z-band. In the M-band, two new variants were discovered with alternative 3 ' splice site in exon363 (Mex5) and alternative 5 ' splice site in intron 362. However, only the sheep heart expresses two new variants rather than other species. Skeletal muscles express three M-band variants with altered ratios of Mex5 inclusion to Mex5 exclusion. Finally, we revealed that RBM20 does not regulate the Z- and M-band splicing in the heart, but does in skeletal muscles. Taken together, we characterized the Z- and M-band splicing and provided the first evidence of the role of RBM20 in the Z- and M-band TTN splicing.
C1 [Chen, Zhilong; Cai, Hanfang] Northwest A&F Univ, Dept Anim Sci, Coll Anim Sci & Technol, Yangling, Shanxi, Peoples R China.
   [Chen, Zhilong; Maimaiti, Rexiati; Zhu, Chaoqun; Cai, Hanfang; Ford, Stephen P.; Nathanielsz, Peter W.; Guo, Wei] Univ Wyoming, Dept Anim Sci, Laramie, WY 82071 USA.
   [Stern, Allysa; Mozdziak, Paul] North Carolina State Univ, Prestage Dept Poultry Sci, Raleigh, NC USA.
   [Ge, Ying] Univ Wisconsin, Dept Cell & Regenerat Biol, Human Prote Program, Madison, WI USA.
   [Ge, Ying] Univ Wisconsin, Dept Chem, Human Prote Program, 1101 Univ Ave, Madison, WI 53706 USA.
C3 Northwest A&F University - China; University of Wyoming; North Carolina
   State University; University of Wisconsin System; University of
   Wisconsin Madison; University of Wisconsin System; University of
   Wisconsin Madison
RP Guo, W (corresponding author), Univ Wyoming, Dept Anim Sci, Laramie, WY 82071 USA.
EM wguo3@uwyo.edu
RI Guo, Wei/KJM-4941-2024
OI guo, wei/0000-0002-9158-8107; Stern, Rachel/0000-0001-9503-1931;
   Nathanielsz, Peter/0000-0001-8410-6280; mozdziak,
   paul/0000-0002-1575-3123
FU American Heart Association [16BGIA27790136]; National Institute of Food
   and Agriculture [1009266]; National Institute of Health [HL096971,
   HL109810]; National Institute of General Medical Sciences
   [NIGMSP20GM103432]; Eunice Kennedy Shriver National Institute of Child
   Health and Human Development [HD070096]; American Heart Association
   (AHA) [16BGIA27790136] Funding Source: American Heart Association (AHA)
FX American Heart Association, Grant/Award Number: 16BGIA27790136; National
   Institute of Food and Agriculture, Grant/Award Number: 1009266; National
   Institute of Health, Grant/Award Numbers: HL096971, HL109810; National
   Institute of General Medical Sciences, Grant/Award Number:
   NIGMSP20GM103432; Eunice Kennedy Shriver National Institute of Child
   Health and Human Development, Grant/Award Number: HD070096
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NR 48
TC 7
Z9 11
U1 0
U2 11
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0730-2312
EI 1097-4644
J9 J CELL BIOCHEM
JI J. Cell. Biochem.
PD DEC
PY 2018
VL 119
IS 12
BP 9986
EP 9996
DI 10.1002/jcb.27328
PG 11
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA HA3DO
UT WOS:000450130500034
PM 30133019
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Watanabe, F
   Furuya, E
AF Watanabe, F
   Furuya, E
TI Tissue-specific alternative splicing of rat brain fructose 6-phosphate
   2-kinase/fructose 2,6-bisphosphatase
SO FEBS LETTERS
LA English
DT Article
DE brain; fructose 6-phosphate 2-kinase; fructose 2,6-bisphosphatase;
   alternative splicing; RNAse protection assay
ID HEART 6-PHOSPHOFRUCTO-2-KINASE FRUCTOSE-2,6-BISPHOSPHATASE; MYOCARDIAL
   FRUCTOSE-6-PHOSPHATE,2-KINASE; PHOSPHORYLATION SITES; MOLECULAR-CLONING;
   SEQUENCE; GENE; 6-PHOSPHOFRUCTO-2-KINASE/FRUCTOSE-2,6-BISPHOSPHATASE;
   EXPRESSION; FORMS
AB We have reported the occurrence of eight splice variants of rat brain fructose B-phosphate 2-kinase/fructose 2,6-bisphosphatase (RB2K), In the present study, we quantified these splice variants in various tissues using a RNAse protection assay and found a tissue-specific pattern of alternative splicing of the RB2K gene, Splice variants containing exon F were specifically expressed in brain. Moreover, exons D and E, were spliced in brain, skeletal muscle and heart, Consequently, eight, six, four and two splice variants were expressed in brain, skeletal muscle, heart and liver plus testis, respectively. These results suggest that distinct RB2K isoforms could be involved in regulation of glycolysis in a tissue-specific manner. (C) 1999 Federation of European Biochemical Societies.
C1 Osaka Med Coll, Dept Chem, Takatsuki, Osaka 5690084, Japan.
C3 Osaka Medical & Pharmaceutical University
RP Watanabe, F (corresponding author), Osaka Med Coll, Dept Chem, 2-41 Sawaragi Cho, Takatsuki, Osaka 5690084, Japan.
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NR 21
TC 17
Z9 18
U1 0
U2 0
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0014-5793
J9 FEBS LETT
JI FEBS Lett.
PD SEP 24
PY 1999
VL 458
IS 3
BP 304
EP 308
DI 10.1016/S0014-5793(99)01174-6
PG 5
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA 240ZL
UT WOS:000082856600007
PM 10570929
OA Bronze
DA 2025-04-10
ER

PT J
AU Zhang, T
   Lin, Y
   Liu, J
   Zhang, ZG
   Fu, W
   Guo, LY
   Pan, L
   Kong, X
   Zhang, MK
   Lu, YH
   Huang, ZR
   Xie, Q
   Li, WH
   Xu, XQ
AF Zhang, Tao
   Lin, Yu
   Liu, Jing
   Zhang, Zi Guan
   Fu, Wei
   Guo, Li Yan
   Pan, Lei
   Kong, Xu
   Zhang, Meng Kai
   Lu, Ying Hua
   Huang, Zheng Rong
   Xie, Qiang
   Li, Wei Hua
   Xu, Xiu Qin
TI Rbm24 Regulates Alternative Splicing Switch in Embryonic Stem Cell
   Cardiac Lineage Differentiation
SO STEM CELLS
LA English
DT Article
DE Rbm24; Alternative splicing; Embryonic stem cell; Cardiac; RNA binding
   protein
ID HIGHLY ENRICHED CARDIOMYOCYTES; BINDING PROTEIN RBM24; HEART;
   EXPRESSION; TRANSCRIPTION; PLURIPOTENCY; CYTOSKELETON; PROGENITORS;
   MESODERM; NETWORKS
AB The transition of embryonic stem cell (ESC) pluripotency to differentiation is accompanied by an expansion of mRNA and proteomic diversity. Post-transcriptional regulation of ESCs is critically governed by cell type-specific splicing. However, little is known about the splicing factors and the molecular mechanisms directing ESC early lineage differentiation. Our study identifies RNA binding motif protein 24 (Rbm24) as a key splicing regulator that plays an essential role in controlling post-transcriptional networks during ESC transition into cardiac differentiation. Using an inducible mouse ESC line in which gene expression could be temporally regulated, we demonstrated that forced expression of Rbm24 in ESCs dramatically induced a switch to cardiac specification. Genome-wide RNA sequencing analysis identified more than 200 Rbm24-regulated alternative splicing events (AS) which occurred in genes essential for the ESC pluripotency or differentiation. Remarkably, AS genes regulated by Rbm24 composed of transcriptional factors, cytoskeleton proteins, and ATPase gene family members which are critical components required for cardiac development and functionality. Furthermore, we show that Rbm24 regulates ESC differentiation by promoting alternative splicing of pluripotency genes. Among the Rbm24-regulated events, Tpm1, an actin filament family gene, was identified to possess ESC/tissue specific isoforms. We demonstrated that these isoforms were functionally distinct and that their exon AS switch was essential for ESC differentiation. Our results suggest that ESC's switching into the differentiation state can be initiated by a tissue-specific splicing regulator, Rbm24. This finding offers a global view on how an RNA binding protein influences ESC lineage differentiation by a splicing-mediated regulatory mechanism. Stem Cells2016;34:1776-1789
C1 [Zhang, Tao; Lin, Yu; Liu, Jing; Zhang, Zi Guan; Fu, Wei; Guo, Li Yan; Pan, Lei; Kong, Xu; Zhang, Meng Kai; Xu, Xiu Qin] Xiamen Univ, Inst Stem Cell & Regenerat Med, Coll Med, Chengzhi Bldg,Xiangan Campus, Xiamen 361100, Fujian, Peoples R China.
   [Liu, Jing] Xiamen Univ, ShenZhen Res Inst, Xiamen, Fujian, Peoples R China.
   [Zhang, Zi Guan; Huang, Zheng Rong; Xie, Qiang; Li, Wei Hua] Xiamen Univ, Affiliated Hosp 1, Dept Cardiol, Xiamen, Fujian, Peoples R China.
   [Lu, Ying Hua] Xiamen Univ, Dept Chem & Biochem Engn, Coll Chem & Chem Engn, Xiamen, Fujian, Peoples R China.
C3 Xiamen University; Xiamen University; Xiamen University; Xiamen
   University
RP Xu, XQ (corresponding author), Xiamen Univ, Inst Stem Cell & Regenerat Med, Coll Med, Chengzhi Bldg,Xiangan Campus, Xiamen 361100, Fujian, Peoples R China.
EM xuxq@xmu.edu.cn
RI Kong, Fanxu/GSI-7088-2022; GUO, LIYAN/MFH-9811-2025
OI guo, li yan/0000-0002-5347-4993
FU National Natural Science Foundation of China (NSFC) [81270199]; Major
   State Basic Research Development Program of China [2014CB965101]; Xiamen
   Joint Research Fund for Major Diseases [3502Z20159014]; Research Fund of
   Xiamen Oceanic Administration [14PYY051SF04]; Natural Science Foundation
   of Guangdong Province [2015A030310008]; Key Science Foundation of Fujian
   Province [2013D020]; Natural Science Foundation of Fujian Province
   [2012D038]
FX We thank Dr. Michael Kyba and Dr. Ceddric Blanpain for their kind
   donation of the A2Lox ESCs and the p2Lox-Mesp1-tag plasmid,
   respectively; Dr. Leah Vardy and Yew Mun Lee for critical reading of
   manuscript. This work was supported by the National Natural Science
   Foundation of China (NSFC) (Grant no. 81270199), the Major State Basic
   Research Development Program of China (Grant no. 2014CB965101), Xiamen
   Joint Research Fund for Major Diseases (3502Z20159014), Research Fund of
   Xiamen Oceanic Administration (14PYY051SF04), the Natural Science
   Foundation of Guangdong Province (2015A030310008), the Key Science
   Foundation of Fujian Province (2013D020), and the Natural Science
   Foundation of Fujian Province (2012D038).
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NR 46
TC 52
Z9 60
U1 2
U2 22
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1066-5099
EI 1549-4918
J9 STEM CELLS
JI Stem Cells
PD JUL
PY 2016
VL 34
IS 7
BP 1776
EP 1789
DI 10.1002/stem.2366
PG 14
WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology;
   Oncology; Cell Biology; Hematology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology
GA DR4WD
UT WOS:000379902900006
PM 26990106
DA 2025-04-10
ER

PT J
AU Torelli, S
   Muntoni, F
AF Torelli, S
   Muntoni, F
TI Alternative splicing of dystrophin exon 4 in normal human muscle
SO HUMAN GENETICS
LA English
DT Article
ID BECKER MUSCULAR-DYSTROPHY; DUCHENNE; DELETION
AB The dystrophin gene is composed of at least 86 exons and the occurrence of several alternative splicing sites, mainly occurring in its 3' region, is a well recognised phenomenon. We have found that exon 4 can also be alternatively spliced in human skeletal and cardiac muscle.
C1 HAMMERSMITH HOSP,ROYAL POSTGRAD MED SCH,DEPT PAEDIAT & NEONATAL MED,NEUROMUSCULAR UNIT,LONDON W12 0NN,ENGLAND.
C3 Imperial College London
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NR 18
TC 10
Z9 10
U1 0
U2 0
PU SPRINGER VERLAG
PI NEW YORK
PA 175 FIFTH AVE, NEW YORK, NY 10010
SN 0340-6717
J9 HUM GENET
JI Hum. Genet.
PD APR
PY 1996
VL 97
IS 4
BP 521
EP 523
PG 3
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA TZ783
UT WOS:A1996TZ78300023
PM 8834255
DA 2025-04-10
ER

PT J
AU Kim, HK
   Pham, MHC
   Ko, KS
   Rhee, BD
   Han, J
AF Kim, Hyoung Kyu
   Pham, Michael Huy Cuong
   Ko, Kyung Soo
   Rhee, Byoung Doo
   Han, Jin
TI Alternative splicing isoforms in health and disease
SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
LA English
DT Review
DE Cancer; Neurodegenerative diseases; Cardiovascular disease; Metabolic
   disease; Mitochondria; Splicing factor; Intron; Exon skipping
ID CA(V)1.2 CALCIUM-CHANNELS; BINDING-PROTEIN 1; MESSENGER-RNA; OXIDATIVE
   STRESS; SKELETAL-MUSCLE; CARDIAC-FUNCTION; GENE-EXPRESSION; COMPLEX-I;
   ANTISENSE OLIGONUCLEOTIDES; MYOCARDIAL-INFARCTION
AB Alternative splicing (AS) of protein-coding messenger RNAs is an essential regulatory mechanism in eukaryotic gene expression that controls the proper function of proteins. It is also implicated in the physiological regulation of mitochondria and various ion channels. Considering that mis-splicing can result in various human diseases by modifying or abrogating important physiological protein functions, a fine-tuned balance of AS is essential for human health. Accumulated data highlight the importance of alternatively spliced isoforms in various diseases, including neurodegenerative disorders, cancer, immune and infectious diseases, cardiovascular diseases, and metabolic conditions. However, basic understanding of disease mechanisms and development of clinical applications still require the integration and interpretation of physiological roles of AS. This review discusses the roles of AS in health and various diseases, while highlighting potential AS-targeting therapeutic applications.
C1 [Kim, Hyoung Kyu; Ko, Kyung Soo; Rhee, Byoung Doo; Han, Jin] Inje Univ, Natl Res Lab Mitochondrial Signaling, Cardiovasc & Metab Dis Ctr,Coll Med, Dept Physiol,Dept Hlth Sci & Technol,Plus Project, Bokji Ro 75, Busan 47392, South Korea.
   [Kim, Hyoung Kyu] Inje Univ, Dept Integrated Biomed Sci, Coll Med, Busan, South Korea.
   [Pham, Michael Huy Cuong] Univ Copenhagen, Sch Med, Copenhagen, Denmark.
C3 Inje University; Inje University; University of Copenhagen
RP Han, J (corresponding author), Inje Univ, Natl Res Lab Mitochondrial Signaling, Cardiovasc & Metab Dis Ctr,Coll Med, Dept Physiol,Dept Hlth Sci & Technol,Plus Project, Bokji Ro 75, Busan 47392, South Korea.
EM phyhanj@inje.ac.kr
RI Kim, Hyung/J-5451-2012; Pham, Michael Huy Cuong/KHW-4474-2024
OI Pham, Michael Huy Cuong/0000-0002-6577-0079; Kim, Hyoung
   Kyu/0000-0002-1791-7865
FU Priority Research Centers Program through the National Research
   Foundation of Korea (NRF) - Ministry of Education, Science, and
   Technology [2010-0020224, 2015R1A2A1A13001900, 2015R1D1A1A01057937];
   Basic Science Research Program through the National Research Foundation
   of Korea (NRF) - Ministry of Education, Science, and Technology
   [2010-0020224, 2015R1A2A1A13001900, 2015R1D1A1A01057937]
FX This study was supported by grants from the Priority Research Centers
   Program and Basic Science Research Program through the National Research
   Foundation of Korea (NRF), funded by the Ministry of Education, Science,
   and Technology (2010-0020224, 2015R1A2A1A13001900, and
   2015R1D1A1A01057937).
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NR 172
TC 102
Z9 115
U1 1
U2 27
PU SPRINGER HEIDELBERG
PI HEIDELBERG
PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY
SN 0031-6768
EI 1432-2013
J9 PFLUG ARCH EUR J PHY
JI Pflugers Arch.
PD JUL
PY 2018
VL 470
IS 7
BP 995
EP 1016
DI 10.1007/s00424-018-2136-x
PG 22
WC Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Physiology
GA GK2XC
UT WOS:000436000700001
PM 29536164
DA 2025-04-10
ER

PT J
AU Medina, MW
   Gao, F
   Naidoo, D
   Rudel, LL
   Temel, RE
   McDaniel, AL
   Marshall, SM
   Krauss, RM
AF Medina, Marisa Wong
   Gao, Feng
   Naidoo, Devesh
   Rudel, Lawrence L.
   Temel, Ryan E.
   McDaniel, Allison L.
   Marshall, Stephanie M.
   Krauss, Ronald M.
TI Coordinately Regulated Alternative Splicing of Genes Involved in
   Cholesterol Biosynthesis and Uptake
SO PLOS ONE
LA English
DT Article
ID LOW-DENSITY-LIPOPROTEIN; COENZYME-A REDUCTASE; HEPATOMA-CELL LINE;
   MEVALONATE KINASE; MESSENGER-RNA; SYNTHASE; TRACT; SIMVASTATIN;
   SEQUENCE; EXON
AB Genes involved in cholesterol biosynthesis and uptake are transcriptionally regulated in response to cellular sterol content in a coordinated manner. A number of these genes, including 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and LDL receptor (LDLR), undergo alternative splicing, resulting in reductions of enzyme or protein activity. Here we demonstrate that cellular sterol depletion suppresses, and sterol loading induces, alternative splicing of multiple genes involved in the maintenance of cholesterol homeostasis including HMGCR and LDLR, the key regulators of cellular cholesterol biosynthesis and uptake, respectively. These changes were observed in both in vitro studies of the HepG2 human hepatoma derived cell line, as well as in vivo studies of St. Kitts vervets, also known as African green monkeys, a commonly used primate model for investigating cholesterol metabolism. These effects are mediated in part by sterol regulation of polypyrimidine tract binding protein 1 (PTBP1), since knock-down of PTBP1 eliminates sterol induced changes in alternative splicing of several of these genes. Single nucleotide polymorphisms (SNPs) that influence HMGCR and LDLR alternative splicing (rs3846662 and rs688, respectively), have been associated with variation in plasma LDL-cholesterol levels. Sterol-induced changes in alternative splicing are blunted in carriers of the minor alleles for each of these SNPs, indicating an interaction between genetic and non-genetic regulation of this process. Our results implicate alternative splicing as a novel mechanism of enhancing the robust transcriptional response to conditions of cellular cholesterol depletion or accumulation. Thus coordinated regulation of alternative splicing may contribute to cellular cholesterol homeostasis as well as plasma LDL levels.
C1 [Medina, Marisa Wong; Gao, Feng; Naidoo, Devesh; Krauss, Ronald M.] Childrens Hosp, Oakland Res Inst, Dept Atherosclerosis Res, Oakland, CA 94609 USA.
   [Rudel, Lawrence L.; Temel, Ryan E.; McDaniel, Allison L.; Marshall, Stephanie M.] Wake Forest Univ Hlth Sci, Dept Pathol Lipid Sci, Winston Salem, NC USA.
C3 Children's Hospital Oakland Research Institute; Children's Hospital Los
   Angeles; Wake Forest University; Wake Forest University School of
   Medicine
RP Medina, MW (corresponding author), Childrens Hosp, Oakland Res Inst, Dept Atherosclerosis Res, 747 52nd St, Oakland, CA 94609 USA.
EM mwmedina@chori.org; rkrauss@chori.org
RI Krauss, Ronald M./LTD-4078-2024
FU National Institutes of Health [U01 HL69757, R01 HL 104133-01, R21
   HL093507-01A1]
FX This work was funded by a grant from the National Institutes of Health,
   U01 HL69757. Additional support was provided by National Institutes of
   Health grants R01 HL 104133-01 and R21 HL093507-01A1. The funders had no
   role in study design, data collection and analysis, decision to publish,
   or preparation of the manuscript.
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NR 45
TC 54
Z9 65
U1 0
U2 9
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD APR 29
PY 2011
VL 6
IS 4
AR e19420
DI 10.1371/journal.pone.0019420
PG 13
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 756OZ
UT WOS:000290024700164
PM 21559365
OA gold, Green Published, Green Submitted
DA 2025-04-10
ER

PT J
AU Kanemoto, Y
   Sanada, F
   Shibata, K
   Tsunetoshi, Y
   Katsuragi, N
   Koibuchi, N
   Yoshinami, T
   Yamamoto, K
   Morishita, R
   Taniyama, Y
   Shimazu, K
AF Kanemoto, Yuko
   Sanada, Fumihiro
   Shibata, Kana
   Tsunetoshi, Yasuo
   Katsuragi, Naruto
   Koibuchi, Nobutaka
   Yoshinami, Tetsuhiro
   Yamamoto, Koichi
   Morishita, Ryuichi
   Taniyama, Yoshiaki
   Shimazu, Kenzo
TI Expression of Periostin Alternative Splicing Variants in Normal Tissue
   and Breast Cancer
SO BIOMOLECULES
LA English
DT Article
DE periostin; extracellular matrix protein; alternative splicing variants;
   breast cancer
AB (1) Background: Periostin (Pn) is a secreted protein found in the extracellular matrix, and it plays a variety of roles in the human body. Physiologically, Pn has a variety of functions, including bone formation and wound healing. However, it has been implicated in the pathogenesis of various malignant tumors and chronic inflammatory diseases. Pn has alternative splicing variants (ASVs), and our previous research revealed that aberrant ASVs contribute to the pathogenesis of breast cancer and heart failure. However, the difference in expression pattern between physiologically expressed Pn-ASVs and those expressed during pathogenesis is not clear. (2) Methods and results: We examined normal and breast cancer tissues, focusing on the Pn-ASVs expression pattern to assess the significance of pathologically expressed Pn-ASVs as potential diagnostic and therapeutic targets. We found that most physiologically expressed Pn isoforms lacked exon 17 and 21. Next, we used human breast cancer and normal adjacent tissue (NAT) to investigate the expression pattern of Pn-ASVs under pathological conditions. Pn-ASVs with exon 21 were significantly increased in tumor tissues compared with NAT. In situ hybridization identified the synthesis of Pn-ASVs with exon 21 in peri-tumoral stromal cells. Additionally, the in vivo bio-distribution of 89Zr-labeled Pn antibody against exon 21 (Pn-21Ab) in mice bearing breast cancer demonstrated selective and specific accumulation in tumors, while Pn-21Ab significantly suppressed tumor growth in the mouse breast cancer model. (3) Conclusions: Together, these data indicate that Pn-ASVs might have potential for use as diagnostic and therapeutic targets for breast cancer.
C1 [Kanemoto, Yuko; Yoshinami, Tetsuhiro; Shimazu, Kenzo] Osaka Univ, Dept Breast & Endocrine Surg, Grad Sch Med, Suita 5650871, Japan.
   [Sanada, Fumihiro; Tsunetoshi, Yasuo; Katsuragi, Naruto; Koibuchi, Nobutaka; Morishita, Ryuichi] Osaka Univ, Dept Clin Gene Therapy, Grad Sch Med, Suita 5650871, Japan.
   [Shibata, Kana; Taniyama, Yoshiaki] Osaka Univ, Dept Adv Mol Therapy, Grad Sch Med, Suita 5650871, Japan.
   [Yamamoto, Koichi] Osaka Univ, Dept Geriatr & Gen Med, Grad Sch Med, Suita 5650871, Japan.
C3 The University of Osaka; The University of Osaka; The University of
   Osaka; The University of Osaka
RP Shimazu, K (corresponding author), Osaka Univ, Dept Breast & Endocrine Surg, Grad Sch Med, Suita 5650871, Japan.
EM y.kanemoto@onsurg.med.osaka-u.ac.jp; sanada@cgt.med.osaka-u.ac.jp;
   tsunetoshi@geriat.med.osaka-u.ac.jp; katsuragi@cgt.med.osaka-u.ac.jp;
   koibuchi@cgt.med.osaka-u.ac.jp; yosinami-te@onsurg.med.osaka-u.ac.jp;
   kyamamoto@geriat.med.osaka-u.ac.jp; morishit@cgt.med.osaka-u.ac.jp;
   taniyama@cgt.med.osaka-u.ac.jp; kshimazu@onsurg.med.osaka-u.ac.jp
FU JSPS KAKENHI; Japan Agency for Medical Research and Development
   [22ck0106731h0001]; G7 Foundation [2024-2029, 24K11740]; START Project
   of the Ministry of Education, Culture, Sports, Science and Technology
   (MEXT), Japan;  [JP24K11764]
FX This work was supported by a grant-in-aid from JSPS KAKENHI (grant
   number JP24K11764), a grant-in-aid from the Japan Agency for Medical
   Research and Development (grant number 22ck0106731h0001), and a
   grant-in-aid from the G7 Foundation. In addition, this study was also
   supported by grants from the Grants in Aid for Scientific Research (C),
   2024-2029, 24K11740, and the START Project of the Ministry of Education,
   Culture, Sports, Science and Technology (MEXT), Japan.
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NR 35
TC 1
Z9 1
U1 1
U2 1
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2218-273X
J9 BIOMOLECULES
JI Biomolecules
PD SEP
PY 2024
VL 14
IS 9
AR 1093
DI 10.3390/biom14091093
PG 17
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA H4O3Q
UT WOS:001323246700001
PM 39334860
OA gold
DA 2025-04-10
ER

PT J
AU Peters, T
   Hermans-Beijnsberger, S
   Beqqali, A
   Bitsch, N
   Nakagawa, S
   Prasanth, KV
   de Windt, LJ
   van Oort, RJ
   Heymans, S
   Schroen, B
AF Peters, Tim
   Hermans-Beijnsberger, Steffie
   Beqqali, Abdelaziz
   Bitsch, Nicole
   Nakagawa, Shinichi
   Prasanth, Kannanganattu V.
   de Windt, Leon J.
   van Oort, Ralph J.
   Heymans, Stephane
   Schroen, Blanche
TI Long Non-Coding RNA Malat-1 Is Dispensable during Pressure
   Overload-Induced Cardiac Remodeling and Failure in Mice
SO PLOS ONE
LA English
DT Article
ID ENDOTHELIAL GROWTH-FACTOR; XIST GENE; CARDIOMYOPATHY; METASTASIS;
   INHIBITION; EXPRESSION; MICRORNAS; LNCRNA
AB Background
   Long non-coding RNAs (lncRNAs) are a class of RNA molecules with diverse regulatory functions during embryonic development, normal life, and disease in higher organisms. However, research on the role of lncRNAs in cardiovascular diseases and in particular heart failure is still in its infancy. The exceptionally well conserved nuclear lncRNA Metastasis associated in lung adenocarcinoma transcript 1 (Malat-1) is a regulator of mRNA splicing and highly expressed in the heart. Malat-1 modulates hypoxia-induced vessel growth, activates ERK/MAPK signaling, and scavenges the anti-hypertrophic microRNA-133. We therefore hypothesized that Malat-1 may act as regulator of cardiac hypertrophy and failure during cardiac pressure overload induced by thoracic aortic constriction (TAC) in mice.
   Results
   Absence of Malat-1 did not affect cardiac hypertrophy upon pressure overload: Heart weight to tibia length ratio significantly increased in WT mice (sham: 5.78 +/- 0.55, TAC 9.79 +/- 1.82 g/mm; p<0.001) but to a similar extend also in Malat-1 knockout (KO) mice (sham: 6.21 +/- 1.12, TAC 8.91 +/- 1.74 g/mm; p<0.01) with no significant difference between genotypes. As expected, TAC significantly reduced left ventricular fractional shortening in WT (sham: 38.81 +/- 6.53%, TAC: 23.14 +/- 11.99%; p<0.01) but to a comparable degree also in KO mice (sham: 37.01 +/- 4.19%, TAC: 25.98 +/- 9.75%; p<0.05). Histological hallmarks of myocardial remodeling, such as cardiomyocyte hypertrophy, increased interstitial fibrosis, reduced capillary density, and immune cell infiltration, did not differ significantly between WT and KO mice after TAC. In line, the absence of Malat-1 did not significantly affect angiotensin II-induced cardiac hypertrophy, dysfunction, and overall remodeling. Above that, pressure overload by TAC significantly induced mRNA levels of the hypertrophy marker genes Nppa, Nppb and Acta1, to a similar extend in both genotypes. Alternative splicing of Ndrg2 after TAC was apparent in WT (isoform ratio; sham: 2.97 +/- 0.26, TAC 1.57 +/- 0.40; p<0.0001) and KO mice (sham: 3.64 +/- 0.37; TAC: 2.24 +/- 0.76; p<0.0001) and interestingly differed between genotypes both at baseline and after pressure overload (p<0.05 each).
   Conclusion
   These findings confirm a role for the lncRNA Malat-1 in mRNA splicing. However, no critical role for Malat-1 was found in pressure overload-induced heart failure in mice, despite its reported role in vascularization, ERK/MAPK signaling, and regulation of miR-133.
C1 [Peters, Tim; Hermans-Beijnsberger, Steffie; Heymans, Stephane; Schroen, Blanche] Maastricht Univ, Ctr Heart Failure Res, Dept Cardiol, CARIM Sch Cardiovasc Dis, NL-6200 MD Maastricht, Netherlands.
   [Beqqali, Abdelaziz; van Oort, Ralph J.] Univ Amsterdam, Acad Med Ctr, Dept Expt Cardiol, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands.
   [Bitsch, Nicole; de Windt, Leon J.] Maastricht Univ, Dept Cardiol, CARIM Sch Cardiovasc Dis, NL-6200 MD Maastricht, Netherlands.
   [Nakagawa, Shinichi] RIKEN, RNA Biol Lab, Wako, Saitama, Japan.
   [Prasanth, Kannanganattu V.] Univ Illinois, Dept Cell & Dev Biol, Urbana, IL USA.
   [Heymans, Stephane] Netherlands Heart Inst ICIN, Utrecht, Netherlands.
   [Heymans, Stephane] Katholieke Univ Leuven, Dept Cardiovasc Sci, CMVB, Leuven, Belgium.
C3 Maastricht University; University of Amsterdam; Maastricht University;
   RIKEN; University of Illinois System; University of Illinois
   Urbana-Champaign; KU Leuven
RP Schroen, B (corresponding author), Maastricht Univ, Ctr Heart Failure Res, Dept Cardiol, CARIM Sch Cardiovasc Dis, NL-6200 MD Maastricht, Netherlands.
EM B.Schroen@maastrichtuniversity.nl
RI van Oort, Ralph/C-5713-2011; Peters, Tim/HNI-2741-2023; de Windt,
   Leon/AAO-6395-2020; Nakagawa, Shinichi/I-4192-2014; Beqqali,
   Abdelaziz/F-8568-2013
OI Nakagawa, Shinichi/0000-0002-6806-7493; Beqqali,
   Abdelaziz/0000-0003-1390-5821; Heymans, Stephane/0000-0001-9477-7803; De
   Windt, Leon/0000-0002-7793-2856
FU Dutch Heart Foundation [2009B025, 2012T094]; Netherlands CardioVascular
   Research Initiative: the Dutch Heart Foundation; Dutch Federation of
   University Medical Centers; Netherlands Organization for Health Research
   and Development (ZonMW); Royal Netherlands Academy of Sciences
   (CVON-ARENA); Netherlands Organization for Scientific Research (NWO)
   [Vidi 91714363]; European Union Commission [261409]; European Research
   Council [311549]; Ministry of Education, Science, Sports, and Culture of
   Japan (MEXT) [26113005]; National Institutes of Health [GM088252];
   American Cancer Society [RSG-11-174-01-RMC]; European Research Council
   (ERC) [311549] Funding Source: European Research Council (ERC);
   Grants-in-Aid for Scientific Research [15K21720, 26113005] Funding
   Source: KAKEN
FX The research leading to these results has received funding from the
   Dutch Heart Foundation (2009B025 to BS and 2012T094 to RJVO,
   www.hartstichting.nl); the Netherlands CardioVascular Research
   Initiative: the Dutch Heart Foundation, Dutch Federation of University
   Medical Centers, the Netherlands Organization for Health Research and
   Development (ZonMW) and the Royal Netherlands Academy of Sciences
   (CVON-ARENA to SH and LJDW and CVON-ARENA young talent grant to AB,
   www.cvonarena.nl); from the Netherlands Organization for Scientific
   Research (NWO Vidi 91714363 to BS, www.nwo.nl); from the European Union
   Commission's Seventh Framework program (261409,
   ec.europa.eu/research/fp7/index_en.cfm); from the European Research
   Council (311549 to LJDW, erc.europa.eu); from the Ministry of Education,
   Science, Sports, and Culture of Japan (MEXT, Grant-in-Aid for Scientific
   Research on Innovative Areas 26113005 to SN, www.mext.go.jp/english);
   from the National Institutes of Health (GM088252 to KVP, www.nih.gov);
   and from the American Cancer Society (RSG-11-174-01-RMC to KVP,
   www.cancer.org). The funders had no role in study design, data
   collection and analysis, decision to publish, or preparation of the
   manuscript.
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NR 42
TC 39
Z9 45
U1 0
U2 9
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD FEB 26
PY 2016
VL 11
IS 2
AR e0150236
DI 10.1371/journal.pone.0150236
PG 12
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA DF3UU
UT WOS:000371274400108
PM 26919721
OA Green Published, Green Submitted, gold
DA 2025-04-10
ER

PT J
AU Tucholski, T
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   Hite, Z
   Vikhorev, PG
   Marston, SB
   Lal, S
   Li, A
   dos Remedios, C
   Kohmoto, T
   Hermsen, J
   Ralphe, JC
   Kamp, TJ
   Moss, RL
   Ge, Y
AF Tucholski, Trisha
   Cai, Wenxua
   Gregorich, Zachery R.
   Bayne, Elizabeth F.
   Mitchell, Stanford D.
   McIlwain, Sean J.
   de Lange, Willem J.
   Wrobbel, Max
   Karp, Hannah
   Hite, Zachary
   Vikhorev, Petr G.
   Marston, Steven B.
   Lal, Sean
   Li, Amy
   dos Remedios, Cristobal
   Kohmoto, Takushi
   Hermsen, Joshua
   Ralphe, J. Carter
   Kamp, Timothy J.
   Moss, Richard L.
   Ge, Ying
TI Distinct hypertrophic cardiomyopathy genotypes result in convergent
   sarcomeric proteoform profiles revealed by top-down proteomics
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
   AMERICA
LA English
DT Article
DE hypertrophic cardiomyopathy; proteoform; posttranslational
   modifications; phosphorylation; top-down proteomics
ID CARDIAC TROPONIN-I; LIM DOMAIN PROTEINS; Z-DISC; HEART-FAILURE;
   PHOSPHORYLATION; TROPOMYOSIN; MYOFILAMENT; MUTATIONS; CYPHER;
   CALSARCIN-1
AB Hypertrophic cardiomyopathy (HCM) is the most common heritable heart disease. Although the genetic cause of HCM has been linked to mutations in genes encoding sarcomeric proteins, the ability to predict clinical outcomes based on specific mutations in HCM patients is limited. Moreover, how mutations in different sarcomeric proteins can result in highly similar clinical phenotypes remains unknown. Posttranslational modifications (PTMs) and alternative splicing regulate the function of sarcomeric proteins; hence, it is critical to study HCM at the level of proteoforms to gain insights into the mechanisms underlying HCM. Herein, we employed high-resolution mass spectrometry-based top-down proteomics to comprehensively characterize sarcomeric proteoforms in septal myectomy tissues from HCM patients exhibiting severe outflow track obstruction (n = 16) compared to nonfailing donor hearts (n = 16). We observed a complex landscape of sarcomeric proteoforms arising from combinatorial PTMs, alternative splicing, and genetic variation in HCM. A coordinated decrease of phosphorylation in important myofilament and Z-disk proteins with a linear correlation suggests PTM cross-talk in the sarcomere and dysregulation of protein kinase A pathways in HCM. Strikingly, we discovered that the sarcomeric proteoform alterations in the myocardium of HCM patients undergoing septal myectomy were remarkably consistent, regardless of the underlying HCM-causing mutations. This study suggests that the manifestation of severe HCM coalesces at the proteoform level despite distinct genotype, which underscores the importance of molecular characterization of HCM phenotype and presents an opportunity to identify broad-spectrum treatments to mitigate the most severe manifestations of this genetically heterogenous disease.
C1 [Tucholski, Trisha; Bayne, Elizabeth F.; Ge, Ying] Univ Wisconsin, Dept Chem, 1101 Univ Ave, Madison, WI 53706 USA.
   [Cai, Wenxua; Mitchell, Stanford D.; Ge, Ying] Univ Wisconsin, Mol & Cellular Pharmacol Training Program, Madison, WI 53705 USA.
   [Cai, Wenxua; Gregorich, Zachery R.; Mitchell, Stanford D.; Wrobbel, Max; Karp, Hannah; Hite, Zachary; Kamp, Timothy J.; Moss, Richard L.; Ge, Ying] Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53705 USA.
   [McIlwain, Sean J.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53705 USA.
   [McIlwain, Sean J.] Univ Wisconsin, Carbone Canc Ctr, Madison, WI 53705 USA.
   [de Lange, Willem J.; Ralphe, J. Carter] Univ Wisconsin, Dept Pediat, Madison, WI 53705 USA.
   [Vikhorev, Petr G.; Marston, Steven B.] Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England.
   [Lal, Sean; Li, Amy; dos Remedios, Cristobal] Univ Sydney, Fac Med & Hlth, Sch Med Sci, Camperdown, NSW 2006, Australia.
   [Li, Amy] La Trobe Univ, Dept Pharm & Biomed Sci, Bundoora, Vic 3086, Australia.
   [dos Remedios, Cristobal] Victor Chang Cardiac Res Inst, Dept Mol Cardiol & Biophys, Darlinghurst, NSW 2010, Australia.
   [Kohmoto, Takushi; Hermsen, Joshua] Univ Wisconsin, Sch Med & Publ Hlth, Dept Surg, Madison, WI 53706 USA.
   [Kamp, Timothy J.] Univ Wisconsin, Dept Med, Madison, WI 53705 USA.
   [Ge, Ying] Univ Wisconsin, Human Prote Program, Madison, WI 53705 USA.
C3 University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison;
   Imperial College London; University of Sydney; La Trobe University;
   Victor Chang Cardiac Research Institute; University of Wisconsin System;
   University of Wisconsin Madison; University of Wisconsin System;
   University of Wisconsin Madison; University of Wisconsin System;
   University of Wisconsin Madison
RP Ge, Y (corresponding author), Univ Wisconsin, Dept Chem, 1101 Univ Ave, Madison, WI 53706 USA.; Ge, Y (corresponding author), Univ Wisconsin, Mol & Cellular Pharmacol Training Program, Madison, WI 53705 USA.; Ge, Y (corresponding author), Univ Wisconsin, Dept Cell & Regenerat Biol, Madison, WI 53705 USA.; Ge, Y (corresponding author), Univ Wisconsin, Human Prote Program, Madison, WI 53705 USA.
EM ying.ge@wisc.edu
RI li, amy/KGL-5437-2024; Kamp, Timothy/ABD-1343-2020
OI Karp, Hannah/0000-0002-1619-5901; Marston, Steven/0000-0001-6054-6070;
   Gregorich, Zachery/0000-0002-4013-4869; Li, Amy/0000-0001-5413-3771;
   Vikhorev, Petr/0000-0002-0859-1082; Bayne, Elizabeth/0000-0002-6252-2934
FU NIH [R01 HL139883, R01 HL096971, R01 HL129798, U01 HL134764, T32
   GM008688]; NIH Chemistry-Biology Interface Training Program [T32
   GM008505]; American Heart Association [17PRE33660224]; NSF
   [EEC-1648035]; British Heart Foundation [PG/17/5/32705];  [R01
   GM117058];  [GM125085];  [HL109810];  [S10 OD018475]; American Heart
   Association (AHA) [17PRE33660224] Funding Source: American Heart
   Association (AHA)
FX Financial support was provided by NIH R01 HL096971 (to Y.G.). Y.G. also
   acknowledges R01 GM117058, GM125085, HL109810, and S10 OD018475. T.T.
   acknowledges support from the NIH Chemistry-Biology Interface Training
   Program T32 GM008505. W.C. acknowledges American Heart Association
   predoctoral fellowship 17PRE33660224. S.D.M. acknowledges support from
   NIH Training Grant T32 GM008688. T.J.K. acknowledges NSF Grant
   EEC-1648035 and NIH grants R01 HL129798 and U01 HL134764. R.L.M.
   acknowledges support of NIH Grant R01 HL139883. P.G.V. and S.B.M.
   acknowledge the British Heart Foundation (PG/17/5/32705). We thank James
   Anderson, the Surgical Recovery and Organ Preservation Manager, and
   Carrie Sparks, the Data Coordinator for Organ and Tissue Donation Office
   at University of Wisconsin, for their assistance in compiling donor
   data. We also thank Samantha Knott for assistance with graphics for our
   paper.
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NR 70
TC 70
Z9 76
U1 1
U2 12
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD OCT 6
PY 2020
VL 117
IS 40
BP 24691
EP 24700
DI 10.1073/pnas.2006764117
PG 10
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA OC3LI
UT WOS:000579059100020
PM 32968017
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Abascal, F
   Ezkurdia, I
   Rodriguez-Rivas, J
   Rodriguez, JM
   del Pozo, A
   Vázquez, J
   Valencia, A
   Tress, ML
AF Abascal, Federico
   Ezkurdia, Iakes
   Rodriguez-Rivas, Juan
   Manuel Rodriguez, Jose
   del Pozo, Angela
   Vazquez, Jesus
   Valencia, Alfonso
   Tress, Michael L.
TI Alternatively Spliced Homologous Exons Have Ancient Origins and Are
   Highly Expressed at the Protein Level
SO PLOS COMPUTATIONAL BIOLOGY
LA English
DT Article
ID DILATED CARDIOMYOPATHY; PROTEOMICS; IDENTIFICATION; ISOFORMS; DOMAIN;
   TRANSCRIPTOME; TROPOMYOSIN; ANNOTATION; PREDICTION; DISCOVERY
AB Alternative splicing of messenger RNA can generate a wide variety of mature RNA transcripts, and these transcripts may produce protein isoforms with diverse cellular functions. While there is much supporting evidence for the expression of alternative transcripts, the same is not true for the alternatively spliced protein products. Large-scale mass spectroscopy experiments have identified evidence of alternative splicing at the protein level, but with conflicting results. Here we carried out a rigorous analysis of the peptide evidence from eight large-scale proteomics experiments to assess the scale of alternative splicing that is detectable by high-resolution mass spectroscopy. We find fewer splice events than would be expected: we identified peptides for almost 64% of human protein coding genes, but detected just 282 splice events. This data suggests that most genes have a single dominant isoform at the protein level. Many of the alternative isoforms that we could identify were only subtly different from the main splice isoform. Very few of the splice events identified at the protein level disrupted functional domains, in stark contrast to the two thirds of splice events annotated in the human genome that would lead to the loss or damage of functional domains. The most striking result was that more than 20% of the splice isoforms we identified were generated by substituting one homologous exon for another. This is significantly more than would be expected from the frequency of these events in the genome. These homologous exon substitution events were remarkably conserved-all the homologous exons we identified evolved over 460 million years ago-and eight of the fourteen tissue-specific splice isoforms we identified were generated from homologous exons. The combination of proteomics evidence, ancient origin and tissue-specific splicing indicates that isoforms generated from homologous exons may have important cellular roles.
C1 [Abascal, Federico; Rodriguez-Rivas, Juan; Valencia, Alfonso; Tress, Michael L.] Spanish Natl Canc Res Ctr CNIO, Struct Biol & Bioinformat Programme, Madrid, Spain.
   [Ezkurdia, Iakes] CNIC, Unidad Prote, Madrid, Spain.
   [Manuel Rodriguez, Jose; Valencia, Alfonso] Spanish Natl Canc Res Ctr CNIO, INB, Madrid, Spain.
   [del Pozo, Angela] Hosp Univ La Paz, Inst Genet Med & Mol, Madrid, Spain.
   [Vazquez, Jesus] CNIC, Lab Prote Cardiovasc, Madrid, Spain.
C3 Centro Nacional de Investigaciones Oncologicas (CNIO); Centro Nacional
   de Investigaciones Cardiovasculares (CNIC); Centro Nacional de
   Investigaciones Oncologicas (CNIO); Hospital Universitario La Paz;
   Centro Nacional de Investigaciones Cardiovasculares (CNIC)
RP Abascal, F (corresponding author), Spanish Natl Canc Res Ctr CNIO, Struct Biol & Bioinformat Programme, Madrid, Spain.
EM valencia@cnio.es; mtress@cnio.es
RI Abascal, Federico/F-2267-2016; Rodriguez, Jose/JGE-4733-2023; Ezkurdia,
   Iakes/H-9334-2015; valencia, alfonso/I-3127-2015; Vazquez,
   Jesus/B-7697-2015
OI Tress, Michael/0000-0001-9046-6370; Ezkurdia, Iakes/0000-0001-9074-5302;
   valencia, alfonso/0000-0002-8937-6789; Rodriguez,
   Jose/0000-0002-9948-5073; del Pozo Mate, Angela/0000-0001-6690-1619;
   Rodriguez-Rivas, Juan/0000-0001-6262-9371; Vazquez,
   Jesus/0000-0003-1461-5092
FU National Institutes of Health [U41 HG007234]; Spanish Ministry of
   Science and Innovation [BIO2012-40205, BIO2012/37926, RD07-0067-0014];
   Spanish Ministry of Science and Innovation [COMBIOMED]; Instituto de
   Salud Carlos III [RIC-RD12/0042/0056, PT13/0001/0017]; Spanish National
   Institute of Bioinformatics, "Instituto de Salud Carlos III"
   [INB-ISCIII] [PRB2]
FX This work was supported by the National Institutes of Health [grant
   number U41 HG007234], by the Spanish Ministry of Science and Innovation
   [grant numbers BIO2012-40205, BIO2012/37926 and RD07-0067-0014,
   COMBIOMED] and by the "Instituto de Salud Carlos III" [grant numbers
   RIC-RD12/0042/0056 and PT13/0001/0017]. JMR was supported by the Spanish
   National Institute of Bioinformatics (www.inab.org), a platform of the
   "Instituto de Salud Carlos III" [INB-ISCIII, PRB2]. The funders had no
   role in study design, data collection and analysis, decision to publish,
   or preparation of the manuscript.
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NR 85
TC 57
Z9 63
U1 0
U2 12
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1553-734X
EI 1553-7358
J9 PLOS COMPUT BIOL
JI PLoS Comput. Biol.
PD JUN
PY 2015
VL 11
IS 6
AR e1004325
DI 10.1371/journal.pcbi.1004325
PG 29
WC Biochemical Research Methods; Mathematical & Computational Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Mathematical & Computational Biology
GA CM0AH
UT WOS:000357340100037
PM 26061177
OA Green Published, gold, Green Submitted
DA 2025-04-10
ER

PT J
AU Fagg, WS
   Liu, NY
   Braunschweig, U
   de Castro, KLP
   Chen, XT
   Ditmars, FS
   Widen, SG
   Donohue, JP
   Modis, K
   Russell, WK
   Fair, JH
   Weirauch, MT
   Blencowe, BJ
   Garcia-Blanco, MA
AF Fagg, W. Samuel
   Liu, Naiyou
   Braunschweig, Ulrich
   Pereira de Castro, Karen Larissa
   Chen, Xiaoting
   Ditmars, Frederick S.
   Widen, Steven G.
   Donohue, John Paul
   Modis, Katalin
   Russell, William K.
   Fair, Jeffrey H.
   Weirauch, Matthew T.
   Blencowe, Benjamin J.
   Garcia-Blanco, Mariano A.
TI Definition of germ layer cell lineage alternative splicing programs
   reveals a critical role for Quaking in specifying cardiac cell fate
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID RNA-BINDING PROTEIN; EMBRYONIC STEM-CELLS; MESSENGER-RNAS;
   TRANSCRIPTIONAL REGULATION; TARGETED DISRUPTION; REGULATORY NETWORKS;
   MASS-SPECTROMETRY; CLIP-SEQ; GENE; BIN1
AB Alternative splicing is critical for development; however, its role in the specification of the three embryonic germ layers is poorly understood. By performing RNA-Seq on human embryonic stem cells (hESCs) and derived definitive endoderm, cardiac mesoderm, and ectoderm cell lineages, we detect distinct alternative splicing programs associated with each lineage. The most prominent splicing program differences are observed between definitive endoderm and cardiac mesoderm. Integrative multi-omics analyses link each program with lineage-enriched RNA binding protein regulators, and further suggest a widespread role for Quaking (QKI) in the specification of cardiac mesoderm. Remarkably, knockout of QKI disrupts the cardiac mesoderm-associated alternative splicing program and formation of myocytes. These changes arise in part through reduced expression of BIN1 splice variants linked to cardiac development. Mechanistically, we find that QKI represses inclusion of exon 7 in BIN1 pre-mRNA via an exonic ACUAA motif, and this is concomitant with intron removal and cleavage from chromatin. Collectively, our results uncover alternative splicing programs associated with the three germ lineages and demonstrate an important role for QKI in the formation of cardiac mesoderm.
C1 [Fagg, W. Samuel; Liu, Naiyou; Pereira de Castro, Karen Larissa; Ditmars, Frederick S.; Modis, Katalin; Fair, Jeffrey H.] Univ Texas Med Branch, Dept Surg, Galveston, TX 77555 USA.
   [Fagg, W. Samuel; Widen, Steven G.; Russell, William K.; Garcia-Blanco, Mariano A.] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA.
   [Braunschweig, Ulrich; Blencowe, Benjamin J.] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.
   [Chen, Xiaoting; Weirauch, Matthew T.] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol CAGE, Cincinnati, OH 45229 USA.
   [Donohue, John Paul] Univ Calif Santa Cruz, Sinsheimer Labs, RNA Ctr Mol Biol, Dept Mol Cell & Dev Biol, Santa Cruz, CA 95064 USA.
   [Weirauch, Matthew T.] Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH 45229 USA.
   [Weirauch, Matthew T.] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH 45229 USA.
   [Weirauch, Matthew T.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA.
   [Blencowe, Benjamin J.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.
   [Garcia-Blanco, Mariano A.] Univ Texas Med Branch, Dept Internal Med, Galveston, TX 77555 USA.
C3 University of Texas System; University of Texas Medical Branch
   Galveston; University of Texas System; University of Texas Medical
   Branch Galveston; University of Toronto; University System of Ohio;
   University of Cincinnati; Cincinnati Children's Hospital Medical Center;
   University of California System; University of California Santa Cruz;
   Cincinnati Children's Hospital Medical Center; Cincinnati Children's
   Hospital Medical Center; University System of Ohio; University of
   Cincinnati; University of Toronto; University of Texas System;
   University of Texas Medical Branch Galveston
RP Fagg, WS (corresponding author), Univ Texas Med Branch, Dept Surg, Galveston, TX 77555 USA.; Fagg, WS (corresponding author), Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA.
EM wsfagg@utmb.edu
RI Braunschweig, Ulrich/I-1070-2019; Weirauch, Matthew/M-5459-2019
OI Fagg, William/0000-0003-2909-1666; Braunschweig,
   Ulrich/0000-0001-6653-0926; Ditmars, Frederick/0000-0003-2121-5716
FU National Cancer Institute [R01CA204806] Funding Source: NIH RePORTER;
   National Institute of Allergy and Infectious Diseases [U01AI130830]
   Funding Source: NIH RePORTER; National Institute of General Medical
   Sciences [R01GM055479] Funding Source: NIH RePORTER
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NR 103
TC 8
Z9 10
U1 0
U2 12
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0305-1048
EI 1362-4962
J9 NUCLEIC ACIDS RES
JI Nucleic Acids Res.
PD MAY 20
PY 2022
VL 50
IS 9
BP 5313
EP 5334
DI 10.1093/nar/gkac327
EA MAY 2022
PG 22
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 1K1NJ
UT WOS:000793419800001
PM 35544276
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Green, ID
   Liu, RJ
   Wong, JJL
AF Green, Immanuel D.
   Liu, Renjing
   Wong, Justin J. L.
TI The Expanding Role of Alternative Splicing in Vascular Smooth Muscle
   Cell Plasticity
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Review
DE alternative splicing; vascular smooth muscle cells; gene expression;
   cardiovascular disease; splicing-modulating therapies
ID INTRON RETENTION PROGRAM; RNA-BINDING PROTEIN; MESSENGER-RNA; ANTISENSE
   OLIGONUCLEOTIDES; NEOINTIMAL FORMATION; INTIMAL HYPERPLASIA;
   CALCIUM-CHANNEL; GENE-EXPRESSION; IN-VITRO; REGULATOR
AB Vascular smooth muscle cells (VSMCs) display extraordinary phenotypic plasticity. This allows them to differentiate or dedifferentiate, depending on environmental cues. The ability to 'switch' between a quiescent contractile phenotype to a highly proliferative synthetic state renders VSMCs as primary mediators of vascular repair and remodelling. When their plasticity is pathological, it can lead to cardiovascular diseases such as atherosclerosis and restenosis. Coinciding with significant technological and conceptual innovations in RNA biology, there has been a growing focus on the role of alternative splicing in VSMC gene expression regulation. Herein, we review how alternative splicing and its regulatory factors are involved in generating protein diversity and altering gene expression levels in VSMC plasticity. Moreover, we explore how recent advancements in the development of splicing-modulating therapies may be applied to VSMC-related pathologies.
C1 [Green, Immanuel D.; Wong, Justin J. L.] Univ Sydney, Epigenet & RNA Biol Program Centenary Inst, Camperdown 2050, Australia.
   [Green, Immanuel D.; Wong, Justin J. L.] Univ Sydney, Fac Med & Hlth, Camperdown 2050, Australia.
   [Liu, Renjing] Victor Chang Cardiac Res Inst, Vasc Epignt Lab, Darlinghurst 2010, Australia.
C3 University of Sydney; University of Sydney; Victor Chang Cardiac
   Research Institute
RP Wong, JJL (corresponding author), Univ Sydney, Epigenet & RNA Biol Program Centenary Inst, Camperdown 2050, Australia.; Wong, JJL (corresponding author), Univ Sydney, Fac Med & Hlth, Camperdown 2050, Australia.
EM i.green@centenary.org.au; r.liu@victorchang.edu.au;
   j.wong@centenary.org.au
RI Wong, Justin/AAE-7986-2020
OI Wong, Justin/0000-0002-7038-5079; Liu, Renjing/0000-0001-9099-0076
FU Australian Government Research Training Program Scholarship; NHF Future
   Leader Fellowship [101856]; National Health and Medical Research Council
   [APP1158997, APP1158998]
FX I.D.G. was a recipient of an Australian Government Research Training
   Program Scholarship. R.L. is the recipient of the NHF Future Leader
   Fellowship (101856), R.L. and J.J.L.W. laboratories are supported by the
   National Health and Medical Research Council (Grant #APP1158997 to R.L.
   and #APP1158998 to R.L. and J.J.L.W).
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NR 78
TC 11
Z9 12
U1 0
U2 6
PU MDPI
PI BASEL
PA MDPI AG, Grosspeteranlage 5, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD OCT
PY 2021
VL 22
IS 19
AR 10213
DI 10.3390/ijms221910213
PG 14
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA XJ9NR
UT WOS:000727105600001
PM 34638554
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Akerberg, AA
   Trembley, M
   Butty, V
   Schwertner, A
   Zhao, L
   Beerens, M
   Liu, XJ
   Mahamdeh, M
   Yuan, SL
   Boyer, L
   MacRae, C
   Nguyen, C
   Pu, WT
   Burns, CE
   Burns, CG
AF Akerberg, Alexander A. A.
   Trembley, Michael
   Butty, Vincent
   Schwertner, Asya
   Zhao, Long
   Beerens, Manu
   Liu, Xujie
   Mahamdeh, Mohammed
   Yuan, Shiaulou
   Boyer, Laurie
   MacRae, Calum
   Nguyen, Christopher
   Pu, William T. T.
   Burns, Caroline E. E.
   Burns, C. Geoffrey
TI RBPMS2 Is a Myocardial-Enriched Splicing Regulator Required for Cardiac
   Function
SO CIRCULATION RESEARCH
LA English
DT Article
DE alternative splicing; human induced pluripotent stem cells; myocytes;
   cardiac; RNA-binding proteins; zebrafish
ID RNA-BINDING PROTEIN; 2ND HEART FIELD; ZEBRAFISH MODEL; SEQ DATA; GENE;
   EXPRESSION; MUTATION; CARDIOMYOPATHY; HERMES; IDENTIFICATION
AB Background:RBPs (RNA-binding proteins) perform indispensable functions in the post-transcriptional regulation of gene expression. Numerous RBPs have been implicated in cardiac development or physiology based on gene knockout studies and the identification of pathogenic RBP gene mutations in monogenic heart disorders. The discovery and characterization of additional RBPs performing indispensable functions in the heart will advance basic and translational cardiovascular research. Methods:We performed a differential expression screen in zebrafish embryos to identify genes enriched in nkx2.5-positive cardiomyocytes or cardiopharyngeal progenitors compared to nkx2.5-negative cells from the same embryos. We investigated the myocardial-enriched gene RNA-binding protein with multiple splicing (variants) 2 [RBPMS2)] by generating and characterizing rbpms2 knockout zebrafish and human cardiomyocytes derived from RBPMS2-deficient induced pluripotent stem cells. Results:We identified 1848 genes enriched in the nkx2.5-positive population. Among the most highly enriched genes, most with well-established functions in the heart, we discovered the ohnologs rbpms2a and rbpms2b, which encode an evolutionarily conserved RBP. Rbpms2 localizes selectively to cardiomyocytes during zebrafish heart development and strong cardiomyocyte expression persists into adulthood. Rbpms2-deficient embryos suffer from early cardiac dysfunction characterized by reduced ejection fraction. The functional deficit is accompanied by myofibril disarray, altered calcium handling, and differential alternative splicing events in mutant cardiomyocytes. These phenotypes are also observed in RBPMS2-deficient human cardiomyocytes, indicative of conserved molecular and cellular function. RNA-sequencing and comparative analysis of genes mis-spliced in RBPMS2-deficient zebrafish and human cardiomyocytes uncovered a conserved network of 29 ortholog pairs that require RBPMS2 for alternative splicing regulation, including RBFOX2, SLC8A1, and MYBPC3. Conclusions:Our study identifies RBPMS2 as a conserved regulator of alternative splicing, myofibrillar organization, and calcium handling in zebrafish and human cardiomyocytes.
C1 [Akerberg, Alexander A. A.; Trembley, Michael; Liu, Xujie; Pu, William T. T.; Burns, Caroline E. E.; Burns, C. Geoffrey] Boston Childrens Hosp, Dept Cardiol, Div Basic & Translat Cardiovasc Res, Boston, MA 02115 USA.
   [Akerberg, Alexander A. A.; Schwertner, Asya; Zhao, Long; Mahamdeh, Mohammed; Yuan, Shiaulou; Nguyen, Christopher; Burns, Caroline E. E.; Burns, C. Geoffrey] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA.
   [Akerberg, Alexander A. A.; Trembley, Michael; Schwertner, Asya; Zhao, Long; Beerens, Manu; Liu, Xujie; Mahamdeh, Mohammed; Yuan, Shiaulou; MacRae, Calum; Nguyen, Christopher; Pu, William T. T.; Burns, Caroline E. E.; Burns, C. Geoffrey] Harvard Med Sch, Boston, MA USA.
   [Butty, Vincent] MIT, BioMicro Ctr, Dept Biol, Cambridge, MA USA.
   [Butty, Vincent; Boyer, Laurie] MIT, Dept Biol, Cambridge, MA USA.
   [Boyer, Laurie] MIT, Dept Biol Engn, Cambridge, MA USA.
   [Beerens, Manu; MacRae, Calum] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA USA.
   [Nguyen, Christopher] Cleveland Clin, Heart Vasc & Thorac Inst, Cardiovasc Innovat Res Ctr, Cleveland, OH USA.
   [Pu, William T. T.; Burns, Caroline E. E.] Harvard Stem Cell Inst, Cambridge, MA USA.
C3 Harvard University; Harvard University Medical Affiliates; Boston
   Children's Hospital; Harvard University; Harvard University Medical
   Affiliates; Massachusetts General Hospital; Harvard University; Harvard
   Medical School; Massachusetts Institute of Technology (MIT);
   Massachusetts Institute of Technology (MIT); Massachusetts Institute of
   Technology (MIT); Harvard University; Harvard University Medical
   Affiliates; Brigham & Women's Hospital; Cleveland Clinic Foundation;
   Harvard University
RP Burns, CE; Burns, CG (corresponding author), Boston Childrens Hosp, Dept Cardiol, Div Basic & Translat Cardiovasc Res, Boston, MA 02115 USA.
EM caroline.burns@childrens.harvard.edu; geoff.burns@childrens.harvard.edu
RI xujie, liu/AAW-6608-2021; Mahamdeh, Mohammed/AAG-6530-2019; Zhao,
   Long/A-6439-2014
OI Zhao, Long/0000-0003-2691-7055; Schwertner, Asya/0000-0002-1899-9401;
   Yuan, Shiaulou/0000-0002-5061-6132; Mahamdeh,
   Mohammed/0000-0003-3985-6992
FU American Heart Association (AHA) [20POST35110027]; National Institutes
   of Health (NIH) [T32HL007208]; NIH [T32HL007572, 1R01HL165241-01,
   7R01HL139806, 940516, P30-CA14051]; Charles Hood Foundation; AHA
   [R01-HL140471]; Koch Institute from the National Cancer Institute
   [7R35HL135831]; Executive Committee on Research at MGH; Department of
   Defense [W81XWH-20-1-0165]; Boston Children's Hospital Department of
   Cardiology.; National Heart Lung and Blood Institute [R01HL139806]
   Funding Source: NIH RePORTER; American Heart Association (AHA)
   [20POST35110027, 940516] Funding Source: American Heart Association
   (AHA)
FX A.A. Akerberg was supported by an American Heart Association (AHA)
   Post-doctoral Fellowship (20POST35110027). A.A. Akerberg and A.
   Schwertner were supported by a National Institutes of Health (NIH)
   training grant awarded to Massachusetts General Hospital (MGH;
   T32HL007208; Principal Investigator [PI]: A. Rosenzweig). M. Trembley
   was supported by an NIH training grant awarded to Boston Children's
   Hospital (T32HL007572; PI: W.T. Pu). S. Yuan was supported by NIH grant
   1R01HL165241-01, the Charles Hood Foundation, and AHA grant 940516. L.
   Boyer was supported by NIH grant R01-HL140471. The bioinformatics
   analysis was supported in part by the Koch Institute Support (core)
   Grant P30-CA14051 from the National Cancer Institute. The Burns
   Laboratory was supported by NIH grants 7R01HL139806 (formerly
   1R01HL13980 6) and 7R35HL135831 (formerly 1R35H135831) to C.G. Burns and
   C.E. Burns, respectively, by awards from the Executive Committee on
   Research at MGH to C.G. Burns, and by Department of Defense
   Peer-Reviewed Medical Research Program (PRMRP) grant W81XWH-20-1-0165 to
   C.E. Burns. C.E. Burns was a d'Arbelhoff MGH Research Scholar. C.E.
   Burns and C.G. Burns were Hassenfeld Cardiovascular Scholars at MGH. The
   Burns Laboratory was supported, in part, by funds from the Boston
   Children's Hospital Department of Cardiology.
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NR 129
TC 15
Z9 16
U1 0
U2 10
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7330
EI 1524-4571
J9 CIRC RES
JI Circ.Res.
PD DEC 2
PY 2022
VL 131
IS 12
BP 980
EP 1000
DI 10.1161/CIRCRESAHA.122.321728
PG 21
WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Hematology
GA 6S3TC
UT WOS:000892912600006
PM 36367103
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Belanger, K
   Nutter, CA
   Li, J
   Tasnim, S
   Liu, PR
   Yu, P
   Kuyumcu-Martinez, MN
AF Belanger, KarryAnne
   Nutter, Curtis A.
   Li, Jin
   Tasnim, Sadia
   Liu, Peiru
   Yu, Peng
   Kuyumcu-Martinez, Muge N.
TI CELF1 contributes to aberrant alternative splicing patterns in the type
   1 diabetic heart
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE Diabetic heart; CELF1; Alternative splicing; RNA binding proteins
ID MBNL; CARDIOMYOPATHY; COMPLICATIONS; MECHANISMS; EXPRESSION; PROTEINS;
   PROGRAMS; MUSCLE
AB Dysregulated alternative splicing (AS) that contributes to diabetes pathogenesis has been identified, but little is known about the RNA binding proteins (RBPs) involved. We have previously found that the RBP CELF1 is upregulated in the diabetic heart; however, it is unclear if CELF1 contributes to diabetes-induced AS changes. Utilizing genome wide approaches, we identified extensive changes in AS patterns in Type 1 diabetic (T1D) mouse hearts. We discovered that many aberrantly spliced genes in T1D hearts have CELF1 binding sites. CELF1-regulated AS affects key genes within signaling pathways relevant to diabetes pathogenesis. Disruption of CELF1 binding sites impairs AS regulation by CELF1. In sum, our results indicate that CELF1 target RNAs are aberrantly spliced in the T1D heart leading to abnormal gene expression. These discoveries pave the way for targeting RBPs and their RNA networks as novel therapies for cardiac complications of diabetes. (C) 2018 Elsevier Inc. All rights reserved.
C1 [Belanger, KarryAnne; Nutter, Curtis A.; Tasnim, Sadia; Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA.
   [Li, Jin; Yu, Peng] Texas A&M Univ, Dept Elect & Comp Engn, College Stn, TX 77843 USA.
   [Li, Jin; Yu, Peng] Texas A&M Univ, TEES AgriLife Ctr Bioinformat & Genom Syst Engn, College Stn, TX 77843 USA.
   [Liu, Peiru] Ball High Sch, Galveston, TX 77555 USA.
   [Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Dept Neurosci Cell Biol & Anat, Galveston, TX 77555 USA.
   [Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Inst Translat Sci, Galveston, TX 77555 USA.
C3 University of Texas System; University of Texas Medical Branch
   Galveston; Texas A&M University System; Texas A&M University College
   Station; Texas A&M University System; Texas A&M University College
   Station; University of Texas System; University of Texas Medical Branch
   Galveston; University of Texas System; University of Texas Medical
   Branch Galveston
RP Kuyumcu-Martinez, MN (corresponding author), Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA.; Yu, P (corresponding author), Texas A&M Univ, Dept Elect & Comp Engn, College Stn, TX 77843 USA.; Yu, P (corresponding author), Texas A&M Univ, TEES AgriLife Ctr Bioinformat & Genom Syst Engn, College Stn, TX 77843 USA.
EM pengy@tamu.edu; nmmartin@utmb.edu
RI Peiru, Liu/AAO-8190-2021; Tasnim, Sadia/JPX-9557-2023; Li,
   Jin/GOH-1431-2022
OI Tasnim, Sadia/0000-0003-2077-206X; Kuyumcu-Martinez, Muge
   N./0000-0003-3171-5861
FU American Heart Association [15GRNT22830010]; UTMB Department of
   Biochemistry and Molecular Biology Bridging funds; National Institutes
   of Health/National Heart Lung Blood Institute [R01HL1350311]; ECE
   department and Engineering Experiment Station/Dwight Look College of
   Engineering; TEES-AgriLife Center for Bioinformatics and Genomic Systems
   Engineering (CBGSE; TEES seed grant; CAPES Research Grant Program at
   Texas AM University; American Heart Association (AHA) [15GRNT22830010]
   Funding Source: American Heart Association (AHA)
FX We thank Kuyumcu-Martinez lab members and Dr. Eric Wagner for critically
   reading the manuscript and Dr. Mariano Garcia-Blanco for providing the
   Ad-GFP splicing reporter. This work was supported, in part, by an
   American Heart Association Grant [15GRNT22830010]; UTMB Department of
   Biochemistry and Molecular Biology Bridging funds; and a grant from the
   National Institutes of Health/National Heart Lung Blood Institute
   R01HL1350311 to M.N.K-M. The contents of the manuscript are solely the
   responsibility of the authors and do not necessarily represent the
   official views of NIH. This work was also supported by startup funding
   to P.Y. from the ECE department and Engineering Experiment
   Station/Dwight Look College of Engineering; by funding from
   TEES-AgriLife Center for Bioinformatics and Genomic Systems Engineering
   (CBGSE), by TEES seed grant; and by CAPES Research Grant Program at
   Texas A&M University.
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NR 38
TC 15
Z9 15
U1 1
U2 6
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD SEP 18
PY 2018
VL 503
IS 4
BP 3205
EP 3211
DI 10.1016/j.bbrc.2018.08.126
PG 7
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA GT8MM
UT WOS:000444791600150
PM 30158053
OA Green Accepted, Bronze
DA 2025-04-10
ER

PT J
AU Farrokh, S
   Brillen, AL
   Haendeler, J
   Altschmied, J
   Schaal, H
AF Farrokh, Sabrina
   Brillen, Anna-Lena
   Haendeler, Judith
   Altschmied, Joachim
   Schaal, Heiner
TI Critical Regulators of Endothelial Cell Functions: For a Change Being
   Alternative
SO ANTIOXIDANTS & REDOX SIGNALING
LA English
DT Review
ID NITRIC-OXIDE SYNTHASE; GROWTH-FACTOR-BETA; OF-MAMMALIAN GRAINYHEAD;
   TGF-BETA; TRANSCRIPTION FACTOR; SIGNAL-TRANSDUCTION; OXIDATIVE STRESS;
   TYROSINE PHOSPHORYLATION; SUPEROXIDE GENERATION; PHYSIOLOGICAL LEVELS
AB Significance: The endothelium regulates vessel dilation and constriction, balances hemostasis, and inhibits thrombosis. In addition, pro- and anti-angiogenic molecules orchestrate proliferation, survival, and migration of endothelial cells. Regulation of all these processes requires fine-tuning of signaling pathways, which can easily be tricked into running the opposite direction when exogenous or endogenous signals get out of hand. Surprisingly, some critical regulators of physiological endothelial functions can turn malicious by mere alternative splicing, leading to the expression of protein isoforms with opposite functions. Recent Advances: While reviewing the evidence of alternative splicing on cellular physiology, it became evident that expression of splice factors and their activities are regulated by externally triggered signaling cascades. Furthermore, genome-wide identification of RNA-binding sites of splicing regulatory proteins now offer a glimpse into the splicing code responsible for alternative splicing of molecules regulating endothelial functions. Critical Issues: Due to the constantly growing number of transcript and protein isoforms, it will become more and more important to identify and characterize all transcripts and proteins regulating endothelial cell functions. One critical issue will be a non-ambiguous nomenclature to keep consistency throughout different laboratories. Future Directions: RNA-deep sequencing focusing on exon-exon junction needs to more reliably identify alternative splicing events combined with functional analyses that will uncover more splice variants contributing to or inhibiting proper endothelial functions. In addition, understanding the signals mediating alternative splicing and its regulation might allow us to derive new strategies to preserve endothelial function by suppressing or upregulating specific protein isoforms. Antioxid. Redox Signal. 22, 1212-1229.
C1 [Farrokh, Sabrina; Haendeler, Judith; Altschmied, Joachim] IUF Leibniz Res Inst Environm Med, Heisenberg Grp Environm Induced Cardiovasc Degene, D-40225 Dusseldorf, Germany.
   [Brillen, Anna-Lena; Schaal, Heiner] Univ Dusseldorf, Inst Virol, Dusseldorf, Germany.
   [Haendeler, Judith] Univ Dusseldorf, Cent Inst Clin Chem & Lab Med, Dusseldorf, Germany.
C3 Leibniz Association; Leibniz Institut fur Umweltmedizinische Forschung
   (IUF); Heinrich Heine University Dusseldorf; Heinrich Heine University
   Dusseldorf
RP Altschmied, J (corresponding author), IUF Leibniz Res Inst Environm Med, Heisenberg Grp Environm Induced Cardiovasc Degene, Aufm Hennekamp 50, D-40225 Dusseldorf, Germany.
EM joachim.altschmied@uni-duesseldorf.de; schaal@uni-duesseldorf.de
RI Haendeler, Judith/ISS-3378-2023; Schaal, Heiner/A-5115-2008
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NR 168
TC 5
Z9 7
U1 0
U2 9
PU MARY ANN LIEBERT, INC
PI NEW ROCHELLE
PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA
SN 1523-0864
EI 1557-7716
J9 ANTIOXID REDOX SIGN
JI Antioxid. Redox Signal.
PD MAY 10
PY 2015
VL 22
IS 14
BP 1212
EP 1229
DI 10.1089/ars.2014.6023
PG 18
WC Biochemistry & Molecular Biology; Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Endocrinology & Metabolism
GA CG5KT
UT WOS:000353331300002
PM 25203279
DA 2025-04-10
ER

PT J
AU Tang, ZZ
   Liao, P
   Li, G
   Jiang, FL
   Yu, D
   Hong, X
   Yong, TF
   Tan, G
   Lu, S
   Wang, J
   Soong, TW
AF Tang, Zhen Zhi
   Liao, Ping
   Li, Guang
   Jiang, Feng Li
   Yu, Dejie
   Hong, Xin
   Yong, Tan Fong
   Tan, Gregory
   Lu, Songqing
   Wang, Jing
   Soong, Tuck Wah
TI Differential splicing patterns of L-type calcium channel
   Cav1.2 subunit in hearts of Spontaneously Hypertensive Rats
   and Wistar Kyoto Rats
SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
LA English
DT Article
DE alternative splicing; Ca(v)1.2; voltage gated calcium channel;
   Spontaneously Hypertensive Rat; hypertension; hypertrophied heart
ID MESSENGER-RNA DECAY; CA2+ CHANNELS; ALPHA(1C) SUBUNIT; VENTRICULAR
   MYOCYTES; PACEMAKER ACTIVITY; GENE-EXPRESSION; MUSCLE; HYPERTROPHY;
   TRANSCRIPTS; SUPPRESSION
AB Ca(v)1.2 L-type calcium channels are essential in heart and smooth muscle contraction. Rat Ca(v)1.2 gene contains 11 alternatively spliced exons (la, 1, 8a, 8, 9*, 21, 22, 31, 32, 32-6nt and 33) which can be assorted to generate a large number of functionally distinct splice variants. Until now, it is unknown whether the utilization of these alternatively spliced exons is altered in the hypertrophied hearts of hypertensive rats. By comparing the assortments of these 11 exons in full-length Ca(v)1.2 transcripts derived from Spontaneously Hypertensive Rats (SHRs) and Wistar Kyoto Rats (WKYs) hearts, we found that the inclusion of Ca(v)1.2 alternative exons was significantly different between the two rats both at individual loci and in combinatorial arrangements. Functional characterizations of three Ca(v)1.2 channel splice variants that were identified to be significantly altered in SHR hypertrophied cardiomyocytes demonstrated distinct whole-cell electrophysiological properties when expressed in HEK 293 cells. Interestingly, aberrant splice variants which included or excluded both mutually exclusive exons 21/22 or exons 31/32 were found to be increased in hypertensive rats. Two aberrant splice variants that included both exons 21 and 22 were found to be unable to conduct currents even though they expressed proteins with the predicted molecular mass. Characterization of one of the aberrant splice variants showed that it exerted a dominant negative effect on the functional Ca(v)1.2 channels when co-expressed in HEK293 cells. The altered combinatorial splicing profiles of Ca(v)1.2 transcripts identified in SHR hearts provide a different and new perspective in understanding the possible role of molecular remodeling of Ca(v)1.2 channels in cardiac hypertrophy as a consequence of hypertension. (C) 2007 Elsevier B.V. All rights reserved.
C1 [Tang, Zhen Zhi; Liao, Ping; Li, Guang; Jiang, Feng Li; Hong, Xin; Yong, Tan Fong; Tan, Gregory; Soong, Tuck Wah] Natl Univ Singapore, Dept Physiol, Singapore 117597, Singapore.
   [Tang, Zhen Zhi] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA.
   [Yu, Dejie; Lu, Songqing; Wang, Jing; Soong, Tuck Wah] Natl Inst Neurosci, Singapore 308433, Singapore.
   [Soong, Tuck Wah] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA.
C3 National University of Singapore; University of California System;
   University of California Los Angeles; Howard Hughes Medical Institute;
   National Neuroscience Institute (NNI); Johns Hopkins University
RP Soong, TW (corresponding author), Natl Univ Singapore, Dept Physiol, Singapore 117597, Singapore.
EM phsstw@nus.edu.sg
RI Liao, Ping/LBI-1504-2024; HONG, XIN/AAI-5177-2020
OI Liao, Ping/0000-0002-6205-4042; HONG, XIN/0000-0002-9671-0116
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NR 42
TC 29
Z9 34
U1 1
U2 5
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0167-4889
EI 0006-3002
J9 BBA-MOL CELL RES
JI Biochim. Biophys. Acta-Mol. Cell Res.
PD JAN
PY 2008
VL 1783
IS 1
BP 118
EP 130
DI 10.1016/j.bbamcr.2007.11.003
PG 13
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 260ND
UT WOS:000253016100011
PM 18070605
OA Bronze
DA 2025-04-10
ER

PT J
AU Kim, I
   Koh, GY
   Lee, CO
AF Kim, I
   Koh, GY
   Lee, CO
TI Identification of alternatively spliced Na<SUP>+</SUP>-Ca<SUP>2+</SUP>
   exchanger isoforms expressed in the heart
SO COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR
   BIOLOGY
LA English
DT Article
DE alternative splicing; cardiac fibroblasts; cardiac myocytes;
   development; heart; isoform; mouse; Na+-Ca2+ exchanger
ID TISSUE-SPECIFIC EXPRESSION; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING;
   HELA-CELLS; CDNA
AB Alternatively spliced isoforms of Na+-Ca2+ exchanger were found from various tissues and species. RT-PCR amplification was performed on the basis of our cloned mouse cardiac Na+-Ca2+ exchanger and four alternatively spliced isoforms of Na+-Ca2+ exchanger were identified. Three (NCX1.3, NCX1.4, and NCX1.12) of them were first identified in the heart, and one isoform (NCX1.12) was a novel spliced variant. These four spliced variants were present in the embryonic and adult: atria and ventricles. Different cell types of the heart expressed different spliced isoforms of Na+-Ca2+ exchanger. Southern blot analysis indicated that the Na+-Ca2+ exchanger gene existed as a single copy in the mouse genome. Thus, the Na+-Ca2+ exchanger isoforms expressed in mouse heart are consistent with being produced by alternative splicing and they may have different functions in various cell types in the mouse heart. (C) 1998 Elsevier Science Inc.
C1 Pohang Univ Sci & Technol, Dept Life Sci, Pohang 790784, South Korea.
   Chonnam Natl Univ, Sch Med, Dept Physiol, Chonju 560180, South Korea.
   Chonnam Natl Univ, Sch Med, Cardiovasc Res Inst, Chonju 560180, South Korea.
C3 Pohang University of Science & Technology (POSTECH); Chonnam National
   University; Chonnam National University
RP Lee, CO (corresponding author), Pohang Univ Sci & Technol, Dept Life Sci, Pohang 790784, South Korea.
EM colee@visi-on.postech.ac.kr
RI Koh, Gou/C-1615-2011; Kim, Injune/C-1710-2011
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NR 23
TC 4
Z9 4
U1 0
U2 2
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 0305-0491
J9 COMP BIOCHEM PHYS B
JI Comp. Biochem. Physiol. B-Biochem. Mol. Biol.
PD JAN
PY 1998
VL 119
IS 1
BP 157
EP 161
DI 10.1016/S0305-0491(97)00299-X
PG 5
WC Biochemistry & Molecular Biology; Zoology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Zoology
GA YZ715
UT WOS:000072283600017
PM 9530817
DA 2025-04-10
ER

PT J
AU Liao, RJ
   Tong, LJ
   Huang, C
   Cao, WW
   Wang, YZ
   Wang, J
   Chen, XF
   Zhu, WZ
   Zhang, W
AF Liao, Ru-Jia
   Tong, Li-Juan
   Huang, Chao
   Cao, Wen-Wen
   Wang, Yu-Zhe
   Wang, Jia
   Chen, Xiang-Fan
   Zhu, Wei-Zhong
   Zhang, Wei
TI Rescue of cardiac failing and remodelling by inhibition of protein
   phosphatase 1γ is associated with suppression of the alternative
   splicing factor-mediated splicing of
   Ca<SUP>2+</SUP>/calmodulin-dependent protein kinase δ
SO CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
LA English
DT Article
DE alternative splicing factor; Ca2+/calmodulin-dependent protein kinase
   delta; cardiac hypertrophy; inhibitor 1 of protein phosphatase 1;
   protein phosphatase 1 gamma
ID CAMKII-DELTA; DILATED CARDIOMYOPATHY; ISOFORM PP1-GAMMA-1; ENHANCED
   EXPRESSION; HYPERTROPHY; TYPE-1; OVEREXPRESSION; STIMULATION;
   ACTIVATION; APOPTOSIS
AB Our previous studies showed that protein phosphatase 1 gamma (PP1 gamma) exacerbates cardiomyocyte apoptosis through promotion of Ca2+/calmodulin-dependent protein kinase delta (CaMKII delta) splicing. Here we determine the role of PP1 gamma in abdominal aorta constriction-induced hypertrophy and remodelling in rat hearts. Systolic blood pressure and echocardiographic measurements were used to evaluate the model of cardiac hypertrophy. Sirius red staining and invasive haemodynamic/cardiac index measurements were used to evaluate the effects of PP1 gamma or inhibitor 1 of PP1 transfection. Western blot, reverse transcription polymerase chain reaction and co-immunoprecipitation were applied to investigate the molecular mechanisms. Transfection of PP1 gamma increased the value of the heart mass index, left ventricular mass index and cardiac fibrosis, and simultaneously decreased the value of maximal left ventricular pressure increase and decline rate, ejection fraction, fractional shortening, and left ventricular end-diastolic pressure, as well as left ventricular systolic pressure. Transfection of inhibitor 1 of PP1, however, showed opposite effects on the aforementioned indexes. Overexpression of PP1 gamma potentiated CaMKII delta C production and decreased CaMKII delta B production in the hypertrophic heart. In contrast, inhibition of PP1 gamma re-balanced the CaMKII delta splicing. Furthermore, CaMKII activity was found to be augmented or attenuated by PP1 gamma overexpression or inhibition, respectively. Further mechanistic studies showed that abdominal aorta constriction stress specifically increased the association of alternative splicing factor with PP1 gamma, but not with PP1 beta. Overexpression of PP1 gamma, but not inhibitor 1 of PP1, further potentiated this association. These results suggest that PP1 gamma alters the cardiac hypertrophy and remodelling likely through promotion of the alternative splicing factor-mediated splicing of CaMKII delta.
C1 [Liao, Ru-Jia; Tong, Li-Juan; Huang, Chao; Cao, Wen-Wen; Wang, Yu-Zhe; Wang, Jia; Chen, Xiang-Fan; Zhu, Wei-Zhong; Zhang, Wei] Nantong Univ, Sch Med, Dept Pharmacol, Nantong 226001, Jiangsu, Peoples R China.
C3 Nantong University
RP Zhang, W (corresponding author), Nantong Univ, Sch Med, Dept Pharmacol, 19 Qixiu Rd, Nantong 226001, Jiangsu, Peoples R China.
EM asicampa@aliyun.com
RI Chen, Xiangfan/M-3719-2016; Huang, Chao/L-1445-2019
OI liao, ru-jia/0000-0001-6928-4003
FU National Natural Science Foundation of China [81070197, 81102428];
   Natural Science Foundation of Jiangsu Province [BK20141240]; Priority
   Academic Program Development of Jiangsu Higher Education Institutions
FX This work was supported by the National Natural Science Foundation of
   China to Professor Wei Zhang (No. 81070197) and Dr Chao Huang (No.
   81102428), the Natural Science Foundation of Jiangsu Province to Dr Chao
   Huang (No. BK20141240), and the Priority Academic Program Development of
   Jiangsu Higher Education Institutions.
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NR 40
TC 14
Z9 14
U1 1
U2 17
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0305-1870
EI 1440-1681
J9 CLIN EXP PHARMACOL P
JI Clin. Exp. Pharmacol. Physiol.
PD DEC
PY 2014
VL 41
IS 12
BP 976
EP 985
DI 10.1111/1440-1681.12308
PG 10
WC Pharmacology & Pharmacy; Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy; Physiology
GA AX1SR
UT WOS:000346726900005
PM 25224648
DA 2025-04-10
ER

PT J
AU Liu, ZH
   Tian, HP
   Hua, JH
   Cai, WQ
   Bai, YJ
   Zhan, Q
   Lai, WY
   Zeng, QC
   Ren, H
   Xu, DL
AF Liu, Zuheng
   Tian, Haiping
   Hua, Jinghai
   Cai, Wanqiang
   Bai, Yujia
   Zhan, Qiong
   Lai, Wenyan
   Zeng, Qingchun
   Ren, Hao
   Xu, Dingli
TI A CRM1 Inhibitor Alleviates Cardiac Hypertrophy and Increases the
   Nuclear Distribution of NT-PGC-1α in NRVMs
SO FRONTIERS IN PHARMACOLOGY
LA English
DT Article
DE CRM1; NT-PGC-1 alpha; myocardial infarction; antihypertrophy; nuclear
   distribution; cardiac function
ID FATTY-ACID OXIDATION; HEART-FAILURE; EXPORT; ISOFORM; DISEASE; PINK1;
   ALPHA
AB Chromosomal maintenance 1 (CRM1) inhibitors display antihypertrophic effects and control protein trafficking between the nucleus and the cytoplasm. PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator-1alpha) is a type of transcriptional coactivator that predominantly resides in the nucleus and is downregulated during heart failure. NT-PGC-1 alpha is an alternative splicing variant of PGC-1 alpha that is primarily distributed in the cytoplasm. We hypothesized that the use of a CRM1 inhibitor could shuttle NT-PGC-1 alpha into the nucleus and activate PGC-1 alpha target genes to potentially improve cardiac function in a mouse model of myocardial infarction (MI). We showed that PGC-1 alpha and NT-PGC-1 alpha were decreased in MI-induced heart failure mice. Phenylephrine and angiotensin II were applied to induce hypertrophy in neonatal rat ventricular myocytes (NRVMs). The antihypertrophic effects of the CRM1-inhibitor Selinexor was verified through profiling the expression of beta-MHC and through visualizing the cell cross-sectional area. NRVMs were transfected with adenovirus-NT-PGC-1 alpha or adenovirus-NLS (nucleus localization sequence)-NT-PGC-1 alpha and then exposed to Selinexor. Confocal microscopy was then used to observe the shuttling of NT-PGC-1 alpha. After NT-PGC-1 alpha was shuttled into the nucleus, there was increased expression of its related genes, including PPAR-alpha, Tfam, ERR-gamma, CPT1b, PDK4, and Nrf2. The effects of Selinexor on post-MI C57BL/6j mice were determined by echocardiography and qPCR. We found that Selinexor showed antihypertrophic effects but did not influence the ejection fraction of MI-mice. Interestingly, the antihypertrophic effects of Selinexor might be independent of NT-PGC-1 alpha transportation.
C1 [Liu, Zuheng; Tian, Haiping; Hua, Jinghai; Cai, Wanqiang; Bai, Yujia; Zhan, Qiong; Lai, Wenyan; Zeng, Qingchun; Xu, Dingli] Southern Med Univ, Nanfang Hosp, State Key Lab Organ Failure Res, Dept Cardiol, Guangzhou, Guangdong, Peoples R China.
   [Liu, Zuheng; Tian, Haiping; Hua, Jinghai; Cai, Wanqiang; Bai, Yujia; Zhan, Qiong; Lai, Wenyan; Zeng, Qingchun; Ren, Hao; Xu, Dingli] Minist Educ Peoples Republ China, Key Lab Organ Failure Res, Guangzhou, Guangdong, Peoples R China.
   [Tian, Haiping] Inner Mongolia Med Univ, Dept Cardiol, Affiliated Hosp, Hohhot, Peoples R China.
   [Ren, Hao] Southern Med Univ, Nanfang Hosp, Dept Rheumatol, Guangzhou, Guangdong, Peoples R China.
C3 Southern Medical University - China; Inner Mongolia Medical University;
   Southern Medical University - China
RP Xu, DL (corresponding author), Southern Med Univ, Nanfang Hosp, State Key Lab Organ Failure Res, Dept Cardiol, Guangzhou, Guangdong, Peoples R China.; Ren, H; Xu, DL (corresponding author), Minist Educ Peoples Republ China, Key Lab Organ Failure Res, Guangzhou, Guangdong, Peoples R China.; Ren, H (corresponding author), Southern Med Univ, Nanfang Hosp, Dept Rheumatol, Guangzhou, Guangdong, Peoples R China.
EM renhao67@aliyun.com; dinglixu@fimmu.com
RI Xu, Dingli/AAA-6176-2019; Li, zhuangzhuang/JAD-1371-2023
FU National Natural Science Foundation of China [81670367, 81270320];
   National Key Research and Development Program of China [2017YFC1308304]
FX The present study was supported by the National Natural Science
   Foundation of China (81670367 and 81270320) and partially supported by
   The National Key Research and Development Program of China
   (2017YFC1308304).
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NR 25
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Z9 9
U1 2
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PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
EI 1663-9812
J9 FRONT PHARMACOL
JI Front. Pharmacol.
PD MAY 7
PY 2019
VL 10
AR 465
DI 10.3389/fphar.2019.00465
PG 10
WC Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Pharmacology & Pharmacy
GA HX3TT
UT WOS:000467316600001
PM 31133853
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Kalea, AZ
   Schmidt, AM
   Hudson, BI
AF Kalea, Anastasia Z.
   Schmidt, Ann Marie
   Hudson, Barry I.
TI Alternative splicing of RAGE: roles in biology and disease
SO FRONTIERS IN BIOSCIENCE-LANDMARK
LA English
DT Article
DE Alternative splicing; receptors; Advanced Glycation End-products; mRNA;
   Review
ID GLYCATION END-PRODUCTS; ENDOGENOUS SECRETORY RAGE; COMMUNITY-DWELLING
   WOMEN; CORONARY-ARTERY-DISEASE; NUCLEAR RIBONUCLEOPROTEIN H; TYPE-1
   DIABETIC-PATIENTS; DECREASED PLASMA-LEVELS; CELL-SURFACE RECEPTOR;
   E-NULL MICE; SOLUBLE RECEPTOR
AB The Receptor for Advanced Glycation End-products (RAGE) is a complex, multi-ligand signaling system implicated in the pathogenesis of diabetes, cardiovascular disease and various cancers. RAGE undergoes extensive alternative splicing to produce a variety of transcripts with diverse functions, including soluble antagonists and variants with altered ligand binding domains. Studies focused on the major soluble variant (RAGEv1/esRAGE) have revealed this to function by binding RAGE-ligands and preventing activation of RAGE signaling in vascular and tumor cells. Furthermore, measurement of this variant in human serum has revealed that RAGEv1/esRAGE levels may represent a novel biomarker for RAGE-ligand related pathogenic states. Understanding the full plethora of RAGE alternative splicing and its regulation is central to elucidating the role of RAGE in biology and disease.
C1 [Hudson, Barry I.] Univ Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, Miami, FL 33136 USA.
   [Kalea, Anastasia Z.] Northwestern Univ, Feinberg Sch Med, Div Nephrol Hypertens, Evanston, IL 60208 USA.
   [Schmidt, Ann Marie] NYU, Langone Med Ctr, Dept Med & Pharmacol, New York, NY 10003 USA.
C3 University of Miami; Northwestern University; Feinberg School of
   Medicine; New York University; NYU Langone Medical Center
RP Hudson, BI (corresponding author), Univ Miami, Miller Sch Med, Div Endocrinol Diabet & Metab, 608 Batchelor Bldg, Miami, FL 33136 USA.
EM bhudson@med.miami.edu
RI Hudson, Barry/B-3122-2009; Kalea, Anastasia/JNS-4075-2023
OI Hudson, Barry/0000-0001-7647-8121; Kalea, Anastasia
   Z./0000-0001-5775-3984
FU Juvenile Diabetes Research Foundation International (JDRF)
FX AZK is a recipient of a Postdoctoral Fellowship from Juvenile Diabetes
   Research Foundation International (JDRF). BIH is a recipient of a Career
   Development Award from the JDRF.
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   Zeng S, 2009, J HEPATOL, V50, P929, DOI 10.1016/j.jhep.2008.11.022
   Zhang L, 2008, J BIOL CHEM, V283, P35507, DOI 10.1074/jbc.M806948200
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NR 101
TC 71
Z9 82
U1 0
U2 14
PU FRONTIERS IN BIOSCIENCE INC
PI MANHASSET
PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY
   DR, MANHASSET, NY 11030 USA
SN 1093-9946
J9 FRONT BIOSCI-LANDMRK
JI Front. Biosci.
PD JUN 1
PY 2011
VL 16
BP 2756
EP 2770
DI 10.2741/3884
PG 14
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 757OK
UT WOS:000290097400023
PM 21622207
OA Bronze
DA 2025-04-10
ER

PT J
AU Latorre, E
   Harries, LW
AF Latorre, Eva
   Harries, Lorna. W.
TI Splicing regulatory factors, ageing and age-related disease
SO AGEING RESEARCH REVIEWS
LA English
DT Article
DE Splicing; SRSF; hnRNPs; Dementia; Cancer; Cardiovascular
ID PRE-MESSENGER-RNA; GENE-EXPRESSION PROFILES; LIFE-SPAN;
   PROTEIN-PHOSPHORYLATION; HNRNP A1; CANCER; NONSENSE; MUTATIONS; GENOME;
   GROWTH
AB Alternative splicing is a co-transcriptional process, which allows for the production of multiple transcripts from a single gene and is emerging as an important control point for gene expression. Alternatively expressed isoforms often have antagonistic function and differential temporal or spatial expression patterns, yielding enormous plasticity and adaptability to cells and increasing their ability to respond to environmental challenge. The regulation of alternative splicing is critical for numerous cellular functions in both pathological and physiological conditions, and deregulated alternative splicing is a key feature of common chronic diseases. Isoform choice is controlled by a battery of splicing regulatory proteins, which include the serine arginine rich (SRSF) proteins and the heterogeneous ribonucleoprotein (hnRNP) classes of genes. These important splicing regulators have been implicated in age-related disease, and in the ageing process itself. This review will outline the important contribution of splicing regulator proteins to ageing and age-related disease. (C) 2017 Elsevier B.V. All rights reserved.
C1 [Latorre, Eva; Harries, Lorna. W.] Univ Exeter, Med Sch, Inst Biomed & Clin Sci, Barrack Rd, Exeter EX2 5DW, Devon, England.
C3 University of Exeter
RP Harries, LW (corresponding author), Univ Exeter, Med Sch, Inst Biomed & Clin Sci, Barrack Rd, Exeter EX2 5DW, Devon, England.
EM L.W.Harries@exeter.ac.uk
RI Latorre, Eva/Y-7043-2019; Harries, Lorna/D-2241-2014
OI Latorre, Eva/0000-0002-5797-3909
FU Dunhill Medical Trust [R386/1114]
FX This work was supported by The Dunhill Medical Trust [grant number:
   R386/1114].
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NR 104
TC 43
Z9 47
U1 0
U2 18
PU ELSEVIER IRELAND LTD
PI CLARE
PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000,
   IRELAND
SN 1568-1637
EI 1872-9649
J9 AGEING RES REV
JI Ageing Res. Rev.
PD JUL
PY 2017
VL 36
BP 165
EP 170
DI 10.1016/j.arr.2017.04.004
PG 6
WC Cell Biology; Geriatrics & Gerontology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Geriatrics & Gerontology
GA EX0YT
UT WOS:000402947400016
PM 28456680
DA 2025-04-10
ER

PT J
AU Terenzi, F
   Ladd, AN
AF Terenzi, Fulvia
   Ladd, Andrea N.
TI Conserved developmental alternative splicing of muscleblind-like (MBNL)
   transcripts regulates MBNL localization and activity
SO RNA BIOLOGY
LA English
DT Article
DE muscleblind-like; MBNL; alternative splicing; development; heart
ID MYOTONIC-DYSTROPHY TYPE-1; NUCLEAR FOCI; CUG REPEATS; CTG REPEAT; RNA;
   PROTEINS; BINDING; FAMILY; CELF; REPRESSION
AB Muscleblind-like (MBNL) proteins have been shown to regulate pre-mRNA alternative splicing, and MBNL1 has been implicated in regulating fetal-to-adult transitions in alternative splicing in the heart. MBNL1 is highly conserved, exhibiting more than 95% identity at the amino acid level between birds and mammals. To investigate MBNL1 expression during embryonic heart development, we examined MBNL1 transcript and protein expression in the embryonic chicken heart from the formation of the primitive heart tube through cardiac morphogenesis (embryonic days 1.5 through 8). MBNL1 transcript levels remained steady throughout these stages, whereas MBNL1 protein levels increased and exhibited a shift in isoforms. MBNL1 has several alternatively spliced exons. Using RT-PCR, we determined that the inclusion of one of these, exon 5, decreases dramatically during cardiac morphogenesis. This developmental transition is conserved in mice. Functional analyses of MBNL1 isoforms containing or lacking exon 5-encoded sequences revealed that exon 5 is important for the regulation of the subcellular localization, RNA binding affinity, and alternative splicing activity of MBNL1 proteins. A second MBNL protein, MBNL2, is also expressed in the embryonic heart. We found that MBNL2 exon 5, which is paralogous to MBNL1 exon 5, is similarly regulated during embryonic heart development. Analysis of MBNL1 and MBNL2 transcripts in several embryonic tissues in chicken and mouse indicate that exon 5 alternative splicing is highly conserved and tissue-specific. Thus, we propose that conserved developmental stage-and tissue-specific alternative splicing of MBNL transcripts is an important mechanism by which MBNL activity is regulated during embryonic development.
C1 [Terenzi, Fulvia; Ladd, Andrea N.] Cleveland Clin, Lerner Res Inst, Dept Cell Biol, Cleveland, OH 44106 USA.
   [Ladd, Andrea N.] Case Western Reserve Univ, Cleveland Clin, Dept Mol Med, Lerner Coll Med, Cleveland, OH 44106 USA.
C3 Cleveland Clinic Foundation; University System of Ohio; Case Western
   Reserve University; Cleveland Clinic Foundation
RP Ladd, AN (corresponding author), Cleveland Clin, Lerner Res Inst, Dept Cell Biol, Cleveland, OH 44106 USA.
EM ladda@ccf.org
OI Ladd, Andrea/0000-0003-4725-5644
FU March of Dimes [5-FY05-1226]; American Heart Association [O865420D]
FX We thank Natalie Vajda for assisting with the collection of primary
   cardiomyocytes, and Tom Cooper for providing COS-M6 cells. We thank
   Donna Driscoll for critical review of this manuscript. This work was
   supported by grants from the March of Dimes (5-FY05-1226) and the
   American Heart Association (O865420D).
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NR 38
TC 49
Z9 66
U1 0
U2 7
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 1547-6286
EI 1555-8584
J9 RNA BIOL
JI RNA Biol.
PD JAN-FEB
PY 2010
VL 7
IS 1
BP 43
EP 55
DI 10.4161/rna.7.1.10401
PG 13
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 577CF
UT WOS:000276197800007
PM 20009516
OA Bronze
DA 2025-04-10
ER

PT J
AU Cunha, SR
   Le Scouarnec, S
   Schott, JJ
   Mohler, PJ
AF Cunha, Shane R.
   Le Scouarnec, Solena
   Schott, Jean-Jacques
   Mohler, Peter J.
TI Exon organization and novel alternative splicing of the human
   ANK2 gene: Implications for cardiac function and human cardiac
   disease
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Article
DE Ankyrin-B; ANK2; Cardiomyocytes; Alternative splicing; Arrhythmia
ID HUMAN ERYTHROCYTE ANKYRIN; AXON INITIAL SEGMENT; C-TERMINAL DOMAIN;
   HEREDITARY SPHEROCYTOSIS; NEONATAL CARDIOMYOCYTES; MEMBRANE-SKELETON;
   INOSITOL 1,4,5-TRISPHOSPHATE; SARCOPLASMIC-RETICULUM; ISOFORM
   SPECIFICITY; 440-KD ANKYRIN(B)
AB Recent findings illustrate a critical role for ankyrin-B function in normal cardiovascular physiology. Specifically, decreased expression of ankyrin-B in mice or human mutations in the ankyrin-B gene (ANK2) results in potentially fatal cardiac arrhythmias. Despite the clear role of ankyrin-B in heart, the mechanisms underlying transcriptional regulation of ANK2 are unknown. In fact, to date there is no description of ANK2 genomic organization. The aims of this study were to provide a comprehensive description of the ANK2 gene and to evaluate the relative expression of alternative splicing events associated with ANK2 transcription in heart. Using reverse-transcriptase PCR on mRNA isolated from human hearts, we identify seven new exons associated with the ANK2 gene including an alternative first exon located similar to 145 kb upstream of the previously-identified first exon. In addition, we identify over thirty alternative splicing events associated with ANK2 mRNA transcripts. Using real-time PCR and exon boundary-spanning primers to selectively amplify these splice variants, we demonstrate that these Variants are expressed at varying levels in human heart. Finally, ankyrin-B immunoblot analysis demonstrates the expression of a heterogeneous population of ankyrin-B polypeptides in heart. ANK2 consists of 53 exons that span similar to 560 kb on human chromosome 4. Additionally, our data demonstrates that ANK2 is subject to complex transcriptional regulation that likely results in differential ankyrin-B polypeptide function. (C) 2008 Elsevier Inc. All Rights reserved.
C1 [Cunha, Shane R.; Mohler, Peter J.] Univ Iowa, Carver Coll Med, Dept Internal Med, Div Cardiovasc Med, Iowa City, IA 52242 USA.
   [Mohler, Peter J.] Univ Iowa, Carver Coll Med, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA.
   [Le Scouarnec, Solena; Schott, Jean-Jacques] INSERM, Inst Thorax, UMR915, F-44000 Nantes, France.
   [Le Scouarnec, Solena; Schott, Jean-Jacques] CNRS, ERL3147, F-44000 Nantes, France.
   [Le Scouarnec, Solena; Schott, Jean-Jacques] Univ Nantes, F-44000 Nantes, France.
   [Schott, Jean-Jacques] CHU Nantes, Inst Thorax, Serv Cardiol, F-44000 Nantes, France.
C3 University of Iowa; University of Iowa; Institut National de la Sante et
   de la Recherche Medicale (Inserm); Nantes Universite; CHU de Nantes;
   Centre National de la Recherche Scientifique (CNRS); Nantes Universite;
   Institut National de la Sante et de la Recherche Medicale (Inserm);
   Nantes Universite; CHU de Nantes
RP Cunha, SR (corresponding author), Univ Iowa, Carver Coll Med, Dept Internal Med, Div Cardiovasc Med, 285 Newton Rd CBRB,Room 2283, Iowa City, IA 52242 USA.
EM shane-cunha@uiowa.edu
RI Le Scouarnec, Solena/D-3547-2015; Schott, jean-Jacques/F-8842-2013
OI Schott, jean-Jacques/0000-0002-9578-9475
FU National Institutes of Health [HL084583, HL083422]; Pew Scholars Trust;
   Fondation Leducq Trans-Atlantic network of Excellence [05 CVD 01];
   Association Francaise contre les Myopathies
FX We thank the following people for their assistance: Jordan Miller (UI)
   for coordinating the procurement of human hearts, Madhu Singh (UI) for
   helpful advice on real-time PCR, and Dr. Michael Welsh (UI) for the use
   of the phosphorimage machine. We thank Andras Varro (University of
   Szeged) and Sophie Demolombe (l'institut du thorax, Nantes, France) for
   providing the human tissues. Funding: National Institutes of Health
   (HL084583 and HL083422 to PJM); Pew Scholars Trust to PJM. Fondation
   Leducq Trans-Atlantic network of Excellence grant (05 CVD 01, Preventing
   Sudden Death) and Association Francaise contre les Myopathies (JJS).
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NR 50
TC 31
Z9 35
U1 0
U2 5
PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
PI LONDON
PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD DEC
PY 2008
VL 45
IS 6
BP 724
EP 734
DI 10.1016/j.yjmcc.2008.08.005
PG 11
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA 381IJ
UT WOS:000261529000005
PM 18790697
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Cui, Y
   Zhang, ZL
   Lv, MF
   Duan, ZY
   Liu, WH
   Gao, JC
   Xu, R
   Wan, Q
AF Cui, Yu
   Zhang, Zhaolong
   Lv, Mengfei
   Duan, Zhongying
   Liu, Wenhao
   Gao, Jingchen
   Xu, Rui
   Wan, Qi
TI Article Chromatin target of protein arginine methyltransferases
   alleviates cerebral ischemia/ reperfusion-induced injury by regulating
   RNA alternative splicing
SO ISCIENCE
LA English
DT Article
ID CHTOP; EXPRESSION; RICH
AB RNA splicing is a post-transcriptional event that regulates many physiological and pathological events. However, whether RNA splicing regulates cerebral I/R-induced brain injury remains largely unknown. In this study, we found that the chromatin target of Prmts (CHTOP) was highly expressed in neurons, and anti-inflammatory cytokine interleukin-10 (IL-10) upregulates its expression after ischemia. In addition, overexpression or knockdown of CHTOP alleviated or exacerbated neuronal death in both experimental stroke mice and cultured neurons. Mechanistically, RNA alternative splicing is altered early after oxygen and glucose deprivation/reoxygenation (OGD/R). CHTOP interacted with nuclear speckle-related proteins to regulate alternative mRNA splicing of neuronal survival-related genes after OGD/R. In addition, I/R injury-induced cytokines IL-10 regulate CHTOP-mediated RNA splicing to alleviate ischemic brain injury. Taken together, this study reveals the alteration of RNA splicing after OGD/R and identifies the IL-10-CHTOP-RNA splicing axis as a modulator of brain injury, which may be promising therapeutic targets for ischemic stroke.
C1 [Cui, Yu; Lv, Mengfei; Duan, Zhongying; Gao, Jingchen; Wan, Qi] Qingdao Univ, Inst Neuroregenerat & Neurorehabil, 308 Ningxia Rd, Qingdao 266071, Shandong, Peoples R China.
   [Cui, Yu; Lv, Mengfei; Duan, Zhongying; Wan, Qi] Qingdao Univ, Qingdao Med Coll, Qingdao 266071, Peoples R China.
   [Zhang, Zhaolong; Liu, Wenhao; Xu, Rui] Qingdao Univ, Dept Intervent Radiol, Affiliated Hosp, 16 Jiangsu Rd, Qingdao 266000, Shandong, Peoples R China.
C3 Qingdao University; Qingdao University; Qingdao University
RP Cui, Y; Wan, Q (corresponding author), Qingdao Univ, Inst Neuroregenerat & Neurorehabil, 308 Ningxia Rd, Qingdao 266071, Shandong, Peoples R China.; Cui, Y; Wan, Q (corresponding author), Qingdao Univ, Qingdao Med Coll, Qingdao 266071, Peoples R China.
EM cuiyu@qdu.edu.cn; qiwan1@hotmail.com
RI Cui, Yu/AAK-7640-2021; zhang, zhaolong/AGO-3633-2022
OI Cui, Yu/0000-0002-3480-0730
FU Science and Technology Support Plan for Youth Innovation of Colleges and
   Universities of Shandong Province of China [2022KJ146]; National Natural
   Science Foundation of China [82071385, 82101380]; Natural Science
   Foundation of Shandong Province [ZR202102280316]; Postdoctoral Applied
   Research Project of Qingdao [QDBSH20220201049]
FX The authors wish to thank Dr. Shengli Gao from the Biomedical Center of
   Qingdao University for the use of some instruments and assistance with
   the measurements. This work was supported by Science and Technology
   Support Plan for Youth Innovation of Colleges and Universities of
   Shandong Province of China (2022KJ146) to Yu Cui; National Natural
   Science Foundation of China (82071385) to Qi Wan; National Natural
   Science Foundation of China (82101380) , Natural Science Foundation of
   Shandong Province (ZR202102280316) and Postdoctoral Applied Research
   Project of Qingdao (QDBSH20220201049) to Zhaolong Zhang.
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NR 49
TC 4
Z9 4
U1 0
U2 0
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
EI 2589-0042
J9 ISCIENCE
JI iScience
PD JAN 19
PY 2024
VL 27
IS 1
AR 108688
DI 10.1016/j.isci.2023.108688
EA DEC 2023
PG 20
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA EX7W4
UT WOS:001142307900001
PM 38188517
OA Green Published
DA 2025-04-10
ER

PT J
AU Orengo, JP
   Ward, AJ
   Cooper, TA
AF Orengo, James P.
   Ward, Amanda J.
   Cooper, Thomas A.
TI Alternative Splicing Dysregulation Secondary to Skeletal Muscle
   Regeneration
SO ANNALS OF NEUROLOGY
LA English
DT Article
ID RNA-BINDING PROTEINS; PRE-MESSENGER-RNA; MUSCULAR-DYSTROPHY;
   MYOTONIC-DYSTROPHY; MOUSE MODEL; NUCLEAR; CUGBP1; IDENTIFICATION;
   EXPRESSION; REPEATS
AB Objective: Dysregulation of alternative splicing has become a molecular hallmark of myotonic dystrophy type 1 (DM1), in which neonatal splice variants are expressed in adult skeletal muscle. Splicing dysregulation is induced by RNA containing expanded CUG repeats expressed from the expanded mutant allele by sequestration of muscleblindlike 1 (MBNL1) protein within nuclear RNA foci and increased CUGBP, ELAV-like family member 1 (CELF1) protein levels. Dysregulated splicing has also been identified in other neuromuscular disorders, suggesting either that diseases with different molecular causes share a common pathogenic mechanism or that dysregulated splicing can also be a common secondary consequence of muscle degeneration and regeneration.
   Methods: In this study, we examined regulation of alternative splicing in 4 different mouse models of muscular dystrophy, including DM1, limb-girdle muscular dystrophy, congenital merosin-deficient muscular dystrophy, and Duchenne muscular dystrophy, and 2 myotoxin (cardiotoxin and notexin) muscle injury models.
   Results: We show that DM1-like alternative splicing dysregulation and altered expression of MBNL1 and CELF1 occur in non-DM1 mouse models of muscular dystrophy and muscle injury, most likely due to recapitulation of neonatal splicing patterns in regenerating fibers. In contrast, CELF1 was elevated in nuclei of mature myofibers of the DM1 model, consistent with a primary effect of pathogenic RNA expression.
   Interpretation: Splicing dysregulation in DM1 is a primary effect of RNA containing expanded CUG repeats. However, we conclude that splicing changes can also be observed secondary to muscle regeneration, and this possibility must be taken into account when evaluating cause-effect relationships between dysregulated splicing and disease processes. ANN NEUROL 2011; 69: 681-690
C1 [Orengo, James P.; Ward, Amanda J.; Cooper, Thomas A.] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA.
   [Orengo, James P.; Ward, Amanda J.; Cooper, Thomas A.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Baylor College of Medicine
RP Cooper, TA (corresponding author), Baylor Coll Med, Dept Pathol & Immunol, 1 Baylor Plaza, Houston, TX 77030 USA.
EM tcooper@bcm.edu
RI Orengo, James/AAF-1667-2021
OI Orengo, James/0000-0002-3912-4575; Whipple, Amanda/0000-0002-7000-2453
FU National Institutes of Health [R01AR45653, F30NS057884, F31NS067740];
   Muscular Dystrophy Association
FX Support for this work was provided by National Institutes of Health
   grants R01AR45653 (T. A. C.), F30NS057884 (J.P.O.), and F31NS067740
   (A.J.W.), and by the Muscular Dystrophy Association (T. A. C.). All
   histological samples were processed by the Center for Comparative
   Medicine pathology core facility at Baylor College of Medicine; special
   thanks to B. Bhatti for her assistance. We thank Dr M. Fiorotto for
   providing mdx mice as well as general advice and Dr O. Agbulut for
   providing neonatal myosin heavy chain polyclonal antibody.
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NR 42
TC 51
Z9 58
U1 0
U2 6
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0364-5134
EI 1531-8249
J9 ANN NEUROL
JI Ann. Neurol.
PD APR
PY 2011
VL 69
IS 4
BP 681
EP 690
DI 10.1002/ana.22278
PG 10
WC Clinical Neurology; Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 758HV
UT WOS:000290155800014
PM 21400563
OA Green Accepted, Bronze
DA 2025-04-10
ER

PT J
AU Dennehey, BK
   Leinwand, LA
   Krauter, KS
AF Dennehey, Briana K.
   Leinwand, Leslie A.
   Krauter, Kenneth S.
TI Diversity in transcriptional start site selection and alternative
   splicing affects the 5′-UTR of mouse striated muscle myosin transcripts
SO JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY
LA English
DT Article
DE striated muscle; myosin heavy chain; transcription; alternative
   splicing; 5 '-UTR
ID CHAIN GENE-EXPRESSION; IN-VIVO ANALYSIS; HEAVY-CHAINS; SKELETAL-MUSCLE;
   SMOOTH-MUSCLE; REGULATORY ELEMENTS; ISOFORM TRANSITIONS;
   EXTRAOCULAR-MUSCLE; NONMUSCLE MYOSIN; LIGHT CHAIN-1
AB We have analyzed nearly 2,000 myosin heavy chain gene (Myh) clones representing over 30 different transcripts from seven of eight striated muscle Myh genes expressed in mouse. We also report the transcriptional start sites (TSS) for the mouse developmental Myh genes. The data reveal a previously unknown diversity of TSSs and 5'-end alternative splicing in these transcripts. The cardiac Myh6 gene had two major TSSs. Use of the major downstream site led to an alternatively spliced second exon. Each of the other Myh genes had one major TATA-directed TSS and one or more minor alternative TSSs, some associated with alternative splicing. The minor transcripts were associated with polysomes and their spatial-temporal expression largely mirrored that of the major transcripts in wild-type, Myh1 null, Myh4 null, injured, and uninjured muscle, except that one form of Myh7, detected in heart, was not detected in diaphragm, and the ratio of the two major Myh6 transcripts varied in some circumstances. These findings indicate that alternative TSS usage and alternative splicing in the 5'-UTR are a general feature of murine Myh gene expression and that Myh gene regulation is more complex than previously appreciated.
C1 Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA.
C3 University of Colorado System; University of Colorado Boulder
RP Krauter, KS (corresponding author), Univ Colorado, Dept Mol Cellular & Dev Biol, Campus Box 347, Boulder, CO 80309 USA.
EM krauter@colorado.edu
RI L, A/HZI-4043-2023
OI Dennehey, Briana/0000-0002-9238-1079; LEINWAND,
   LESLIE/0000-0003-1470-4810
FU NHLBI NIH HHS [HL050560, T32 HL007851, HL007851] Funding Source:
   Medline; NIAMS NIH HHS [AR048817] Funding Source: Medline; NIDA NIH HHS
   [R01 DA012845, P60 DA011015] Funding Source: Medline; NIGMS NIH HHS [R01
   GM029090, GM029090] Funding Source: Medline
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NR 64
TC 9
Z9 11
U1 0
U2 3
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 0142-4319
EI 1573-2657
J9 J MUSCLE RES CELL M
JI J. Muscle Res. Cell Motil.
PD NOV
PY 2006
VL 27
IS 8
BP 559
EP 575
DI 10.1007/s10974-006-9071-8
PG 17
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 100RO
UT WOS:000241686500002
PM 16819597
DA 2025-04-10
ER

PT J
AU Kashyap, A
   Tripathi, G
   Tripathi, A
   Rao, R
   Kashyap, M
   Bhat, A
   Kumar, D
   Rajhans, A
   Kumar, P
   Chandrashekar, DS
   Mahmood, R
   Husain, A
   Zayed, H
   Bharti, AC
   Kashyap, MK
AF Kashyap, Anjali
   Tripathi, Greesham
   Tripathi, Avantika
   Rao, Rashmi
   Kashyap, Manju
   Bhat, Anjali
   Kumar, Deepak
   Rajhans, Anjali
   Kumar, Pravindra
   Chandrashekar, Darshan Shimoga
   Mahmood, Riaz
   Husain, Amjad
   Zayed, Hatem
   Bharti, Alok Chandra
   Kashyap, Manoj Kumar
TI RNA splicing: a dual-edged sword for hepatocellular carcinoma
SO MEDICAL ONCOLOGY
LA English
DT Review
DE Alternative RNA splicing; ARS; RNA processing; Spliceosome; Transcript
   variants; Hepatocellular carcinoma; Hepatoma; NAFLD; RNA splicing; NASH;
   Cirrhosis; Splicing factors; RNA-Seq; Intron retention; Exon skipping
ID INDICATES POOR-PROGNOSIS; CRYO-EM STRUCTURE; THERAPEUTIC TARGET;
   CELL-PROLIFERATION; LIVER-DISEASE; GENE-PRODUCT; CANCER-CELLS;
   COPY-NUMBER; SMN COMPLEX; BCL-X
AB RNA splicing is the fundamental process that brings diversity at the transcriptome and proteome levels. The spliceosome complex regulates minor and major processes of RNA splicing. Aberrant regulation is often associated with different diseases, including diabetes, stroke, hypertension, and cancer. In the majority of cancers, dysregulated alternative RNA splicing (ARS) events directly affect tumor progression, invasiveness, and often lead to poor survival of the patients. Alike the rest of the gastrointestinal malignancies, in hepatocellular carcinoma (HCC), which alone contributes to similar to 75% of the liver cancers, a large number of ARS events have been observed, including intron retention, exon skipping, presence of alternative 3'-splice site (3'SS), and alternative 5'-splice site (5'SS). These events are reported in spliceosome and non-spliceosome complexes genes. Molecules such as MCL1, Bcl-X, and BCL2 in different isoforms can behave as anti-apoptotic or pro-apoptotic, making the spliceosome complex a dual-edged sword. The anti-apoptotic isoforms of such molecules bring in resistance to chemotherapy or cornerstone drugs. However, in contrast, multiple malignant tumors, including HCC that target the proapoptotic favoring isoforms/variants favor apoptotic induction and make chemotherapy effective. Herein, we discuss different splicing events, aberrations, and antisense oligonucleotides (ASOs) in modulating RNA splicing in HCC tumorigenesis with a possible therapeutic outcome.
C1 [Kashyap, Anjali] Thapar Inst Engn & Technol, Dept Biotechnol, Patiala, Punjab, India.
   [Tripathi, Greesham; Tripathi, Avantika; Rajhans, Anjali; Kashyap, Manoj Kumar] Amity Univ Haryana, Amity Med Sch, Amity Stem Cell Inst, Panchgaon 122413, Haryana, India.
   [Rao, Rashmi; Kumar, Pravindra] Glocal Univ, Sch Life & Allied Hlth Sci, Saharanpur, UP, India.
   [Kashyap, Manju] Univ San Sebastian, Fac Ingn & Tecnol, Concepcion, Chile.
   [Kashyap, Manju] Natl Inst Immunol, Aruna Asaf Ali Marg, Delhi 110067, India.
   [Bhat, Anjali; Bharti, Alok Chandra; Kashyap, Manoj Kumar] Univ Delhi, Mol Oncol Lab, Dept Zool, North Campus, New Delhi 110007, India.
   [Kumar, Deepak] ThermoFisher Sci, Carlsbad, CA 92008 USA.
   [Chandrashekar, Darshan Shimoga] Univ Alabama Birmingham, Dept Pathol, Mol & Cellular Pathol, Birmingham, AL 35294 USA.
   [Mahmood, Riaz] Kuvempu Univ, Dept Biotechnol & Bioinformat, Jnanasahyadri 577451, Karnataka, India.
   [Husain, Amjad] Indian Inst Sci Educ & Res IISER, Ctr Sci & Soc, Bhopal, India.
   [Husain, Amjad] Indian Inst Sci Educ & Res IISER, Innovat & Incubat Ctr Entrepreneurship IICE, Bhopal, India.
   [Zayed, Hatem] Qatar Univ, Coll Hlth & Sci, Dept Biomed Sci, QU Hlth, Doha, Qatar.
C3 Thapar Institute of Engineering & Technology; Universidad San Sebastian;
   Department of Biotechnology (DBT) India; National Institute of
   Immunology (NII); University of Delhi; University of Alabama System;
   University of Alabama Birmingham; Kuvempu University; Indian Institute
   of Science Education & Research (IISER) - Bhopal; Indian Institute of
   Science Education & Research (IISER) - Bhopal; Qatar University
RP Kashyap, MK (corresponding author), Amity Univ Haryana, Amity Med Sch, Amity Stem Cell Inst, Panchgaon 122413, Haryana, India.; Bharti, AC; Kashyap, MK (corresponding author), Univ Delhi, Mol Oncol Lab, Dept Zool, North Campus, New Delhi 110007, India.
EM alokchandrab@yahoo.com; mkkashyap@ggn.amity.edu
RI Zayed, Hatem/R-1800-2019; Kumar, Deepak/E-5386-2014; KUMAR,
   PRAVINDRA/AAF-2859-2020; Kashyap, Manoj/H-2828-2019; Bharti, Prof.
   AC/AGL-5994-2022
OI Bharti, Alok Chandra/0000-0002-5996-2832; Zayed,
   Hatem/0000-0001-8838-6638; Kashyap, Manoj/0000-0002-3064-8452
FU Science and Engineering Research Board Department of Science and
   Technology, Government of India (DST-SERB) [(EMR/2017/004018/BBM)];
   Institution of Eminence University of Delhi [IoE/2021/12/FRP]; TARE SERB
   [SERB/F/13036/2018-2019]; ICMR [5/13/55/2020/NCD-III]; ICMR, New Delhi,
   India [5/13/4/ACB/ICRC/2020/NCD-III]; CCRH
   [17-51/2016-17/CCRH/Tech/Coll./DU-Cervical Cancer.4850]
FX Financial support from the Science and Engineering Research Board
   Department of Science and Technology, Government of India (DST-SERB
   (EMR/2017/004018/BBM)) and Institution of Eminence University of Delhi
   (Ref. No./IoE/2021/12/FRP) to ACB and grant from TARE SERB to MKK & ACB,
   MKK (SERB/F/13036/2018-2019; dated: 28/03/2019), a grant from ICMR to
   MKK (sanction #: 5/13/55/2020/NCD-III) and ACB
   (No.5/13/4/ACB/ICRC/2020/NCD-III) from ICMR, New Delhi, India, CCRH to
   ACB (17-51/2016-17/CCRH/Tech/Coll./DU-Cervical Cancer.4850) are also
   thankfully acknowledged.
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NR 193
TC 8
Z9 10
U1 0
U2 9
PU HUMANA PRESS INC
PI TOTOWA
PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA
SN 1357-0560
EI 1559-131X
J9 MED ONCOL
JI Med. Oncol.
PD AUG 16
PY 2022
VL 39
IS 11
AR 173
DI 10.1007/s12032-022-01726-8
PG 31
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 3U9NK
UT WOS:000841289400016
PM 35972700
DA 2025-04-10
ER

PT J
AU Daoud, R
   Mies, G
   Smialowska, A
   Oláh, L
   Hossmann, KA
   Stamm, S
AF Daoud, R
   Mies, G
   Smialowska, A
   Oláh, L
   Hossmann, KA
   Stamm, S
TI Ischemia induces a translocation of the splicing factor tra2-β1 and
   changes alternative splicing patterns in the brain
SO JOURNAL OF NEUROSCIENCE
LA English
DT Article
DE alternative pre-mRNA processing; SR proteins; ischemia; phosphorylation;
   calcium; stroke
ID CEREBRAL-ARTERY OCCLUSION; SR PROTEIN-KINASES; MESSENGER-RNA;
   GENE-EXPRESSION; TERMINAL DOMAIN; SITE SELECTION; IN-VIVO;
   TRANSCRIPTION; CELL; ENHANCER
AB Alternative splice-site selection is regulated by the relative concentration of individual members of the serine-arginine family of proteins and heterogeneous nuclear ribonucleoproteins. Most of these proteins accumulate predominantly in the nucleus, and a subset of them shuttles continuously between nucleus and cytosol. We demonstrate that in primary neuronal cultures, a rise in intracellular calcium concentration induced by thapsigargin leads to a translocation of the splicing regulatory protein tra2-beta1 and a consequent change in splice-site selection. To investigate this phenomenon under physiological conditions, we used an ischemia model. Ischemia induced in the brain causes a cytoplasmic accumulation and hyperphosphorylation of tra2-beta1. In addition, several of the proteins binding to tra2-beta1, such as src associated in mitosis 68 and serine/arginine-rich proteins, accumulate in the cytosol. Concomitant with this subcellular relocalization, we observed a change in alternative splice-site usage of the ICH-1 gene. The increased usage of its alternative exons is in agreement with previous studies demonstrating its repression by a high concentration of proteins with serine/arginine-rich domains. Our findings suggest that a change in the calcium concentration associated with ischemia is part of a signaling event, which changes pre-mRNA splicing pathways by causing relocalization of proteins that regulate splice-site selection.
C1 Univ Erlangen Nurnberg, Inst Biochem, D-91054 Erlangen, Germany.
   Max Planck Inst Neurol Res, D-50931 Cologne, Germany.
C3 University of Erlangen Nuremberg; Max Planck Society
RP Univ Erlangen Nurnberg, Inst Biochem, D-91054 Erlangen, Germany.
EM stefan@stamms-lab.net
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NR 72
TC 75
Z9 85
U1 0
U2 6
PU SOC NEUROSCIENCE
PI WASHINGTON
PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA
SN 0270-6474
J9 J NEUROSCI
JI J. Neurosci.
PD JUL 15
PY 2002
VL 22
IS 14
BP 5889
EP 5899
PG 11
WC Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 573PR
UT WOS:000176840500014
PM 12122051
DA 2025-04-10
ER

PT J
AU Goren, A
   Kim, E
   Amit, M
   Bochner, R
   Lev-Maor, G
   Ahituv, N
   Ast, G
AF Goren, Amir
   Kim, Eddo
   Amit, Maayan
   Bochner, Ron
   Lev-Maor, Galit
   Ahituv, Nadav
   Ast, Gil
TI Alternative approach to a heavy weight problem
SO GENOME RESEARCH
LA English
DT Article
ID SINGLE-NUCLEOTIDE POLYMORPHISMS; RNA SPLICE JUNCTIONS; BODY-MASS INDEX;
   REGULATORY ELEMENTS; PURIFYING SELECTION; MUTATIONS; OBESITY; DIVERSITY;
   MECHANISM; ENHANCERS
AB Obesity is reaching epidemic proportions in developed countries and represents a significant risk factor for hypertension, heart disease, diabetes, and dyslipidemia. Splicing mutations constitute at least 14% of disease-causing mutations, thus implicating polymorphisms that affect splicing as likely candidates for disease susceptibility. A recent study suggested that genes associated with obesity were significantly enriched for rare nucleotide variants. Here, we examined these variants and revealed that they are located near splice junctions and tend to affect exonic splicing regulatory sequences. We also show that the majority of the exons that harbor these SNPs are constitutively spliced, yet they exhibit weak splice sites, typical to alternatively spliced exons, and are hence suboptimal for recognition by the splicing machinery and prone to become alternatively spliced. Using ex vivo assays, we tested a few representative variants and show that they indeed affect splicing by causing a shift from a constitutive to an alternative pattern, suggesting a possible link between extreme body mass index and abnormal splicing patterns.
C1 [Goren, Amir; Kim, Eddo; Amit, Maayan; Bochner, Ron; Lev-Maor, Galit; Ast, Gil] Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel.
   [Ahituv, Nadav] Univ Calif San Francisco, Dept Biopharmaceut Sci, San Francisco, CA 94143 USA.
   [Ahituv, Nadav] Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA.
C3 Tel Aviv University; Sackler Faculty of Medicine; University of
   California System; University of California San Francisco; University of
   California System; University of California San Francisco
RP Ast, G (corresponding author), Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel.
EM gilast@post.tau.ac.il
OI Ast, Gil/0000-0001-6674-0931; Ahituv, Nadav/0000-0002-7434-8144
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PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
PI COLD SPRING HARBOR
PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA
SN 1088-9051
EI 1549-5469
J9 GENOME RES
JI Genome Res.
PD FEB
PY 2008
VL 18
IS 2
BP 214
EP 220
DI 10.1101/gr.6661308
PG 7
WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology;
   Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology;
   Genetics & Heredity
GA 258ID
UT WOS:000252860700004
PM 18096750
OA Green Published, Bronze
DA 2025-04-10
ER

PT J
AU Aufiero, S
   van den Hoogenhof, MMG
   Reckman, YJ
   Beqqali, A
   van der Made, I
   Kluin, J
   Khan, MAF
   Pinto, YM
   Creemers, EE
AF Aufiero, Simona
   van den Hoogenhof, Maarten M. G.
   Reckman, Yolan J.
   Beqqali, Abdelaziz
   van der Made, Ingeborg
   Kluin, Jolanda
   Khan, Mohsin A. F.
   Pinto, Yigal M.
   Creemers, Esther E.
TI Cardiac circRNAs arise mainly from constitutive exons rather than
   alternatively spliced exons
SO RNA
LA English
DT Article
DE circRNAs; splicing; gene expression; heart; Rbm20
ID CIRCULAR RNA EXPRESSION; BIOGENESIS; SEQUENCES; MOUSE; TITIN; GENE;
   CARDIOMYOPATHY; TRANSLATION; ABUNDANT; REVEALS
AB Circular RNAs (circRNAs) are a relatively new class of RNA molecules, and knowledge about their biogenesis and function is still in its infancy. It was recently shown that alternative splicing underlies the formation of circular RNAs (circRNA) arising from the Titin (TTN) gene. Since the main mechanism by which circRNAs are formed is still unclear, we hypothesized that alternative splicing, and in particular exon skipping, is a major driver of circRNA production. We performed RNA sequencing on human and mouse hearts, mapped alternative splicing events, and overlaid these with expressed circRNAs at exon-level resolution. In addition, we performed RNA sequencing on hearts of Rbm20 KO mice to address how important Rbm20-mediated alternative splicing is in the production of cardiac circRNAs. In human and mouse hearts, we show that cardiac circRNAs are mostly (similar to 90%) produced from constitutive exons and less (similar to 10%) from alternatively spliced exons. In Rbm20 KO hearts, we identified 38 differentially expressed circRNAs of which 12 were produced from the Ttn gene. Even though Ttn appeared the most prominent target of Rbm20 for circularization, we also detected Rbm20-dependent circRNAs arising from other genes including Fan1, Stk39, Xdh, Bcl2l13, and Sorbs1. Interestingly, only Ttn circRNAs seemed to arise from Rbm20-mediated skipped exons. In conclusion, cardiac circRNAs are mostly derived from constitutive exons, suggesting that these circRNAs are generated at the expense of their linear counterpart and that circRNA production impacts the accumulation of the linear mRNA.
C1 [Aufiero, Simona; van den Hoogenhof, Maarten M. G.; Reckman, Yolan J.; Beqqali, Abdelaziz; van der Made, Ingeborg; Khan, Mohsin A. F.; Pinto, Yigal M.; Creemers, Esther E.] Acad Med Ctr, Dept Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands.
   [Aufiero, Simona; Khan, Mohsin A. F.] Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, NL-1105 AZ Amsterdam, Netherlands.
   [Kluin, Jolanda] Acad Med Ctr, Cardiothorac Surg, NL-1105 AZ Amsterdam, Netherlands.
C3 University of Amsterdam; Academic Medical Center Amsterdam; University
   of Amsterdam; Academic Medical Center Amsterdam; University of
   Amsterdam; Academic Medical Center Amsterdam
RP Creemers, EE (corresponding author), Acad Med Ctr, Dept Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands.
EM e.e.creemers@amc.uva.nl
RI ; Beqqali, Abdelaziz/F-8568-2013
OI Reckman, Yolan/0000-0002-8327-5688; Creemers,
   Esther/0000-0002-9001-3854; Kluin, Jolanda/0000-0002-5942-4727; ,
   yigal/0000-0002-2836-571X; Beqqali, Abdelaziz/0000-0003-1390-5821; van
   den Hoogenhof, Maarten/0000-0003-2768-3457; Aufiero,
   Simona/0000-0003-0782-3985
FU Nederlandse Organisatie voor Wetenschappelijk Onderzoek [NWO-836.12.002,
   NWO-821.02.021]; Cardiovasculair Onderzoek Nederland (CVON)
   [CVON-ARENA-2011-11]
FX This work was supported by the Nederlandse Organisatie voor
   Wetenschappelijk Onderzoek (NWO-836.12.002, NWO-821.02.021) and by the
   Cardiovasculair Onderzoek Nederland (CVON): CVON-ARENA-2011-11.
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NR 52
TC 62
Z9 66
U1 0
U2 5
PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
PI COLD SPRING HARBOR
PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA
SN 1355-8382
EI 1469-9001
J9 RNA
JI RNA
PD JUN
PY 2018
VL 24
IS 6
BP 815
EP 827
DI 10.1261/rna.064394.117
PG 13
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA GK3ZG
UT WOS:000436090100006
PM 29567830
OA Green Accepted, Bronze, Green Published
DA 2025-04-10
ER

PT J
AU Liu, L
   Kryvokhyzha, D
   Rippe, C
   Jacob, A
   Borreguero-Muñoz, A
   Stenkula, KG
   Hansson, O
   Smith, CWJ
   Fisher, SA
   Swärd, K
AF Liu, Li
   Kryvokhyzha, Dmytro
   Rippe, Catarina
   Jacob, Aishwarya
   Borreguero-Munoz, Andrea
   Stenkula, Karin G.
   Hansson, Ola
   Smith, Christopher W. J.
   Fisher, Steven A.
   Sward, Karl
TI Myocardin regulates exon usage in smooth muscle cells through induction
   of splicing regulatory factors
SO CELLULAR AND MOLECULAR LIFE SCIENCES
LA English
DT Article
DE Splicing code; Actin-binding; Focal adhesion; Heart; Differentiation
ID LIGHT-CHAIN KINASE; MYOSIN PHOSPHATASE ISOFORMS; SERUM RESPONSE FACTOR;
   CALCIUM-CHANNEL; BINDING PROTEIN; GENE; SENSITIVITY; EXPRESSION;
   TRA2-BETA; PROGRAM
AB Differentiation of smooth muscle cells (SMCs) depends on serum response factor (SRF) and its co-activator myocardin (MYOCD). The role of MYOCD for the SMC program of gene transcription is well established. In contrast, the role of MYOCD in control of SMC-specific alternative exon usage, including exon splicing, has not been explored. In the current work we identified four splicing factors (MBNL1, RBPMS, RBPMS2, and RBFOX2) that correlate with MYOCD across human SMC tissues. Forced expression of MYOCD family members in human coronary artery SMCs in vitro upregulated expression of these splicing factors. For global profiling of transcript diversity, we performed RNA-sequencing after MYOCD transduction. We analyzed alternative transcripts with three different methods. Exon-based analysis identified 1637 features with differential exon usage. For example, usage of 3 ' exons in MYLK that encode telokin increased relative to 5 ' exons, as did the 17 kDa telokin to 130 kDa MYLK protein ratio. Dedicated event-based analysis identified 239 MYOCD-driven splicing events. Events involving MBNL1, MCAM, and ACTN1 were among the most prominent, and this was confirmed using variant-specific PCR analyses. In support of a role for RBPMS and RBFOX2 in MYOCD-driven splicing we found enrichment of their binding motifs around differentially spliced exons. Moreover, knockdown of either RBPMS or RBFOX2 antagonized splicing events stimulated by MYOCD, including those involving ACTN1, VCL, and MBNL1. Supporting an in vivo role of MYOCD-SRF-driven splicing, we demonstrate altered Rbpms expression and splicing in inducible and SMC-specific Srf knockout mice. We conclude that MYOCD-SRF, in part via RBPMS and RBFOX2, induce a program of differential exon usage and alternative splicing as part of the broader program of SMC differentiation.
C1 [Liu, Li; Rippe, Catarina; Borreguero-Munoz, Andrea; Stenkula, Karin G.; Sward, Karl] Dept Expt Med Sci, BMC D12, SE-22184 Lund, Sweden.
   [Liu, Li] Guangzhou Med Univ, Qingyuan Peoples Hosp, Affiliated Hosp 6, Dept Urol, Qingyuan, Peoples R China.
   [Kryvokhyzha, Dmytro; Hansson, Ola] Lund Univ, Diabet Ctr, CRC, Dept Clin Sci, S-21428 Malmo, Sweden.
   [Jacob, Aishwarya; Smith, Christopher W. J.] Univ Cambridge, Dept Biochem, Cambridge, England.
   [Hansson, Ola] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.
   [Fisher, Steven A.] Univ Maryland, Dept Med Cardiol & Physiol & Biophys, Baltimore, MD 21201 USA.
C3 Guangzhou Medical University; Lund University; University of Cambridge;
   University of Helsinki; University System of Maryland; University of
   Maryland Baltimore
RP Swärd, K (corresponding author), Dept Expt Med Sci, BMC D12, SE-22184 Lund, Sweden.
EM karl.sward@med.lu.se
RI Kryvokhyzha, Dmytro/A-4755-2016; sward, karl/J-5798-2012; Hansson,
   Ola/F-1793-2011
OI Sward, Karl/0000-0002-7255-5510; Stenkula, Karin G/0000-0002-0739-1150;
   Hansson, Ola/0000-0002-7394-7639
FU Lund University; Swedish Research Council VR [2020-00908, 2018-02635];
   Heart-Lung Foundation [20200222]; Royal Physiographic Society [F
   2022/207]; NIH [R01 HL142971-A1]; VA MERIT award [BX004443]; Wellcome
   Trust [209368/Z/17/Z]; Wellcome Trust [209368/Z/17/Z] Funding Source:
   Wellcome Trust; Formas [2020-00908] Funding Source: Formas; National
   Heart Lung and Blood Institute [R01HL142971] Funding Source: NIH
   RePORTER; Swedish Heart-Lung Foundation [20200222, 20200222] Funding
   Source: Swedish Heart-Lung Foundation; Swedish Research Council
   [2018-02635, 2020-00908] Funding Source: Swedish Research Council
FX Open access funding provided by Lund University. This work was supported
   by grants from the Swedish Research Council VR (2020-00908, to KS,
   2018-02635 to OH), the Heart-Lung Foundation (20200222, to KS), the
   Royal Physiographic Society (F 2022/207, to LL), NIH (R01 HL142971-A1 to
   SF), a VA MERIT award (BX004443, to SF), and Wellcome Trust
   (209368/Z/17/Z, to CWJS).
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NR 77
TC 10
Z9 11
U1 0
U2 13
PU SPRINGER BASEL AG
PI BASEL
PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND
SN 1420-682X
EI 1420-9071
J9 CELL MOL LIFE SCI
JI Cell. Mol. Life Sci.
PD AUG
PY 2022
VL 79
IS 8
AR 459
DI 10.1007/s00018-022-04497-7
PG 21
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 3L6CW
UT WOS:000834849300002
PM 35913515
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Zhu, CQ
   Yin, ZY
   Tan, BH
   Guo, W
AF Zhu, Chaoqun
   Yin, Zhiyong
   Tan, Bihua
   Guo, Wei
TI Insulin regulates titin pre-mRNA splicing through the PI3K-Akt-mTOR
   kinase axis in a RBM20-dependent manner
SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
LA English
DT Article
DE RBM20; Titin; Insulin; PI3K/Akt/mTOR kinase axis
ID CARDIAC TITIN; GENETIC-VARIATION; PROTEIN; RBM20; PHOSPHORYLATION;
   CARDIOMYOPATHY; STIFFNESS; PATHWAY; MECHANISMS; EXPRESSION
AB Titin, a giant sarcomeric protein, is largely responsible for the diastolic properties of the heart. It has two major isoforms, N2B and N2BA due to pre-mRNA splicing regulated mainly by a splicing factor RNA binding motif 20 (RBM20). Mis-splicing of titin pre-mRNA in response to external stimuli may lead to altered ratio of N2B to N2BA, and thus, impaired cardiac contractile function. However, little is known about titin alternative splicing in response to external stimuli. Here, we reported the detailed mechanisms of titin alternative splicing in response to insulin. Insulin treatment in cultured neonatal rat cardiomyocytes (NRCMs) activated the PI3K-Aktm-TOR kinase axis, leading to increased N2B expression in the presence of RBM20, but not in NRCMs in the absence of RBM20. By inhibiting this kinase axis with inhibitors, decreased N2B isoform was observed in NRCMs and also in diabetic rat model treated with streptozotocin, but not in NRCMs and diabetic rats in the absence of RBM20. In addition to the alteration of titin isoform ratios in response to insulin, we found that RBM20 expression was increased in NRCMs with insulin treatment, suggesting that RBM20 levels were also regulated by insulin-induced kinase axis. Further, knockdown of p70S6K1 with siRNA reduced both RBM20 and N2B levels, while knockdown of 4E-BP1 elevated expression levels of RBM20 and N2B. These findings reveal a major signal transduction pathway for insulin-induced titin alternative splicing, and place RBM20 in a central position in the pathway, which is consistent with the reputed role of RBM20 in titin alternative splicing. Findings from this study shed light on gene therapeutic strategies at the molecular level by correction of pre-mRNA mis-splicing.
C1 [Zhu, Chaoqun; Yin, Zhiyong; Guo, Wei] Univ Wyoming, Anim Sci, Laramie, WY 82071 USA.
   [Guo, Wei] Univ Wyoming, Ctr Cardiovasc Res & Alternat Med, Laramie, WY 82071 USA.
   [Yin, Zhiyong] Fourth Mil Med Univ, Xi Jing Hosp, Dept Cardiol, Xian 710032, Shaanxi, Peoples R China.
   [Tan, Bihua] Penn State Univ, Coll Med, Dept Pediat, Hershey, PA 17033 USA.
C3 University of Wyoming; University of Wyoming; Air Force Medical
   University; Pennsylvania Commonwealth System of Higher Education
   (PCSHE); Pennsylvania State University; Penn State Health
RP Guo, W (corresponding author), Univ Wyoming, Anim Sci, Laramie, WY 82071 USA.
EM wguo3@uwyo.edu
RI Guo, Wei/KJM-4941-2024
OI guo, wei/0000-0002-9158-8107
FU National Institute of Health/ National Institute of General Medical
   Sciences [NIGMSP2OGM103432]; BGIA from the American Heart Association
   [16BGIA27790136]; USDA National Institute of Food and Agriculture (Hatch
   project) [1009266]; SDG from the American Heart Association
   [11SDG7470009]; American Heart Association (AHA) [11SDG7470009,
   16BGIA27790136] Funding Source: American Heart Association (AHA); NIFA
   [913202, 1009266] Funding Source: Federal RePORTER
FX This work was supported by the National Institute of Health/ National
   Institute of General Medical Sciences (NIGMSP2OGM103432); the BGIA from
   the American Heart Association (16BGIA27790136 to WG); the USDA National
   Institute of Food and Agriculture (Hatch project 1009266 to WG) and the
   SDG from the American Heart Association (11SDG7470009 to BT).
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NR 58
TC 26
Z9 33
U1 0
U2 10
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0925-4439
EI 1879-260X
J9 BBA-MOL BASIS DIS
JI Biochim. Biophys. Acta-Mol. Basis Dis.
PD SEP
PY 2017
VL 1863
IS 9
BP 2363
EP 2371
DI 10.1016/j.bbadis.2017.06.023
PG 9
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA FD6SC
UT WOS:000407657200026
PM 28676430
OA Bronze, Green Published, Green Accepted
DA 2025-04-10
ER

PT J
AU Wu, B
   Suo, FM
   Lei, WJ
   Gu, LF
AF Wu, Bin
   Suo, Fengmei
   Lei, Wanjun
   Gu, Lianfeng
TI Comprehensive Analysis of Alternative Splicing in Digitalis
   purpurea by Strand-Specific RNA-Seq
SO PLOS ONE
LA English
DT Article
ID GENE; TRANSCRIPTOME; RICE; IDENTIFICATION; ANNOTATION; ALIGNMENT;
   5-BETA-REDUCTASE; MICROARRAYS; REGULATORS; EXPRESSION
AB Digitalis purpurea (D. purpurea) is one of the most important medicinal plants and is well known in the treatment of heart failure because of the cardiac glycosides that are its main active compounds. However, in the absence of strand specific sequencing information, the post-transcriptional mechanism of gene regulation in D. purpurea thus far remains unknown. In this study, a strand-specific RNA-Seq library was constructed and sequenced using Illumina HiSeq platforms to characterize the transcriptome of D. purpurea with a focus on alternative splicing (AS) events and the effect of AS on protein domains. De novo RNA-Seq assembly resulted in 48,475 genes. Based on the assembled transcripts, we reported a list of 3,265 AS genes, including 5,408 AS events in D. purpurea. Interestingly, both glycosyltransferases and monooxygenase, which were involved in the biosynthesis of cardiac glycosides, are regulated by AS. A total of 2,422 AS events occurred in coding regions, and 959 AS events were located in the regions of 882 unique protein domains, which could affect protein function. This D. purpurea transcriptome study substantially increased the expressed sequence resource and presented a better understanding of post-transcriptional regulation to further facilitate the medicinal applications of D. purpurea for human health.
C1 [Wu, Bin; Suo, Fengmei] Peking Union Med Coll, Beijing 100021, Peoples R China.
   [Wu, Bin; Suo, Fengmei] Chinese Acad Med Sci, Ctr Bioinformat, Inst Med Plant Dev, Beijing 100730, Peoples R China.
   [Lei, Wanjun] Shanxi Agr Univ, Coll Life Sci, Taigu, Peoples R China.
   [Gu, Lianfeng] Univ Calif Riverside, Ctr Plant Cell Biol, Inst Integrat Genome Biol, Dept Bot & Plant Sci, Riverside, CA 92521 USA.
C3 Chinese Academy of Medical Sciences - Peking Union Medical College;
   Peking Union Medical College; Chinese Academy of Medical Sciences -
   Peking Union Medical College; Institute of Medicinal Plant Development -
   CAMS; Shanxi Agricultural University; University of California System;
   University of California Riverside
RP Gu, LF (corresponding author), Univ Calif Riverside, Ctr Plant Cell Biol, Inst Integrat Genome Biol, Dept Bot & Plant Sci, Riverside, CA 92521 USA.
EM lianfeng.gu@ucr.edu
FU Natural Science Foundation of China [81274015]
FX This work was supported by Natural Science Foundation of China (No.
   81274015) granted to BW. The funder had no role in study design, data
   collection and analysis, decision to publish, or preparation of the
   manuscript.
CR [Anonymous], NAT METHODS
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NR 63
TC 12
Z9 12
U1 0
U2 35
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD AUG 28
PY 2014
VL 9
IS 8
AR e106001
DI 10.1371/journal.pone.0106001
PG 8
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA AO4JP
UT WOS:000341303700061
PM 25167195
OA Green Submitted, Green Published, gold
DA 2025-04-10
ER

PT J
AU Zhang, SS
   Shaw, RM
AF Zhang, Shan-Shan
   Shaw, Robin M.
TI Multilayered regulation of cardiac ion channels
SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
LA English
DT Review
DE Connexin 43; Calcium channel; Directed targeting; Cytoskeleton; Gene
   expression
ID GAP-JUNCTION PROTEIN; TISSUE-SPECIFIC EXPRESSION; GATED CALCIUM-CHANNEL;
   TUMOR-SUPPRESSOR BIN1; HEART-FAILURE; CA2+ CHANNEL; C-TERMINUS;
   ATRIOVENTRICULAR-CONDUCTION; VENTRICULAR CONDUCTION; AMPHIPHYSIN-2 BIN1
AB Essential to beat-to-beat heart function is the ability for cardiomyocytes to propagate electrical excitation and generate contractile force. Both excitation and contractility depend on specific ventricular ion channels, which include the L-type calcium channel (LTCC) and the connexin 43 (Cx43) gap junction. Each of these two channels is localized to a distinct subdomain of the cardiomyocyte plasma membrane. In this review, we focus on regulatory mechanisms that govern the lifecycles of LTCC and Cx43, from their biogenesis in the nucleus to directed delivery to T-tubules and intercalated discs, respectively. We discuss recent findings on how alternative promoter usage, tissue-specific transcription, and alternative splicing determine precise ion channel expression levels within a cardiomyocyte. Moreover, recent work on microtubule and actin-dependent trafficking for Cx43 and LTCC are introduced. Lastly, we discuss how human cardiac disease phenotypes can be attributed to defects in distinct mechanisms of channel regulation at the level of gene expression and channel trafficking. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction. (C) 2012 Elsevier B.V. All rights reserved.
C1 [Shaw, Robin M.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA.
   Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.
C3 University of California System; University of California San Francisco;
   University of California System; University of California San Francisco
RP Shaw, RM (corresponding author), Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA.
EM shawrm@medicine.ucsf.edu
RI Zhang, shanshan/HLP-6320-2023
OI Shaw, Robin/0000-0001-7429-6092
FU NHLBI NIH HHS [R01 HL094414] Funding Source: Medline
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NR 158
TC 26
Z9 33
U1 0
U2 28
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0167-4889
EI 1879-2596
J9 BBA-MOL CELL RES
JI Biochim. Biophys. Acta-Mol. Cell Res.
PD APR
PY 2013
VL 1833
IS 4
SI SI
BP 876
EP 885
DI 10.1016/j.bbamcr.2012.10.020
PG 10
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 112KL
UT WOS:000316591000013
PM 23103513
OA Green Accepted, Bronze
DA 2025-04-10
ER

PT J
AU Morita, T
   Hayashi, K
AF Morita, Tsuyoshi
   Hayashi, Ken'ichiro
TI Regulation of Arp5 expression by alternative splicing coupled to
   nonsense-mediated RNA decay
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE Actin -related protein 5; Alternative splicing; Nonsense -mediated mRNA
   decay; Splice acceptor site
ID SITE SELECTION; MUTATIONS; NMD; SEQUENCE; REVEALS; COMPLEX; MEIS2
AB Actin-related protein 5 (ARP5) inhibits the differentiation of skeletal, smooth, and cardiac muscle tissues, and ARP5 expression increases or decreases according to physiological and pathological changes in the muscle differentiation status. However, the regulatory mechanisms of ARP5 expression are largely un-known. Here, we identified a novel Arp5 mRNA isoform that contains premature termination codons in alternative exon 7b and is thus targeted by nonsense-mediated mRNA decay (NMD). In mouse skeletal muscle cells, switching from the canonical Arp5 isoform, i.e., Arp5(7a), to the NMD-targeted isoform Arp5(7b) occurred during differentiation, suggesting that Arp5 expression is regulated by alternative splicing coupled to NMD (AS-NMD). We developed an original method to accurately quantify the pro-portion of both Arp5 isoforms and measured higher levels of Arp5(7b) in muscle and brain tissues, where ARP5 is less expressed. The 30 splice site in Arp5 exon 7 has an unusual acceptor sequence that often leads to the skip of the authentic splice site and the use of the cryptic splice site localized 16 bases down-stream. When the unusual acceptor sequence was mutated to the usual one, the Arp5(7b) isoform was barely detectable. The expression of several splicing factors involved in 30 splice site recognition was reduced after muscle differentiation. Additionally, knockdown of splicing factors increased the levels of Arp5(7b) and decreased the expression of Arp5(7a). Furthermore, strong positive correlations were found between Arp5 expression and the levels of these splicing factors in human skeletal and cardiac muscle tissues. Thus, Arp5 expression in muscle tissues is most likely regulated by the AS-NMD pathway. (c) 2023 Elsevier Inc. All rights reserved.
C1 [Morita, Tsuyoshi] Wakayama Med Univ, Dept Biol, 580 Mikazura, Wakayama 6410011, Japan.
   [Hayashi, Ken'ichiro] Yamaguchi Univ, Dept Ophthalmol, Grad Sch Med, Minami-Kogushi 1-1-1, Ube, Yamaguchi 7558505, Japan.
   [Hayashi, Ken'ichiro] Osaka Univ, Dept RNA Biol & Neurosci, Grad Sch Med, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan.
C3 Wakayama Medical University; Yamaguchi University; The University of
   Osaka
RP Morita, T (corresponding author), Wakayama Med Univ, Dept Biol, 580 Mikazura, Wakayama 6410011, Japan.
EM tsuyo@wakayama-med.ac.jp
OI Morita, Tsuyoshi/0000-0002-9022-298X
FU JSPS KAKENHI [JP15K07076, JP18K06913, JP21K06842]; Grants-in-Aid for
   Scientific Research [21K06842] Funding Source: KAKEN
FX This work was supported by JSPS KAKENHI Grant Numbers JP15K07076 (to T
   Morita) , JP18K06913 (to T Morita) , and JP21K06842 (to T Morita) .
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NR 35
TC 0
Z9 0
U1 0
U2 2
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD MAY 21
PY 2023
VL 657
BP 50
EP 58
DI 10.1016/j.bbrc.2023.03.047
EA MAR 2023
PG 9
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA D1GS7
UT WOS:000966281500001
PM 36977368
DA 2025-04-10
ER

PT J
AU Behjati, M
   Salehi, M
   Moghim, S
   Dashti, GR
AF Behjati, Mohadeseh
   Salehi, Mansoor
   Moghim, Sharareh
   Dashti, Gholam Reza
TI Evaluation of TERT mRNA alternative spliced variants in aortic
   endothelial cells of the rabbit, in the fatty streaks stage of
   atherosclerosis
SO ACTA CARDIOLOGICA
LA English
DT Article
DE atherosclerosis; telomere; telomerase; TERT; alternative splicing
ID TELOMERASE REVERSE-TRANSCRIPTASE; SENESCENCE; LENGTH; ACTIVATION;
   EXPRESSION; INDUCTION; AGE
AB Objectives-There are some lines of evidence about the role of telomeres in atherosclerotic plaque formation and development. Despite the role of telomerase in telomere elongation and protection, its role in atherosclerosis is not fully understood. The present study was designed to evaluate the importance of alternative splicing variants of TERT (telomerase reverse transcriptase) in the atherosclerosis process.
   Methods and results-Six Dutch-Polish rabbits were fed a high-cholesterol diet, and six control animals a normal diet. Alternative splicing was assessed by RT-PCR in aortic endothelial cells of these rabbits. Fatty streaks formation was assessed by H & E staining of aortic tissues. There were no significant differences in variants of TERT in control and test animals; neither in endothelial cells nor in aortic vessel wall.
   Conclusion-Our results demonstrated that a decrease in telomerase activity in atherosclerosis formation is not due to TERT gene alternative splicing.
C1 Isfahan Univ Med Sci, Dept Genet & Mol Biol, Esfahan 81744176, Iran.
   Isfahan Univ Med Sci, Dept Microbiol, Esfahan 81744176, Iran.
   Isfahan Univ Med Sci, Dept Anat Sci, Sch Med, Esfahan 81744176, Iran.
C3 Isfahan University of Medical Sciences; Isfahan University of Medical
   Sciences; Isfahan University of Medical Sciences
RP Behjati, M (corresponding author), Isfahan Univ Med Sci, Fac Med, Dept Genet, Esfahan 81744176, Iran.
EM behjati@med.mui.ac.ir
RI Salehi, Mansoor/W-1959-2017; dashti, Gholam reza/R-8062-2017; moghim,
   sharareh/V-8526-2017
OI moghim, sharareh/0000-0002-7134-3145; dashti, Gholam
   reza/0000-0002-2725-6423
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NR 34
TC 2
Z9 2
U1 0
U2 2
PU TAYLOR & FRANCIS LTD
PI ABINGDON
PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND
SN 0001-5385
EI 1784-973X
J9 ACTA CARDIOL
JI Acta Cardiol.
PD FEB
PY 2007
VL 62
IS 1
BP 7
EP 12
DI 10.2143/AC.62.1.2019364
PG 6
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 142KC
UT WOS:000244647300002
PM 17375886
DA 2025-04-10
ER

PT J
AU Guo, W
   Bharmal, SJ
   Esbona, K
   Greaser, ML
AF Guo, Wei
   Bharmal, Sheila J.
   Esbona, Karla
   Greaser, Marion L.
TI Titin Diversity-Alternative Splicing Gone Wild
SO JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY
LA English
DT Review
ID GIANT PROTEIN TITIN; CARDIAC TITIN; ISOFORM EXPRESSION; ELASTIC PROTEIN;
   M-BAND; GEL-ELECTROPHORESIS; SKELETAL-MUSCLE; CONTOUR-LENGTH; Z-LINE;
   STIFFNESS
AB Titin is an extremely large protein found in highest concentrations in heart and skeletal muscle. The single mammalian gene is expressed in multiple isoforms as a result of alternative splicing. Although titin isoform expression is controlled developmentally and in a tissue specific manner, the vast number of potential splicing pathways far exceeds those described in any other alternatively spliced gene. Over 1 million human splice pathways for a single individual can be potentially derived from the PEVK region alone. A new splicing pattern for the human cardiac N2BA isoform type has been found in which the PEVK region includes only the N2B type exons. The alterations in splicing and titin isoform expression in human heart disease provide impetus for future detailed study of the splicing mechanisms for this giant protein.
C1 [Guo, Wei; Bharmal, Sheila J.; Esbona, Karla; Greaser, Marion L.] Univ Wisconsin Madison, Muscle Biol Lab, Madison, WI 53706 USA.
C3 University of Wisconsin System; University of Wisconsin Madison
RP Greaser, ML (corresponding author), Univ Wisconsin Madison, Muscle Biol Lab, Madison, WI 53706 USA.
EM mgreaser@ansci.wisc.edu
RI Greaser, Marion/C-6147-2012; guo, wei/E-8906-2012
OI guo, wei/0000-0002-9158-8107
FU University of Wisconsin-Madison College of Agricultural and Life
   Sciences; National Institutes of Health [HL77196]
FX This work was supported by the University of Wisconsin-Madison College
   of Agricultural and Life Sciences and a grant from the National
   Institutes of Health (HL77196).
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NR 64
TC 80
Z9 101
U1 0
U2 2
PU HINDAWI LTD
PI LONDON
PA ADAM HOUSE, 3RD FLR, 1 FITZROY SQ, LONDON, W1T 5HF, ENGLAND
SN 1110-7243
EI 1110-7251
J9 J BIOMED BIOTECHNOL
JI J. Biomed. Biotechnol.
PY 2010
AR 753675
DI 10.1155/2010/753675
PG 8
WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Research & Experimental Medicine
GA 577RW
UT WOS:000276242700001
PM 20339475
OA Green Submitted, gold, Green Published
DA 2025-04-10
ER

PT J
AU Iida, K
   Hidaka, K
   Takeuchi, M
   Nakayama, M
   Yutani, C
   Mukai, T
   Morisaki, T
AF Iida, K
   Hidaka, K
   Takeuchi, M
   Nakayama, M
   Yutani, C
   Mukai, T
   Morisaki, T
TI Expression of MEF2 genes during human cardiac development
SO TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE
LA English
DT Article
DE transcription factor; alternative splicing; cardiac development;
   polymerase chain reaction
ID TRANSCRIPTION FACTOR; SKELETAL-MUSCLE; MOUSE EMBRYOGENESIS; HEART;
   MORPHOGENESIS; ISOFORMS; LINEAGES
AB To better understand the reguratory mechanisms in gene expression of human cardiomyocytes, we studied the expression of MEF2 genes encoding transcription factors during the course of cardiac development. Expression of all four MEF2 transcripts (MEF2A, MEF2B, MEF2C, and MEF2D) mere detected in all developmental stage of the human heart, while Mef2b transcripts mere down-regulated in mouse heart development. Although none of the MEF2 genes, besides mouse Mef2b, exhibited any remarkable quantitative change in their transcripts, qualitative changes in MEF2 transcripts were found during the course of cardiac development. In particular, MEF2D transcripts showed prominent changes by alternative splicing in the perinatal period. MEF2D transcripts containing the 21-base exon (exon b) were predominantly expressed after birth. At the same time, transcripts of the alpha myosin heavy chain (alpha MHC) gene increased after birth, as the splicing pattern in transcripts of the cardiac troponin T (cTnT) gene changed to decrease the transcripts of cTnT1 after birth. These changes seemed to be correlated with the alternative splicing changes of MEF2 genes, especially MEF2D. The alternative splicing as well as transcriptional regulation in MEF2 genes might be important for regulating the alpha MHC gene and the maturation of cardiomyocytes. (C) 1999 Tohoku University Medical Press.
C1 Natl Cardiovasc Ctr, Dept Biosci, Suita, Osaka 5658565, Japan.
   Natl Cardiovasc Ctr, Dept Pathol, Suita, Osaka 5658565, Japan.
   Osaka Med Ctr Maternal & Childrens Hlth, Dept Pathol, Izumi, Osaka 5941101, Japan.
C3 National Cerebral & Cardiovascular Center - Japan; National Cerebral &
   Cardiovascular Center - Japan
RP Morisaki, T (corresponding author), Natl Cardiovasc Ctr, Res Inst, Dept Biosci, 5-7-1 Fujishirodai, Osaka 5658665, Japan.
EM morisaki@ri.ncvc.go.jp
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NR 15
TC 25
Z9 37
U1 0
U2 5
PU TOHOKU UNIV MEDICAL PRESS
PI SENDAI
PA 2-1, SEIRYO-MACHI, AOBA-KU, SENDAI, MIYAGI 980-8575, JAPAN
SN 0040-8727
EI 1349-3329
J9 TOHOKU J EXP MED
JI Tohoku J. Exp. Med.
PD JAN
PY 1999
VL 187
IS 1
BP 15
EP 23
DI 10.1620/tjem.187.15
PG 9
WC Medicine, General & Internal; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC General & Internal Medicine; Research & Experimental Medicine
GA 178GH
UT WOS:000079257500002
PM 10458488
OA Bronze
DA 2025-04-10
ER

PT J
AU Nishiyama, T
   Zhang, Y
   Cui, M
   Li, H
   Sanchez-Ortiz, E
   McAnally, JR
   Tan, W
   Kim, J
   Chen, KN
   Xu, L
   Bassel-Duby, R
   Olson, EN
AF Nishiyama, Takahiko
   Zhang, Yu
   Cui, Miao
   Li, Hui
   Sanchez-Ortiz, Efrain
   McAnally, John R.
   Tan, Wei
   Kim, Jiwoong
   Chen, Kenian
   Xu, Lin
   Bassel-Duby, Rhonda
   Olson, Eric N.
TI Precise genomic editing of pathogenic mutations in RBM20 rescues
   dilated cardiomyopathy
SO SCIENCE TRANSLATIONAL MEDICINE
LA English
DT Article
ID DIFFERENTIAL EXPRESSION ANALYSIS; GENE; DNA; TITIN
AB Mutations in RNA binding motif protein 20 (RBM20) are a common cause of familial dilated cardiomyopathy (DCM). Many RBM20 mutations cluster within an arginine/serine-rich (RS-rich) domain, which mediates nuclear localization. These mutations induce RBM20 mis-localization to form aberrant ribonucleoprotein (RNP) granules in the cytoplasm of cardiomyocytes and abnormal alternative splicing of cardiac genes, contributing to DCM. We used adenine base editing (ABE) and prime editing (PE) to correct pathogenic p.R634Q and p.R636S mutations in the RS-rich domain in human isogenic induced pluripotent stem cell (iPSC)-derived cardiomyocytes. Using ABE to correct RBM20(R634Q) human iPSCs, we achieved 92% efficiency of A-to-G editing, which normalized alternative splicing of cardiac genes, restored nuclear localization of RBM20, and eliminated RNP granule formation. In addition, we developed a PE strategy to correct the RBM20(R6365) mutation in iPSCs and observed A-to-C editing at 40% efficiency. To evaluate the potential of ABE for DCM treatment, we also created RBM20(R634Q) mutant mice. Homozygous (R636Q/R636Q) mice developed severe cardiac dysfunction, heart failure, and premature death. Systemic delivery of ABE components containing ABEmax-VRQR-SpCas9 and single-guide RNA by adeno-associated virus serotype 9 in these mice restored cardiac function as assessed by echocardiography and extended life span. As seen by RNA sequencing analysis, ABE correction rescued the cardiac transcriptional profile of treated R636Q/R636Q mice, compared to the abnormal gene expression seen in untreated mice. These findings demonstrate the potential of precise correction of genetic mutations as a promising therapeutic approach for DCM.
C1 [Nishiyama, Takahiko; Zhang, Yu; Cui, Miao; Li, Hui; Sanchez-Ortiz, Efrain; McAnally, John R.; Tan, Wei; Bassel-Duby, Rhonda; Olson, Eric N.] Univ Texas Southwestern Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA.
   [Nishiyama, Takahiko; Zhang, Yu; Cui, Miao; Li, Hui; Sanchez-Ortiz, Efrain; McAnally, John R.; Tan, Wei; Bassel-Duby, Rhonda; Olson, Eric N.] Univ Texas Southwestern Med Ctr Dallas, Senator Paul Wellstone Muscular Dystrophy Special, Dallas, TX 75390 USA.
   [Nishiyama, Takahiko; Zhang, Yu; Cui, Miao; Li, Hui; Sanchez-Ortiz, Efrain; McAnally, John R.; Tan, Wei; Bassel-Duby, Rhonda; Olson, Eric N.] Univ Texas Southwestern Med Ctr Dallas, Hamon Ctr Regenerat Sci & Med, Dallas, TX 75390 USA.
   [Kim, Jiwoong; Chen, Kenian; Xu, Lin] Univ Texas Southwestern Med Ctr Dallas, Quantitat Biomed Res Ctr, Dept Populat & Data Sci, Dallas, TX 75390 USA.
C3 University of Texas System; University of Texas Southwestern Medical
   Center Dallas; University of Texas System; University of Texas
   Southwestern Medical Center Dallas; University of Texas System;
   University of Texas Southwestern Medical Center Dallas; University of
   Texas System; University of Texas Southwestern Medical Center Dallas
RP Olson, EN (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA.; Olson, EN (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Senator Paul Wellstone Muscular Dystrophy Special, Dallas, TX 75390 USA.; Olson, EN (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Hamon Ctr Regenerat Sci & Med, Dallas, TX 75390 USA.
EM eric.olson@utsouthwestern.edu
RI Bassel-Duby, Rhonda/HJP-5742-2023; Olson, Eric/B-4391-2013; Wang,
   Zhaoning/AAB-5893-2021; Kim, Young/H-4235-2013; LI, HUI/G-1227-2011;
   Tan, Wei/KBB-7333-2024
OI Zhang, Yu/0000-0003-3384-8887; mcanally, john/0000-0001-6938-2703;
   Olson, Eric N./0000-0003-1151-8262; Xu, Lin/0000-0001-5815-4457; Li,
   Hui/0000-0002-4114-8349; Nishiyama, Takahiko/0000-0002-2352-5606;
   Bassel-Duby, Rhonda/0000-0001-7568-410X
FU NIH [R01HL130253, P50HD087351, R01HL157281]; Foundation Leducq
   Transatlantic Network of Excellence; Uehara Memorial Foundation; Japan
   Heart Foundation/Bayer Yakuhin Research Grant Abroad Fellowship;
   National Heart Lung and Blood Institute [K99HL153683] Funding Source:
   NIH RePORTER; National Heart Lung and Blood Institute; Eunice Kennedy
   Shriver National Institute of Child Health and Human Development
   [P50HD087351] Funding Source: NIH RePORTER
FX This work was supported by NIH grants R01HL130253, P50HD087351, and
   R01HL157281 to E.N.O. and R.B.-D., Foundation Leducq Transatlantic
   Network of Excellence to E.N.O., Uehara Memorial Foundation Postdoctoral
   Fellowship to T.N., and Japan Heart Foundation/Bayer Yakuhin Research
   Grant Abroad Fellowship to T.N.
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NR 64
TC 81
Z9 85
U1 2
U2 20
PU AMER ASSOC ADVANCEMENT SCIENCE
PI WASHINGTON
PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA
SN 1946-6234
EI 1946-6242
J9 SCI TRANSL MED
JI Sci. Transl. Med.
PD NOV 23
PY 2022
VL 14
IS 672
AR eade1633
DI 10.1126/scitranslmed.ade1633
PG 15
WC Cell Biology; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Research & Experimental Medicine
GA 6R5TM
UT WOS:000892365400006
PM 36417486
DA 2025-04-10
ER

PT J
AU Ohsawa, N
   Koebis, M
   Suo, S
   Nishino, I
   Ishiura, S
AF Ohsawa, Natsumi
   Koebis, Michinori
   Suo, Satoshi
   Nishino, Ichizo
   Ishiura, Shoichi
TI Alternative splicing of PDLIM3/ALP, for α-actinin-associated LIM
   protein 3, is aberrant in persons with myotonic dystrophy
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE Actinin-associated LIM protein 3 (PDLIM3/ALP); Alternative splicing;
   MBNL; Myotonic dystrophy; Sarcoplasmic/endoplasmic reticulum Ca-ATPase 1
   (SERCA1); ZASP-like motif
ID SKELETAL-MUSCLE; MESSENGER-RNA; Z-LINE; DILATED CARDIOMYOPATHY; CA-2+
   ATPASE; Z-DISC; RECEPTOR; REPEAT; DOMAIN; MUTATIONS
AB Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder of muscular dystrophy characterized by muscle weakness and wasting. DM1 is caused by expansion of CTG repeats in the 3'-untranslated region (3'-UTR) of DM protein kinase (DMPK) gene. Since CUG-repeat RNA transcribed from the expansion of CTG repeats traps RNA-binding proteins that regulate alternative splicing, several abnormalities of alternative splicing are detected in DM1, and the abnormal splicing of important genes results in the appearance of symptoms. In this study, we identify two abnormal splicing events for actinin-associated LIM protein 3 (PDLIM3/ALP) and fibronectin 1 (FN1) in the skeletal muscles of DM1 patients. From the analysis of the abnormal PDLIM3 splicing, we propose that ZASP-like motif-deficient PDLIM3 causes the muscular symptoms in DM. PDLIM3 binds alpha-actinin 2 in the Z-discs of muscle, and the ZASP-like motif is needed for this interaction. Moreover, in adult humans, PDLIM3 expression is highest in skeletal muscles, and PDLIM3 splicing in skeletal muscles is regulated during human development. (C) 2011 Elsevier Inc. All rights reserved.
C1 [Ohsawa, Natsumi; Koebis, Michinori; Suo, Satoshi; Ishiura, Shoichi] Univ Tokyo, Grad Sch Arts & Sci, Dept Life Sci, Meguro Ku, Tokyo 1538902, Japan.
   [Nishino, Ichizo] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Kodaira, Tokyo 1878502, Japan.
C3 University of Tokyo; National Center for Neurology & Psychiatry - Japan
RP Ishiura, S (corresponding author), Univ Tokyo, Grad Sch Arts & Sci, Dept Life Sci, Meguro Ku, 3-8-1 Komaba, Tokyo 1538902, Japan.
EM cishiura@mail.ecc.u-tokyo.ac.jp
RI Nishino, Ichizo/G-2676-2010
OI Nishino, Ichizo/0000-0001-9452-112X
FU NCNP, Ministry of Health, Labor and Welfare, Japan [20B-13];
   Grants-in-Aid for Scientific Research [23700439] Funding Source: KAKEN
FX We would like to thank Dr. Noboru Sasagawa and Yoko Oma, Ms. Tamami
   Kiyatake, Zhao Yimeng, Mr. Kosuke Oana for valuable discussions. This
   work was supported in part by an intramural research grant (20B-13) for
   Neurological and Psychiatric Disorders from the NCNP, Ministry of
   Health, Labor and Welfare, Japan.
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NR 37
TC 28
Z9 31
U1 0
U2 13
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD MAY 27
PY 2011
VL 409
IS 1
BP 64
EP 69
DI 10.1016/j.bbrc.2011.04.106
PG 6
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA 774IY
UT WOS:000291380100011
PM 21549096
DA 2025-04-10
ER

PT J
AU Lira, ME
   Loomis, AK
   Paciga, SA
   Lloyd, DB
   Thompson, JF
AF Lira, Maruja E.
   Loomis, A. Katrina
   Paciga, Sara A.
   Lloyd, David B.
   Thompson, John F.
TI Expression of CETP and of splice variants induces the same level of ER
   stress despite secretion efficiency differences
SO JOURNAL OF LIPID RESEARCH
LA English
DT Article
DE HDL-cholesterol; atherosclerosis; Alu sequence; endoplasmic reticulum;
   cholesteryl ester transfer protein
ID ESTER TRANSFER PROTEIN; ENDOPLASMIC-RETICULUM STRESS; INSULIN-RESISTANCE
   SYNDROME; HDL-CHOLESTEROL LEVELS; MESSENGER-RNA; ADIPOSE-TISSUE; TAQIB
   POLYMORPHISM; GENE; INHIBITION; DISEASE
AB The cholesteryl ester transfer protein (CETP) gene has been associated with a variety of phenotypes, including HDL-cholesterol levels and, more sporadically, with cardiovascular disease, obesity, and extreme longevity. Alterations of CETP activity levels can be caused by single-base polymorphisms as well as by alternative splicing. In addition to the previously characterized alternative splicing that skips exon 9, we found additional minor variants and characterized the activity of the resultant proteins. The novel variants skipped exon 9 sequences and inserted one of two in-frame exons from Alu-derived intronic sequences. None of the alternatively spliced variants are efficiently secreted, and co-expression of them inhibits wild-type CETP secretion. Expression of the alternative spliced variants causes an induction of genes linked to the endoplasmic reticulum (ER) stress response, including the neighboring HERPUD1 (homocysteine- and ER stress-inducible protein, ubiquitin- like domain-containing) gene. Unexpectedly, even though wild-type CETP is secreted much more efficiently than spliced variants, it induces the same degree of stress response as spliced variants, whereas a control secreted protein does not. CETP plays a complex role in modulating ER stress, with its expression inducing the response and its cholesteryl ester transfer activity and differential splicing modulating the response in other ways.-Lira, M. E., A. K. Loomis, S. A. Paciga, D. B. Lloyd, and J. F. Thompson. Expression of CETP and of splice variants induces the same level of ER stress despite secretion efficiency differences.
C1 [Lira, Maruja E.; Loomis, A. Katrina; Paciga, Sara A.; Lloyd, David B.; Thompson, John F.] Pfizer Global Res & Dev, Mol Med, Groton, CT 06340 USA.
C3 Pfizer; Pfizer USA
RP Lira, ME (corresponding author), Pfizer Global Res & Dev, Mol Med, Groton, CT 06340 USA.
EM jthompson@helicosbio.com
OI Thompson, John/0000-0001-8568-3311
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NR 31
TC 19
Z9 20
U1 0
U2 5
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0022-2275
EI 1539-7262
J9 J LIPID RES
JI J. Lipid Res.
PD SEP
PY 2008
VL 49
IS 9
BP 1955
EP 1962
DI 10.1194/jlr.M800078-JLR200
PG 8
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 337YX
UT WOS:000258472500011
PM 18509195
OA hybrid
DA 2025-04-10
ER

PT J
AU Veikkolainen, V
   Vaparanta, K
   Halkilahti, K
   Iljin, K
   Sundvall, M
   Elenius, K
AF Veikkolainen, Ville
   Vaparanta, Katri
   Halkilahti, Kalle
   Iljin, Kristiina
   Sundvall, Maria
   Elenius, Klaus
TI Function of ERBB4 is determined by alternative splicing
SO CELL CYCLE
LA English
DT Article
DE EGFR; HER4; isoforms; alternative splicing; cancer; non-neoplastic
   diseases
ID EPIDERMAL-GROWTH-FACTOR; RECEPTOR TYROSINE KINASE; BREAST-CANCER CELLS;
   INTRACELLULAR DOMAIN 4ICD; DEPENDENT GAMMA-SECRETASE; ESTROGEN-RECEPTOR;
   IN-VIVO; CHILDHOOD MEDULLOBLASTOMA; DIFFERENTIAL EXPRESSION;
   NUCLEAR-LOCALIZATION
AB Alternative splicing is a central tool of evolution that significantly increases the size of transcriptomes and generates functional specification. Within the human ERBB receptor gene family, only ERBB4 is known to produce functionally distinct isoforms as a result of alternative splicing. While ErbB4 signaling has been demonstrated to regulate cellular processes involved in embryogenesis, carcinogenesis, and cardiovascular and psychiatric diseases, relatively little is known about the contribution of the individual isoforms in the different biological contexts. Here we review recent findings as well as provide novel data about the distribution and functions of the ERBB4 splice variants. These observations represent an example of how minor alterations in the transcripts of a single gene can result in even antagonistic cellular responses. The observations also underline the significance of understanding the unique functions of isoforms of a potential drug target gene.
C1 [Veikkolainen, Ville; Vaparanta, Katri; Halkilahti, Kalle; Sundvall, Maria; Elenius, Klaus] Univ Turku, Dept Med Biochem & Genet, Turku, Finland.
   [Veikkolainen, Ville; Vaparanta, Katri; Halkilahti, Kalle; Sundvall, Maria; Elenius, Klaus] Univ Turku, MediCity Res Lab, Turku, Finland.
   [Veikkolainen, Ville] Turku Grad Sch Biomed Sci, Turku, Finland.
   [Iljin, Kristiina] VTT Tech Res Ctr, Turku, Finland.
   [Sundvall, Maria; Elenius, Klaus] Turku Univ Hosp, Dept Oncol, FIN-20520 Turku, Finland.
C3 University of Turku; University of Turku; University of Turku; VTT
   Technical Research Center Finland; University of Turku
RP Elenius, K (corresponding author), Univ Turku, Dept Med Biochem & Genet, Turku, Finland.
EM klaus.elenius@utu.fi
RI Elenius, Klaus/AAI-7594-2021
OI Sundvall, Maria H/0000-0002-0494-2965; Vaparanta,
   Katri/0000-0002-3574-4427; Iljin, Kristiina/0000-0002-5161-0584;
   Elenius, Klaus/0000-0001-5700-0827
FU Academy of Finland; Finnish Cancer Organizations; Foundation for the
   Finnish Cancer Institute; Sigrid Juselius Foundation; Turku University
   Foundation
FX The authors wish to thank Juha Harju for help with the graphics and
   Maria Tuominen for technical assistance. This work has been supported by
   the Academy of Finland, Finnish Cancer Organizations, Foundation for the
   Finnish Cancer Institute, Sigrid Juselius Foundation and Turku
   University Foundation.
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NR 92
TC 86
Z9 99
U1 0
U2 10
PU LANDES BIOSCIENCE
PI AUSTIN
PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA
SN 1538-4101
J9 CELL CYCLE
JI Cell Cycle
PD AUG 15
PY 2011
VL 10
IS 16
BP 2647
EP 2657
DI 10.4161/cc.10.16.17194
PG 11
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 810VK
UT WOS:000294155600019
PM 21811097
OA Bronze
DA 2025-04-10
ER

PT J
AU Dichmann, DS
   Walentek, P
   Harland, RM
AF Dichmann, Darwin S.
   Walentek, Peter
   Harland, Richard M.
TI The Alternative Splicing Regulator Tra2b Is Required for Somitogenesis
   and Regulates Splicing of an Inhibitory Wnt11b Isoform
SO CELL REPORTS
LA English
DT Article
ID EXPRESSION CLONING; EARLY RESPONSE; XENOPUS; RNA; GENE; MESODERM;
   MOVEMENTS; EMBRYOGENESIS; MORPHOGENESIS; MECHANISMS
AB Alternative splicing is pervasive in vertebrates, yet little is known about most isoforms or their regulation. transformer-2b (tra2b) encodes a splicing regulator whose endogenous function is poorly understood. Tra2b knockdown in Xenopus results in embryos with multiple defects, including defective somitogenesis. Using RNA sequencing, we identify 142 splice changes (mostly intron retention and exon skipping), 89% of which are not in current annotations. A previously undescribed isoform of wnt11b retains the last intron, resulting in a truncated ligand (Wnt11b-short). We show that this isoform acts as a dominant-negative ligand in cardiac gene induction and pronephric tubule formation. To determine the contribution of Wnt11b-short to the tra2b phenotype, we induce retention of intron 4 in wnt11b, which recapitulates the failure to form somites but not other tra2b morphant defects. This alternative splicing of a Wnt ligand adds intricacy to a complex signaling pathway and highlights intron retention as a regulatory mechanism.
C1 [Dichmann, Darwin S.; Walentek, Peter; Harland, Richard M.] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA.
C3 University of California System; University of California Berkeley
RP Dichmann, DS (corresponding author), Univ Calif Berkeley, Dept Mol & Cell Biol, 142 Life Sci Addit 3200, Berkeley, CA 94720 USA.
EM dichmann@berkeley.edu; harland@berkeley.edu
RI Harland, Richard/ABA-9900-2022
OI Walentek, Peter/0000-0002-2332-6068
FU NIH [GM42341, GM086321]; Deutsche Forschungsgemeinschaft [WA 3365/1-1]
FX We thank Sang-Wook Cha from the Heasman/Wylie lab for the HA-tagged
   wnt11b plasmid, and Masazumi Tada for the wnt11b-dn plasmid. We thank
   Professor Don Rio and members of the Harland lab for fruitful
   discussions. This work was funded by NIH grants GM42341 and GM086321 to
   R.M.H. P.W. is supported by a fellowship from the Deutsche
   Forschungsgemeinschaft (WA 3365/1-1).
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PU CELL PRESS
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PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
SN 2211-1247
J9 CELL REP
JI Cell Reports
PD FEB 3
PY 2015
VL 10
IS 4
BP 527
EP 536
DI 10.1016/j.celrep.2014.12.046
PG 10
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA CB1QX
UT WOS:000349404100008
PM 25620705
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Watanabe, T
   Kimura, A
   Kuroyanagi, H
AF Watanabe, Takeshi
   Kimura, Akinori
   Kuroyanagi, Hidehito
TI Alternative Splicing Regulator RBM20 and Cardiomyopathy
SO FRONTIERS IN MOLECULAR BIOSCIENCES
LA English
DT Review
DE RBM20; dilated cardiomyopathy (DCM); alternative splicing; isoform
   switching; mutation; arginine/serine (RS)-rich region; titin; nuclear
   localization
ID FAMILIAL DILATED CARDIOMYOPATHY; TITIN ISOFORM EXPRESSION; HYPERTROPHIC
   CARDIOMYOPATHY; DIASTOLIC DYSFUNCTION; PASSIVE STIFFNESS;
   GENE-EXPRESSION; MOUSE MODEL; PROTEIN; MUTATIONS; PHOSPHORYLATION
AB RBM20 is a vertebrate-specific RNA-binding protein with two zinc finger (ZnF) domains, one RNA-recognition motif (RRM)-type RNA-binding domain and an arginine/serine (RS)-rich region. RBM20 has initially been identified as one of dilated cardiomyopathy (DCM)-linked genes. RBM20 is a regulator of heart-specific alternative splicing and Rbm20(Delta RRM) mice lacking the RRM domain are defective in the splicing regulation. The Rbm20(Delta RRM) mice, however, do not exhibit a characteristic DCM-like phenotype such as dilatation of left ventricles or systolic dysfunction. Considering that most of the RBM20 mutations identified in familial DCM cases were heterozygous missense mutations in an arginine-serine-arginine-serine-proline (RSRSP) stretch whose phosphorylation is crucial for nuclear localization of RBM20, characterization of a knock-in animal model is awaited. One of the major targets for RBM20 is the TTN gene, which is comprised of the largest number of exons in mammals. Alternative splicing of the TTN gene is exceptionally complicated and RBM20 represses > 160 of its consecutive exons, yet detailed mechanisms for such extraordinary regulation are to be elucidated. The TTN gene encodes the largest known protein titin, a multi-functional sarcomeric structural protein specific to striated muscles. As titin is the most important factor for passive tension of cardiomyocytes, extensive heart-specific and developmentally regulated alternative splicing of the TTN pre-mRNA by RBM20 plays a critical role in passive stiffness and diastolic function of the heart. In disease models with diastolic dysfunctions, the phenotypes were rescued by increasing titin compliance through manipulation of the Ttn pre-mRNA splicing, raising RBM20 as a potential therapeutic target.
C1 [Watanabe, Takeshi; Kuroyanagi, Hidehito] TMDU, Med Res Inst, Lab Gene Express, Tokyo, Japan.
   [Watanabe, Takeshi] TMDU, Grad Sch Med & Dent Sci, Dept Psychosomat Dent, Tokyo, Japan.
   [Kimura, Akinori] TMDU, Med Res Inst, Div Pathol, Dept Mol Pathogenesis, Tokyo, Japan.
   [Kimura, Akinori; Kuroyanagi, Hidehito] TMDU, Med Res Inst, Lab Integrated Res Projects Intractable Dis Adv T, Tokyo, Japan.
   [Kuroyanagi, Hidehito] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA.
C3 Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU);
   Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU);
   Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU);
   Institute of Science Tokyo; Tokyo Medical & Dental University (TMDU);
   University of California System; University of California Los Angeles
RP Kuroyanagi, H (corresponding author), TMDU, Med Res Inst, Lab Gene Express, Tokyo, Japan.; Kuroyanagi, H (corresponding author), TMDU, Med Res Inst, Lab Integrated Res Projects Intractable Dis Adv T, Tokyo, Japan.; Kuroyanagi, H (corresponding author), Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA.
EM kuroyana.end@tmd.ac.jp
RI Kimura, Akinori/I-5989-2018; Watanabe, Takeshi/AHA-0210-2022
OI Watanabe, Takeshi/0000-0002-4532-0556
FU Japan Society for the Promotion of Science (JSPS) [JP15H01350,
   JP17H05596, JP17H03633, JP15KK0252]; Takeda Science Foundation
FX The study leading to this article was supported by Grants-in-Aid for
   Scientific Research (KAKENHI, GrantNumbers JP15H01350, JP17H05596,
   JP17H03633, and JP15KK0252) from Japan Society for the Promotion of
   Science (JSPS) (to HK) and a grant from Takeda Science Foundation (to
   HK).
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NR 82
TC 45
Z9 50
U1 1
U2 10
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
EI 2296-889X
J9 FRONT MOL BIOSCI
JI Front. Mol. Biosci.
PD NOV 28
PY 2018
VL 5
AR 105
DI 10.3389/fmolb.2018.00105
PG 11
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA HG8XY
UT WOS:000455291400002
PM 30547036
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Elrick, LL
   Humphrey, MB
   Cooper, TA
   Berget, SM
AF Elrick, LL
   Humphrey, MB
   Cooper, TA
   Berget, SM
TI A short sequence within two purine-rich enhancers determines 5′ splice
   site specificity
SO MOLECULAR AND CELLULAR BIOLOGY
LA English
DT Article
ID PRE-MESSENGER-RNA; T ALTERNATIVE EXON; IMMUNODEFICIENCY-VIRUS TYPE-1;
   SR-PROTEINS; U1 SNRNP; IN-VIVO; ELEMENTS; INTRON; GENE; IDENTIFICATION
AB Purine-rich enhancers are exon sequences that promote inclusion of alternative exons, usually via activation of weak upstream 3' splice sites, A recently described purine-rich enhancer from the caldesmon gene has an additional activity by which it directs selection of competing 5' splice sites within an alternative exon, In this study, we have compared the caldesmon enhancer with another purine-rich enhancer from the chicken cardiac troponin T (cTNT) gene for the ability to regulate flanking splice sites, Although similar in sequence and length, the two enhancers demonstrated strikingly different specificities towards 5' splice site choice when placed between competing 5' splice sites in an internal exon, The 32-nucleotide caldesmon enhancer caused effective usage of the exon-internal 5' splice site, whereas the 30-nucleotide cTNT enhancer caused effective usage of the exon-terminal 5' splice site, Both enhancer-mediated splicing pathways represented modulation of the default pathway in which both 5' splice sites were utilized, Each enhancer is multipartite, consisting of two purine-rich sequences of a simple (GAR)(n) repeat interdigitated with two enhancer-specific sequences, The entire enhancer was necessary for maximal splice site selectivity; however, a 5- to 7-nucleotide region from the 3' end of each enhancer dictated splice site selectivity. Mutations that interchanged this short region of the two enhancers switched specificity. The portion of the cTNT enhancer determinative for 5' splice site selectivity was different than that shown to be maximally important for activation of a 3' splice site, suggesting that enhancer environment can have a major impact on activity, These results are the first indication that individual purine-rich enhancers can differentiate between flanking splice sites, Furthermore, localization of the specificity of splice site choice to a short region within both enhancers indicates that subtle differences in enhancer sequence can have profound effects on the splicing pathway.
C1 Baylor Coll Med, Verna & Marrs Mclean Dept Biochem, Houston, TX 77030 USA.
   Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Baylor College of Medicine
RP Berget, SM (corresponding author), Baylor Coll Med, Verna & Marrs Mclean Dept Biochem, 1 Baylor Plaza, Houston, TX 77030 USA.
RI HUMPHREY, MARY/AFP-3536-2022
FU NIGMS NIH HHS [GM38526, R01 GM038526] Funding Source: Medline
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NR 43
TC 38
Z9 39
U1 0
U2 1
PU AMER SOC MICROBIOLOGY
PI WASHINGTON
PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA
SN 0270-7306
J9 MOL CELL BIOL
JI Mol. Cell. Biol.
PD JAN
PY 1998
VL 18
IS 1
BP 343
EP 352
DI 10.1128/MCB.18.1.343
PG 10
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA YN687
UT WOS:000071195700035
PM 9418881
OA Green Published
DA 2025-04-10
ER

PT J
AU Louadi, Z
   Elkjaer, ML
   Klug, M
   Lio, CT
   Fenn, A
   Illes, Z
   Bongiovanni, D
   Baumbach, J
   Kacprowski, T
   List, M
   Tsoy, O
AF Louadi, Zakaria
   Elkjaer, Maria L.
   Klug, Melissa
   Lio, Chit Tong
   Fenn, Amit
   Illes, Zsolt
   Bongiovanni, Dario
   Baumbach, Jan
   Kacprowski, Tim
   List, Markus
   Tsoy, Olga
TI Functional enrichment of alternative splicing events with NEASE reveals
   insights into tissue identity and diseases
SO GENOME BIOLOGY
LA English
DT Article
DE Alternative splicing; Differential splicing; Functional enrichment;
   Systems biology; Protein-protein interactions; Disease pathways;
   Platelet activation; Multiple sclerosis; Dilated cardiomyopathy
ID MULTIPLE-SCLEROSIS; RETICULATED PLATELETS; PROTEIN-KINASE; RYANODINE
   RECEPTORS; SUBUNIT A1; IN-VITRO; GENE; CARDIOMYOPATHY; ACTIVATION;
   EXPRESSION
AB Alternative splicing (AS) is an important aspect of gene regulation. Nevertheless, its role in molecular processes and pathobiology is far from understood. A roadblock is that tools for the functional analysis of AS-set events are lacking. To mitigate this, we developed NEASE, a tool integrating pathways with structural annotations of protein-protein interactions to functionally characterize AS events. We show in four application cases how NEASE can identify pathways contributing to tissue identity and cell type development, and how it highlights splicing-related biomarkers. With a unique view on AS, NEASE generates unique and meaningful biological insights complementary to classical pathways analysis.
C1 [Louadi, Zakaria; Klug, Melissa; Lio, Chit Tong; Fenn, Amit; List, Markus] Tech Univ Munich, TUM Sch Life Sci, Chair Expt Bioinformat, D-85354 Freising Weihenstephan, Germany.
   [Louadi, Zakaria; Lio, Chit Tong; Fenn, Amit; Baumbach, Jan; Tsoy, Olga] Univ Hamburg, Inst Computat Syst Biol, Notkestr 9, D-22607 Hamburg, Germany.
   [Elkjaer, Maria L.; Illes, Zsolt] Odense Univ Hosp, Dept Neurol, Odense, Denmark.
   [Elkjaer, Maria L.; Illes, Zsolt] Univ Southern Denmark, Inst Clin Res, Odense, Denmark.
   [Elkjaer, Maria L.; Illes, Zsolt] Univ Southern Denmark, Inst Mol Med, Odense, Denmark.
   [Klug, Melissa; Bongiovanni, Dario] Tech Univ Munich, Univ Hosp Rechts Isar, Sch Med, Dept Internal Med 1, Munich, Germany.
   [Klug, Melissa; Bongiovanni, Dario] German Ctr Cardiovasc Res DZHK, Munich Heart Alliance, Partner Site, Munich, Germany.
   [Bongiovanni, Dario] Humanitas Clin & Res Ctr IRCCS, Dept Cardiovasc Med, Milan, Italy.
   [Bongiovanni, Dario] Humanitas Univ, Milan, Italy.
   [Baumbach, Jan] Univ Southern Denmark, Inst Math & Comp Sci, Campusvej 55, DK-5000 Odense, Denmark.
   [Kacprowski, Tim] Tech Univ Carolo Wilhelmina Braunschweig, Peter L Reicheriz Inst Med Informat, Div Data Sci Biomed, Braunschweig, Germany.
   [Kacprowski, Tim] Hannover Med Sch, Braunschweig, Germany.
   [Kacprowski, Tim] TU Braunschweig, Braunschweig Integrated Ctr Syst Biol BRICS, Braunschweig, Germany.
C3 Technical University of Munich; University of Hamburg; University of
   Southern Denmark; Odense University Hospital; University of Southern
   Denmark; University of Southern Denmark; Technical University of Munich;
   Munich Heart Alliance; German Centre for Cardiovascular Research;
   Humanitas University; University of Southern Denmark; Braunschweig
   University of Technology; Hannover Medical School; Braunschweig
   University of Technology
RP List, M (corresponding author), Tech Univ Munich, TUM Sch Life Sci, Chair Expt Bioinformat, D-85354 Freising Weihenstephan, Germany.; Tsoy, O (corresponding author), Univ Hamburg, Inst Computat Syst Biol, Notkestr 9, D-22607 Hamburg, Germany.
EM markus.list@wzw.tum.de; olga.tsoy@uni-hamburg.de
RI Lio, Chit Tong/JVN-3919-2024; Elkjaer, Maria/AFV-8250-2022; List,
   Markus/I-2020-2019; Baumbach, Jörg/E-3725-2014; Kacprowski,
   Tim/N-9692-2019; Louadi, Zakaria/AAC-1456-2021; Bongiovanni,
   Dario/AAB-9161-2021
OI Elkjaer, Maria Louise/0000-0002-8596-142X; Illes,
   Zsolt/0000-0001-9655-0450; Louadi, Zakaria/0000-0003-4763-0264;
   Bongiovanni, Dario/0000-0002-4162-1482; Baumbach,
   Jan/0000-0002-0282-0462; Klug, Melissa E./0000-0001-5193-2770; List,
   Markus/0000-0002-0941-4168; Lio, Chit Tong/0000-0003-2297-831X
FU German Federal Ministry of Education and Research (BMBF) [01ZX1908A];
   VILLUM Young Investigator Grant [13154]; Lundbeckfonden
   [R347-2020-2454]; Scleroseforeningen [A29926, A 31829, A33600]; Projekt
   DEAL
FX This work was supported by the German Federal Ministry of Education and
   Research (BMBF) within the framework of the e:Med research and funding
   concept [grant 01ZX1908A (Sys_CARE)]. JB was partially funded by his
   VILLUM Young Investigator Grant (nr.13154). MLE is grateful for
   financial support from Lundbeckfonden (no. R347-2020-2454). ZI is
   grateful for financial support from Scleroseforeningen (no. A29926, A
   31829, A33600). Open Access funding enabled and organized by Projekt
   DEAL.
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NR 123
TC 11
Z9 12
U1 0
U2 6
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1474-760X
J9 GENOME BIOL
JI Genome Biol.
PD DEC 2
PY 2021
VL 22
IS 1
AR 327
DI 10.1186/s13059-021-02538-1
PG 22
WC Biotechnology & Applied Microbiology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Genetics & Heredity
GA XH6LA
UT WOS:000725542400002
PM 34857024
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Dai, A
   Temporal, S
   Schulz, DJ
AF Dai, A.
   Temporal, S.
   Schulz, D. J.
TI CELL-SPECIFIC PATTERNS OF ALTERNATIVE SPLICING OF VOLTAGE-GATED ION
   CHANNELS IN SINGLE IDENTIFIED NEURONS
SO NEUROSCIENCE
LA English
DT Article
DE stomatogastric; sodium channel; HCN channel; plasticity; variability
ID I-H-CHANNEL; SODIUM-CHANNEL; FUNCTIONAL-CHARACTERIZATION; STOMATOGASTRIC
   GANGLION; NA+ CHANNELS; EXPRESSION; GENE; CURRENTS; VARIANTS; CRAB
AB CbNav, and CbIH encode channels that carry voltage-gated sodium and hyperpolarization activated cation currents respectively in the crab, Cancer borealis. We cloned and sequenced full length cDNAs for both CbNav and CbIH and found nine different regions of alternative splicing for the CbNav gene and four regions of alternative splicing for CbIH. We used RT-PCR to determine tissue-specific differences in splicing of both channel genes among cardiac muscle, skeletal muscle, brain, and stomatogastric ganglion (STG) tissue. We then examined the splice variant isoforms present in single, unambiguously identified neurons of the STG. We found cell-type specific patterns of alternative splicing for CbNav, indicating unique cell-specific pattern of post-transcriptional modification. Furthermore, we detected possible differences in cellular localization of alternatively spliced CbNav transcripts; distinct mRNA isoforms are present between the cell somata and the axons of the neurons. In contrast, we found no qualitative differences among different cell types for CbIH variants present, although this analysis did not represent the full spectrum of all possible CbIH variants. CbIH mRNA was not detected in axon samples. Finally, although cell-type specific patterns of splicing were detected for CbNav, the same cell type within and between animals also displayed variability in which splice forms were detected. These results indicate that channel splicing is differentially regulated at the level of single neurons of the same neural network, providing yet another mechanism by which cell-specific neuronal output can be achieved. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
C1 [Dai, A.; Temporal, S.; Schulz, D. J.] Univ Missouri, Dept Biol Sci, Columbia, MO 65211 USA.
C3 University of Missouri System; University of Missouri Columbia
RP Schulz, DJ (corresponding author), Univ Missouri, Dept Biol Sci, Columbia, MO 65211 USA.
EM SchulzD@missouri.edu
OI Schulz, David/0000-0003-4532-5362
FU NSF [IOB-0615160]
FX This work was supported by a grant to DJS (NSF IOB-0615160). Joseph
   Ransdell contributed to the real-time PCR results. Robert Davis aided in
   some of the initial sequencing of CbNa<INF>v</INF>..
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NR 52
TC 9
Z9 11
U1 0
U2 6
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 0306-4522
EI 1873-7544
J9 NEUROSCIENCE
JI Neuroscience
PD JUN 16
PY 2010
VL 168
IS 1
BP 118
EP 129
DI 10.1016/j.neuroscience.2010.03.001
PG 12
WC Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 601ER
UT WOS:000278041500011
PM 20211705
DA 2025-04-10
ER

PT J
AU Cox, RH
   Fromme, S
AF Cox, Robert H.
   Fromme, Samantha
TI Expression of Calcium Channel Subunit Variants in Small Mesenteric
   Arteries of WKY and SHR
SO AMERICAN JOURNAL OF HYPERTENSION
LA English
DT Article
DE alternative splicing; blood pressure; Ca2+ channel subunits; gene
   expression; hypertension; hypertensive rats; protein abundance; small
   mesenteric arteries; voltage gated Ca2+ channels
ID SPONTANEOUSLY HYPERTENSIVE-RATS; SMOOTH-MUSCLE-CELLS; HIGH
   BLOOD-PRESSURE; CA2+ CHANNEL; WISTAR-KYOTO; UP-REGULATION; DIFFERENTIAL
   EXPRESSION; MOLECULAR DETERMINANTS; BETA-3 SUBUNIT; VOLTAGE
AB BACKGROUND
   Enhanced function of dihydropyridine-sensitive Ca2+ channels (Ca-V) in hypertensive arterial myocytes (HAM) is well accepted. Increased protein expression of pore forming alpha(1)-subunits contributes to this effect, but cannot explain all of the differences in Ca-V properties in HAM. We hypothesized that differences in expression of Ca-V subunits and/or their splice variants also contribute.
   METHODS
   RNA, protein, and myocytes were isolated from small mesenteric arteries (SMA) of 20-week-old male WKY and SHR and analyzed by polymerase chain reaction (PCR), sequencing, immunoblotting, and patch clamp methods.
   RESULTS
   Cav1.2 alpha(1), beta(2c), and alpha(2)delta(1d) were the dominant subunits expressed in both WKY and SHR with a smaller amount of beta(3a). Real-time PCR indicated that the mRNA abundance of beta(3a) and alpha(2)delta(1) but not total Cav1.2 alpha(1) or beta(2c) were significantly larger in SHR. Analysis of alternative splicing of Cav1.2 alpha(1) showed no differences in abundance of mutually exclusive exons1b, 8, 21 and 32 or alternative exons33 and 45. However, inclusion of exon9* was higher and a 73 nucleotide (nt) deletion in exon15 (exon15.73) was lower in SHR. Immunoblot analysis showed higher protein levels of Cav1.2 alpha(1) (1.61 +/- 0.05), beta(3) (1.80 +/- 0.32), and alpha(2)delta(1) (1.80 +/- 0.24) but not beta(2) in SHR.
   CONCLUSIONS
   The lower abundance of exon15.73 transcripts in SHR results in a larger fraction of total Cav1.2 mRNA coding for full-length CaV protein, and the higher abundance of exon9* transcripts and Ca-V beta a protein likely contribute to differences in gating and kinetics of CaV currents in SHR. Functional studies of Ca2+ currents in native SMA myocytes and HEK cells transiently transfected with CaV subunits support these conclusions.
C1 [Cox, Robert H.; Fromme, Samantha] Lankenau Inst Med Res, Program Cardiovasc Dis, Wynnewood, PA 19096 USA.
C3 Lankenau Medical Center; Lankenau Institute for Medical Research
RP Cox, RH (corresponding author), Lankenau Inst Med Res, Program Cardiovasc Dis, Wynnewood, PA 19096 USA.
EM coxr@mlhs.org
OI Cox, Robert/0000-0001-8884-9540
FU National Institutes of Health [HL28476]; American Heart Association
   [0350084N]; W. W. Smith Charitable Trust [H0604]; American Heart
   Association (AHA) [0350084N] Funding Source: American Heart Association
   (AHA)
FX This work was supported by National Institutes of Health grant HL28476
   (to R.H.C), American Heart Association grant 0350084N (to R.H.C.), and
   W. W. Smith Charitable Trust grant H0604 (to R.H.C.).
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NR 33
TC 18
Z9 19
U1 0
U2 5
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0895-7061
EI 1941-7225
J9 AM J HYPERTENS
JI Am. J. Hypertens.
PD OCT
PY 2015
VL 28
IS 10
BP 1229
EP 1239
DI 10.1093/ajh/hpv024
PG 11
WC Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA CT5HP
UT WOS:000362839900006
PM 25820242
OA Green Published, Bronze
DA 2025-04-10
ER

PT J
AU Stevens, M
   Oltean, S
AF Stevens, Megan
   Oltean, Sebastian
TI Alternative Splicing in CKD
SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
LA English
DT Review
ID ENDOTHELIAL GROWTH-FACTOR; CHRONIC KIDNEY-DISEASE; MESSENGER-RNA;
   DIABETIC-NEPHROPATHY; SRPK1 INHIBITION; EPITHELIAL-CELLS;
   RENAL-FUNCTION; VEGF; RECEPTOR; FIBRONECTIN
AB Alternative splicing (AS) has emerged in the postgenomic era as one of the main drivers of proteome diversity, with >= 94% of mu ltiexon genes alternatively spliced in humans. AS is therefore one of the main control mechanisms for cell phenotype, and is a process deregulated in disease. Numerous reports describe pathogenic mutations in splice factors, splice sites, or regulatory sequences. Additionally, compared with the physiologic state, disease often associates with an abnormal proportion of splice isoforms (or novel isoforms), without an apparent driver mutation. It is therefore essential to study how AS is regulated in physiology, how it contributes to pathogenesis, and whether we can manipulate faulty splicing for therapeutic advantage. Although the disease most commonly linked to deregulation of AS in several genes is cancer, many reports detail pathogenic splice variants in diseases ranging from neuromuscular disorders to diabetes or cardiomyopathies. A plethora of splice variants have been implicated in CKDs as well. In this review, we describe examples of these CKD-associated splice variants and ideas on how to manipulate them for therapeutic benefit.
C1 [Stevens, Megan; Oltean, Sebastian] Univ Bristol, Fac Biomed Sci, Sch Physiol & Pharmacol, Dorothy Hodgkin Bldg, Bristol BS1 3NY, Avon, England.
   [Stevens, Megan; Oltean, Sebastian] Univ Bristol, Fac Hlth Sci, Sch Clin Sci, Acad Renal Unit, Bristol BS1 3NY, Avon, England.
C3 University of Bristol; University of Bristol
RP Oltean, S (corresponding author), Univ Bristol, Fac Biomed Sci, Sch Physiol & Pharmacol, Dorothy Hodgkin Bldg, Bristol BS1 3NY, Avon, England.
EM sebastian.oltean@bristol.ac.uk
RI sTEVENS, Megan/GPT-0543-2022
OI stevens, megan/0000-0002-7474-6759; Oltean,
   Sebastian/0000-0001-7890-8439
FU British Heart Foundation [PG/15/53/31371]; Richard Bright VEGF Research
   Trust; BBSRC [BB/J007293/1, BB/P012035/1, BB/J007293/2] Funding Source:
   UKRI
FX Funding for this study was supported by the British Heart Foundation
   (grant no.: PG/15/53/31371 to S.O.) and by the Richard Bright VEGF
   Research Trust (award to S.O.).
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NR 68
TC 15
Z9 16
U1 0
U2 12
PU AMER SOC NEPHROLOGY
PI WASHINGTON
PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA
SN 1046-6673
EI 1533-3450
J9 J AM SOC NEPHROL
JI J. Am. Soc. Nephrol.
PD JUN
PY 2016
VL 27
IS 6
BP 1596
EP 1603
DI 10.1681/ASN.2015080908
PG 8
WC Urology & Nephrology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Urology & Nephrology
GA DN1NY
UT WOS:000376833900007
PM 26763787
OA Bronze, Green Published
DA 2025-04-10
ER

PT J
AU Wu, H
   Lu, YC
   Duan, ZZ
   Wu, JN
   Lin, MH
   Wu, YJ
   Han, SY
   Li, TQ
   Fan, YQ
   Hu, XY
   Xiao, HY
   Feng, JX
   Lu, ZQ
   Kong, DP
   Li, SL
AF Wu, Hao
   Lu, Yicheng
   Duan, Zhenzhen
   Wu, Jingni
   Lin, Minghui
   Wu, Yangjun
   Han, Siyang
   Li, Tongqi
   Fan, Yuqi
   Hu, Xiaoyuan
   Xiao, Hongyan
   Feng, Jiaxuan
   Lu, Zhiqian
   Kong, Deping
   Li, Shengli
TI Nanopore long-read RNA sequencing reveals functional alternative
   splicing variants in human vascular smooth muscle cells
SO COMMUNICATIONS BIOLOGY
LA English
DT Article
ID PHENOTYPIC SWITCH; PROTEIN; MITONEET; IRON; PROLIFERATION;
   BIOENERGETICS; PATHWAYS; DISTINCT
AB Vascular smooth muscle cells (VSMCs) are the major contributor to vascular repair and remodeling, which showed high level of phenotypic plasticity. Abnormalities in VSMC plasticity can lead to multiple cardiovascular diseases, wherein alternative splicing plays important roles. However, alternative splicing variants in VSMC plasticity are not fully understood. Here we systematically characterized the long-read transcriptome and their dysregulation in human aortic smooth muscle cells (HASMCs) by employing the Oxford Nanopore Technologies long-read RNA sequencing in HASMCs that are separately treated with platelet-derived growth factor, transforming growth factor, and hsa-miR-221-3P transfection. Our analysis reveals frequent alternative splicing events and thousands of unannotated transcripts generated from alternative splicing. HASMCs treated with different factors exhibit distinct transcriptional reprogramming modulated by alternative splicing. We also found that unannotated transcripts produce different open reading frames compared to the annotated transcripts. Finally, we experimentally validated the unannotated transcript derived from gene CISD1, namely CISD1-u, which plays a role in the phenotypic switch of HASMCs. Our study characterizes the phenotypic modulation of HASMCs from an insight of long-read transcriptome, which would promote the understanding and the manipulation of HASMC plasticity in cardiovascular diseases.
   Long-read RNA-seq analysis identifies and measures novel transcripts in cultured human aortic smooth muscle cells under basal conditions and after treatment with cytokines or CISD1-u knockdown.
C1 [Wu, Hao; Lu, Zhiqian] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 6, Dept Cardiovasc Surg, Sch Med, Shanghai, Peoples R China.
   [Wu, Hao; Lu, Yicheng; Duan, Zhenzhen; Wu, Jingni; Lin, Minghui; Kong, Deping; Li, Shengli] Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Inst Clin Res, Precis Res Ctr Refractory Dis,Sch Med, Shanghai, Peoples R China.
   [Wu, Yangjun] Fudan Univ, Dept Gynecol Oncol, Shanghai Canc Ctr, Shanghai, Peoples R China.
   [Han, Siyang; Li, Tongqi] Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Dept Ophthalmol, Sch Med, Shanghai, Peoples R China.
   [Fan, Yuqi] North Cross Sch Shanghai, Shanghai, Peoples R China.
   [Hu, Xiaoyuan] Geogia Inst Technol, Coll Engn, H Milton Stewart Sch Ind & Syst Engn, Atlanta, GA USA.
   [Xiao, Hongyan] Wuhan Univ Sci & Technol, Wuhan Asia Heart Hosp, Dept Cardiac Surg, Wuhan, Peoples R China.
   [Feng, Jiaxuan] Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Dept Vasc Surg, Sch Med, Shanghai, Peoples R China.
   [Feng, Jiaxuan] Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Intervent Ctr, Sch Med, Shanghai, Peoples R China.
C3 Shanghai Jiao Tong University; Shanghai Jiao Tong University; Fudan
   University; Shanghai Jiao Tong University; Wuhan University of Science &
   Technology; Shanghai Jiao Tong University; Shanghai Jiao Tong University
RP Lu, ZQ (corresponding author), Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 6, Dept Cardiovasc Surg, Sch Med, Shanghai, Peoples R China.; Kong, DP; Li, SL (corresponding author), Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Inst Clin Res, Precis Res Ctr Refractory Dis,Sch Med, Shanghai, Peoples R China.
EM 18930177678@163.com; deping.kong@shsmu.edu.cn; shengli.li@sjtu.edu.cn
RI Hu, Xiaoyuan/HTM-3321-2023; Lu, Yi-Cheng/JLM-8137-2023
FU This study was supported by the Science and Technology Commission of
   Shanghai Municipality (20410761000, 21QA1407400, 21ZR1481200, and
   21YF1436900), the National Natural Science Foundation of China
   (82170253, 82241018, 32100517, and 82101257), National Key [20410761000,
   21QA1407400, 21ZR1481200, 21YF1436900]; Science and Technology
   Commission of Shanghai Municipality [82170253, 82241018, 32100517,
   82101257]; National Natural Science Foundation of China
   [2021YFA1102300]; National Key Ramp;D Program of China [2021JCPT04];
   Integrated Innovation Fund of Shanghai Jiao Tong University
   [02.06.01.20.06, 02.06.01.20.04]; Shanghai General Hospital Startup
   Funding
FX This study was supported by the Science and Technology Commission of
   Shanghai Municipality (20410761000, 21QA1407400, 21ZR1481200, and
   21YF1436900), the National Natural Science Foundation of China
   (82170253, 82241018, 32100517, and 82101257), National Key R & D Program
   of China (2021YFA1102300), Integrated Innovation Fund of Shanghai Jiao
   Tong University (2021JCPT04), and Shanghai General Hospital Startup
   Funding (02.06.01.20.06 and 02.06.01.20.04).
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NR 67
TC 4
Z9 4
U1 2
U2 17
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
EI 2399-3642
J9 COMMUN BIOL
JI Commun. Biol.
PD OCT 31
PY 2023
VL 6
IS 1
AR 1104
DI 10.1038/s42003-023-05481-y
PG 12
WC Biology; Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Life Sciences & Biomedicine - Other Topics; Science & Technology - Other
   Topics
GA W3OK5
UT WOS:001090753400005
PM 37907652
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Blanco, FJ
   Bernabéu, C
AF Javier Blanco, Francisco
   Bernabeu, Carmelo
TI The splicing factor SRSF1 as a marker for endothelial senescence
SO FRONTIERS IN PHYSIOLOGY
LA English
DT Review
DE alternative splicing; endothelial senescence; SRSF1; endoglin;
   progerin,VEGF; tissue factor
ID CELLULAR SENESCENCE; MESSENGER-RNA; TISSUE FACTOR; ENDOGLIN; MECHANISMS;
   CELLS; EXPRESSION; BETA; VEGF; GENE
AB Aging is the major risk factor per se for the development of cardiovascular diseases. The senescence of the endothelial cells (ECs) that line the lumen of blood vessels is the cellular basis for these age-dependent vascular pathologies, including atherosclerosis and hypertension. During their lifespan, ECs may reach a stage of senescence by two different pathways; a replicative one derived from their preprogrammed finite number of cell divisions; and one induced by stress stimuli. Also, certain physiological stimuli, such as transforming growth factor-beta, are able to modulate cellular senescence. Currently, the cellular aging process is being widely studied to identify novel molecular markers whose changes correlate with senescence. This review focuses on the regulation of alternative splicing mediated by the serine arginine splicing factor 1 (SRSF1, or ASF/SF2) during endothelial senescence, a process that is associated with a differential subcellular localization of SRSF1, which typically exhibits a scattered distribution throughout the cytoplasm. Based on its senescence-dependent involvement in alternative splicing, we postulate that SRSF1 is a key marker of EC senescence, regulating the expression of alternative isoforms of target genes such as endoglin (ENG), vascular endothelial growth factor A (VEGFA), tissue factor (T3), or lamin A (LMNA) that integrate in a common molecular senescence
C1 CSIC, Ctr Invest Biol, Madrid 28040, Spain.
   Ctr Invest Biomed Red Enfermedades Raras, Madrid, Spain.
C3 Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro de
   Investigaciones Biologicas (CIB); CIBER - Centro de Investigacion
   Biomedica en Red; CIBERER
RP Blanco, FJ (corresponding author), CSIC, Ctr Invest Biol, Dept Cellular & Mol Med, C Ramiro de Maeztu 9, Madrid 28040, Spain.
EM fjblanco@cib.csic.es
RI Bernabeu, Carmelo/L-3226-2014; Blanco, Francisco-Javier/H-3413-2012
OI Bernabeu, Carmelo/0000-0002-1563-6162; Blanco,
   Francisco-Javier/0000-0002-9929-6707
FU Ministerio de Ciencia e innovacion of Spain [SAl2010-19222]; Genoma
   Espana (MEICA)
FX This study was supported by grants from the Ministerio de Ciencia e
   innovacion of Spain (SAl2010-19222) and Genoma Espana (MEICA) to Carmelo
   Bernabeu, The Centro de Investigacion Biomedica en Red de Enfermeda.d.es
   Raras (CIBERER) is an initiative of the Institut de Salud Carlos III
   (ISCIII) of Spain.
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NR 60
TC 36
Z9 39
U1 0
U2 8
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 1664-042X
J9 FRONT PHYSIOL
JI Front. Physiol.
PY 2012
VL 3
AR 54
DI 10.3389/fphys.2012.00054
PG 6
WC Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Physiology
GA V35UH
UT WOS:000209173000053
PM 22470345
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Warf, MB
   Diegel, JV
   von Hippel, PH
   Berglund, JA
AF Warf, M. Bryan
   Diegel, Julien V.
   von Hippel, Peter H.
   Berglund, J. Andrew
TI The protein factors MBNL1 and U2AF65 bind alternative RNA structures to
   regulate splicing
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
   AMERICA
LA English
DT Article
DE muscleblind-like 1; myotonic dystrophy; alternative splicing
ID PRE-MESSENGER-RNA; POLYPYRIMIDINE TRACT; MYOTONIC-DYSTROPHY; BRANCH
   POINT; HNRNP A1; EXON; RECOGNITION; SPLICEOSOME; COMPLEX; MECHANISMS
AB Myotonic dystrophy type 1 (DM1) is a genetic disorder linked to a (CTG)(n) repeat expansion in the 3' untranslated region of the DMPK gene. Upon transcription in the nucleus, the CUG repeats form a stable RNA stem-loop that sequesters the RNA-binding protein MBNL1 from its normal function in the cell. MBNL1 regulates the alternative splicing of many pre-mRNAs, and upon MBNL1's sequestration, the alternative splicing of many genes is misregulated, leading to disease symptoms. MBNL1 is known to bind directly to at least 3 of the pre-mRNAs that it regulates, but how MBNL1 binding mechanistically regulates alternative splicing is unclear. Here, we demonstrate that MBNL1 controls the splicing of exon 5 in the cardiac troponin T (cTNT) pre-mRNA by competing directly with the essential splicing factor U2AF65 for binding at the 3' end of intron 4. When U2AF65 is prevented from binding to the pre-mRNA, the U2 snRNP can no longer be recruited and the following exon is skipped. Furthermore, MBNL1 and U2AF65 appear to compete by binding to mutually exclusive RNA structures. When bound by splicing factors, the 3' end of intron 4 can form either a stem-loop or a single-stranded structure. MBNL1 binds a portion of the intron as a stem-loop, whereas U2AF65 binds the same region in a single-strand structure. Mutations that strengthen the stem-loop decrease U2AF65 binding affinity and also repress exon 5 inclusion, independently of MBNL1. Thus, U2AF65 binding can be blocked either by MBNL1 binding or by the stabilization of RNA secondary structure.
C1 [Berglund, J. Andrew] Univ Oregon, Inst Mol Biol, Eugene, OR 97403 USA.
   Univ Oregon, Dept Chem, Eugene, OR 97403 USA.
C3 University of Oregon; University of Oregon
RP Berglund, JA (corresponding author), Univ Oregon, Inst Mol Biol, Eugene, OR 97403 USA.
EM aberglund@molbio.uoregon.edu
RI Berglund, Andrew/AAS-1065-2021
OI von Hippel, Peter H./0000-0003-2512-8097
FU National Institutes of Health [AR053903, GM-15792]
FX We thank members of the Berglund, von Hippel, and Barkan labs
   (especially Kausiki Datta and Alice Barkan) for experimental advice and
   help with equipment. This work was supported by National Institutes of
   Health Grants AR053903 (to J.A.B.) and GM-15792 (to P.H.v.H.).
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NR 31
TC 115
Z9 147
U1 0
U2 11
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD JUN 9
PY 2009
VL 106
IS 23
BP 9203
EP 9208
DI 10.1073/pnas.0900342106
PG 6
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 456CN
UT WOS:000266817500020
PM 19470458
OA Green Published
DA 2025-04-10
ER

PT J
AU Salomonis, N
   Nelson, B
   Vranizan, K
   Pico, AR
   Hanspers, K
   Kuchinsky, A
   Ta, L
   Mercola, M
   Conklin, BR
AF Salomonis, Nathan
   Nelson, Brandon
   Vranizan, Karen
   Pico, Alexander R.
   Hanspers, Kristina
   Kuchinsky, Allan
   Ta, Linda
   Mercola, Mark
   Conklin, Bruce R.
TI Alternative Splicing in the Differentiation of Human Embryonic Stem
   Cells into Cardiac Precursors
SO PLOS COMPUTATIONAL BIOLOGY
LA English
DT Article
ID GENE-EXPRESSION; MESSENGER-RNA; DISTINCT FUNCTIONS; DNA-BINDING;
   ISOFORMS; SPECTRIN; VARIANT; KINASE; MUSCLE; MOUSE
AB The role of alternative splicing in self-renewal, pluripotency and tissue lineage specification of human embryonic stem cells (hESCs) is largely unknown. To better define these regulatory cues, we modified the H9 hESC line to allow selection of pluripotent hESCs by neomycin resistance and cardiac progenitors by puromycin resistance. Exon-level microarray expression data from undifferentiated hESCs and cardiac and neural precursors were used to identify splice isoforms with cardiac-restricted or common cardiac/neural differentiation expression patterns. Splice events for these groups corresponded to the pathways of cytoskeletal remodeling, RNA splicing, muscle specification, and cell cycle checkpoint control as well as genes with serine/threonine kinase and helicase activity. Using a new program named AltAnalyze (http://www.AltAnalyze.org), we identified novel changes in protein domain and microRNA binding site architecture that were predicted to affect protein function and expression. These included an enrichment of splice isoforms that oppose cell-cycle arrest in hESCs and that promote calcium signaling and cardiac development in cardiac precursors. By combining genome-wide predictions of alternative splicing with new functional annotations, our data suggest potential mechanisms that may influence lineage commitment and hESC maintenance at the level of specific splice isoforms and microRNA regulation.
C1 [Salomonis, Nathan; Pico, Alexander R.; Hanspers, Kristina; Ta, Linda; Conklin, Bruce R.] Gladstone Inst Cardiovasc Dis, San Francisco, CA USA.
   [Salomonis, Nathan; Conklin, Bruce R.] Univ Calif San Francisco, Pharmaceut Sci & Pharmacogen Grad Program, San Francisco, CA 94143 USA.
   [Nelson, Brandon; Mercola, Mark] Burnham Inst Med Res, La Jolla, CA USA.
   [Vranizan, Karen] Univ Calif Berkeley, Funct Genom Lab, Berkeley, CA 94720 USA.
   [Kuchinsky, Allan] Agilent Technol, Santa Clara, CA USA.
C3 University of California System; University of California San Francisco;
   The J David Gladstone Institutes; University of California System;
   University of California San Francisco; Sanford Burnham Prebys Medical
   Discovery Institute; University of California System; University of
   California Berkeley; Agilent Technologies
RP Salomonis, N (corresponding author), Gladstone Inst Cardiovasc Dis, San Francisco, CA USA.
EM bconklin@gladstone.ucsf.edu
RI Conklin, Bruce/E-4738-2019; Pico, Alexander/HCH-4305-2022
OI Conklin, Bruce/0000-0003-1463-6061; Pico, Alexander/0000-0001-5706-2163
FU National Institutes of Health [GM080223, HG003053, HL66621, R37HL059502,
   R33HL088266]; Agilent Technologies Foundation; Mathers Charitable
   Foundation; California Institute for Regenerative Medicine (CIRM)
   [RC1-00132-1]
FX This work was supported by grants from the National Institutes of Health
   (GM080223, HG003053, HL66621; NS, KH, BRC), (R37HL059502, R33HL088266;
   MM), the Agilent Technologies Foundation (ARP, AK), Mathers Charitable
   Foundation (MM), and the California Institute for Regenerative Medicine
   (CIRM) (RC1-00132-1; MM). The funders had no role in study design, data
   collection and analysis, decision to publish, or preparation of the
   manuscript.
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NR 63
TC 74
Z9 88
U1 0
U2 8
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1553-734X
EI 1553-7358
J9 PLOS COMPUT BIOL
JI PLoS Comput. Biol.
PD NOV
PY 2009
VL 5
IS 11
AR e1000553
DI 10.1371/journal.pcbi.1000553
PG 17
WC Biochemical Research Methods; Mathematical & Computational Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Mathematical & Computational Biology
GA 551SA
UT WOS:000274228500001
PM 19893621
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Berger, DS
   Moyer, M
   Kliment, GM
   van Lunteren, E
   Ladd, AN
AF Berger, Dara S.
   Moyer, Michelle
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   van Lunteren, Erik
   Ladd, Andrea N.
TI Expression of a Dominant Negative CELF Protein In Vivo Leads to
   Altered Muscle Organization, Fiber Size, and Subtype
SO PLOS ONE
LA English
DT Article
ID EXPANDED CTG REPEATS; RNA-BINDING PROTEIN; MYOTONIC-DYSTROPHY; TRIPLET
   REPEAT; SKELETAL-MUSCLE; MOLECULAR-BASIS; MOUSE MODEL; EDEN-BP; MICE;
   CUGBP1
AB Background: CUG-BP and ETR-3-like factor (CELF) proteins regulate tissue-and developmental stage-specific alternative splicing in striated muscle. We previously demonstrated that heart muscle-specific expression of a nuclear dominant negative CELF protein in transgenic mice (MHC-CELFD) effectively disrupts endogenous CELF activity in the heart in vivo, resulting in impaired cardiac function. In this study, transgenic mice that express the dominant negative protein under a skeletal muscle-specific promoter (Myo-CELFD) were generated to investigate the role of CELF-mediated alternative splicing programs in normal skeletal muscle.
   Methodology/Principal Findings: Myo-CELFD mice exhibit modest changes in CELF-mediated alternative splicing in skeletal muscle, accompanied by a reduction of endomysial and perimysial spaces, an increase in fiber size variability, and an increase in slow twitch muscle fibers. Weight gain and mean body weight, total number of muscle fibers, and overall muscle strength were not affected.
   Conclusions/Significance: Although these findings demonstrate that CELF activity contributes to the normal alternative splicing of a subset of muscle transcripts in vivo, the mildness of the effects in Myo-CELFD muscles compared to those in MHC-CELFD hearts suggests CELF activity may be less determinative for alternative splicing in skeletal muscle than in heart muscle. Nonetheless, even these small changes in CELF-mediated splicing regulation were sufficient to alter muscle organization and muscle fiber properties affected in myotonic dystrophy. This lends further evidence to the hypothesis that dysregulation of CELF-mediated alternative splicing programs may be responsible for the disruption of these properties during muscle pathogenesis.
C1 [Berger, Dara S.; Kliment, Gregory M.; Ladd, Andrea N.] Cleveland Clin, Dept Cell Biol, Lerner Res Inst, Cleveland, OH 44106 USA.
   [Moyer, Michelle; van Lunteren, Erik] Cleveland Vet Affairs Med Ctr, Cleveland, OH USA.
   [van Lunteren, Erik] Case Western Reserve Univ, Dept Med, Div Pulm & Crit Care, Cleveland, OH 44106 USA.
C3 Cleveland Clinic Foundation; University System of Ohio; Case Western
   Reserve University
RP Berger, DS (corresponding author), Montefiore Med Ctr, Inst Reprod Med & Hlth, Hartsdale, NY USA.
EM ladda@ccf.org
OI Ladd, Andrea/0000-0003-4725-5644
FU Muscular Dystrophy Association [MDA3812, MDA87845]; Department of
   Veterans Affairs Medical Research Service; National Institutes of Health
   [T32HL007914]
FX This work was supported by grants to A.N.L. from the Muscular Dystrophy
   Association (Development Grant MDA3812 and Research Grant MDA87845) and
   to E. v. L. from the Department of Veterans Affairs Medical Research
   Service. D. S. B. was supported by a National Institutes of Health
   training grant (T32HL007914). The funders had no role in study design,
   data colletion and analysis, decision to publish, or preparation of the
   manuscript.
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NR 39
TC 16
Z9 18
U1 0
U2 4
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD APR 26
PY 2011
VL 6
IS 4
AR e19274
DI 10.1371/journal.pone.0019274
PG 11
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 756NE
UT WOS:000290018400038
PM 21541285
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Chang, SH
   Elemento, O
   Zhang, JS
   Zhuang, ZW
   Simons, M
   Hla, T
AF Chang, Sung-Hee
   Elemento, Olivier
   Zhang, Jiasheng
   Zhuang, Zhen W.
   Simons, Michael
   Hla, Timothy
TI ELAVL1 regulates alternative splicing of eIF4E transporter to promote
   postnatal angiogenesis
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
   AMERICA
LA English
DT Article
DE angiogenesis; RNA binding protein; eIF4e transporter; alternative
   splicing; tumor angiogenesis
ID BINDING PROTEIN HUR; MESSENGER-RNA; TRANSGENIC MOUSE; BODY FORMATION;
   STABILIZATION; MECHANISMS; EXPRESSION; 4E-T
AB Posttranscriptional RNA regulation is important in determining the plasticity of cellular phenotypes. However, mechanisms of how RNA binding proteins (RBPs) influence cellular behavior are poorly understood. We show here that the RBP embryonic lethal abnormal vision like 1 (ELAVL1, also know as HuR) regulates the alternative splicing of eukaryotic translation initiation factor 4E nuclear import factor 1 (Eif4enif1), which encodes an eukaryotic translation initiation factor 4E transporter (4E-T) protein and suppresses the expression of capped mRNAs. In the absence of ELAVL1, skipping of exon 11 of Eif4enif1 forms the stable, short isoform, 4E-T-s. This alternative splicing event results in the formation of RNA processing bodies (PBs), enhanced turnover of angiogenic mRNAs, and suppressed sprouting behavior of vascular endothelial cells. Further, endothelial-specific Elavl1 knockout mice exhibited reduced revascularization after hind limb ischemia and tumor angiogenesis in oncogene-induced mammary cancer, resulting in attenuated blood flow and tumor growth, respectively. ELAVL1-regulated alternative splicing of Eif4enif1 leading to enhanced formation of PB and mRNA turnover constitutes a novel posttranscriptional mechanism critical for pathological angiogenesis.
C1 [Chang, Sung-Hee; Hla, Timothy] Cornell Univ, Weill Cornell Med Coll, Dept Pathol & Lab Med, Ctr Vasc Biol, New York, NY 10065 USA.
   [Elemento, Olivier] Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, Inst Computat Biomed, New York, NY 10065 USA.
   [Zhang, Jiasheng; Zhuang, Zhen W.; Simons, Michael] Yale Univ, Sch Med, Yale Cardiovasc Res Ctr, New Haven, CT 06520 USA.
C3 Cornell University; Weill Cornell Medicine; Cornell University; Weill
   Cornell Medicine; Yale University
RP Chang, SH (corresponding author), Cornell Univ, Weill Cornell Med Coll, Dept Pathol & Lab Med, Ctr Vasc Biol, New York, NY 10065 USA.
EM sch2002@med.cornell.edu; tih2002@med.cornell.edu
RI Elemento, Olivier/ADL-3192-2022; Simons, Michael/G-8553-2014; Hla,
   Timothy/G-5873-2012
OI Simons, Michael/0000-0003-0348-7734; Hla, Timothy/0000-0001-8355-4065
FU National Institutes of Health [HL49094, HL117798, CA77839]
FX We thank Professor Thomas Tuschl (The Rockefeller University) for
   critical comments and Dr. Jerry Pelletier (McGill University) for the
   gift of reagents. This work was supported by National Institutes of
   Health Grants HL49094, HL117798, and CA77839 (to T.H.).
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NR 34
TC 57
Z9 64
U1 0
U2 12
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD DEC 23
PY 2014
VL 111
IS 51
BP 18309
EP 18314
DI 10.1073/pnas.1412172111
PG 6
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA AX2IP
UT WOS:000346767200060
PM 25422430
OA Green Published, Bronze
DA 2025-04-10
ER

PT J
AU Burkhardt, R
   Kenny, EE
   Lowe, JK
   Birkeland, A
   Josowitz, R
   Noel, M
   Salit, J
   Maller, JB
   Pe'er, I
   Daly, MJ
   Altshuler, D
   Stoffel, M
   Friedman, JM
   Breslow, JL
AF Burkhardt, Ralph
   Kenny, Eimear E.
   Lowe, Jennifer K.
   Birkeland, Andrew
   Josowitz, Rebecca
   Noel, Martha
   Salit, Jacqueline
   Maller, Julian B.
   Pe'er, Itsik
   Daly, Mark J.
   Altshuler, David
   Stoffel, Markus
   Friedman, Jeffrey M.
   Breslow, Jan L.
TI Common SNPs in HMGCR in Micronesians and Whites Associated With
   LDL-Cholesterol Levels Affect Alternative Splicing of Exon13
SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
LA English
DT Article
DE HMG-CoA reductase; SNP; genome-wide association study; LDL-C;
   alternative splicing
ID GENOME-WIDE ASSOCIATION; COENZYME-A REDUCTASE; DENSITY-LIPOPROTEIN
   CHOLESTEROL; FEDERATED STATES; CANDIDATE GENES; RISK-FACTORS; LOCI;
   HYPERCHOLESTEROLEMIA; PATHOGENESIS; INSIGHTS
AB Background-Variation in LDL-cholesterol (LDL-C) among individuals is a complex genetic trait involving multiple genes and gene-environment interactions.
   Methods and Results-In a genome-wide association study (GWAS) to identify genetic variants influencing LDL-C in an isolated population from Kosrae, we observed associations for SNPs in the gene encoding 3hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (HMGCR). Three of these SNPs (rs7703051, rs12654264, and rs3846663) met the statistical threshold of genome-wide significance when combined with data from the Diabetes Genetics Initiative GWAS. We followed up the association results and identified a functional SNP in intron13 (rs3846662), which was in linkage disequilibrium with the SNPs of genome-wide significance and affected alternative splicing of HMGCR mRNA. In vitro studies in human lymphoblastoid cells demonstrated that homozygosity for the rs3846662 minor allele was associated with up to 2.2-fold lower expression of alternatively spliced HMGCR mRNA lacking exon13, and minigene transfection assays confirmed that allele status at rs3846662 directly modulated alternative splicing of HMGCR exon13 (42.9 +/- 3.9 versus 63.7 +/- 1.0%Delta exon13/total HMGCR mRNA, P = 0.02). Further, the alternative splice variant could not restore HMGCR activity when expressed in HMGCR deficient UT-2 cells.
   Conclusion-We identified variants in HMGCR that are associated with LDL-C across populations and affect alternative splicing of HMGCR exon13. (Arterioscler Thromb Vasc Biol. 2008; 28: 2078-2084)
C1 [Breslow, Jan L.] Rockefeller Univ, Lab Biochem Genet, New York, NY 10065 USA.
   [Friedman, Jeffrey M.] Rockefeller Univ, Howard Hughes Med Inst, Mol Genet Lab, New York, NY 10065 USA.
   [Lowe, Jennifer K.; Maller, Julian B.; Daly, Mark J.; Altshuler, David] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA.
   [Lowe, Jennifer K.; Maller, Julian B.; Daly, Mark J.; Altshuler, David] MIT, Cambridge, MA 02139 USA.
   [Pe'er, Itsik] Columbia Univ, Dept Comp Sci, New York, NY 10027 USA.
   [Maller, Julian B.; Daly, Mark J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.
   [Lowe, Jennifer K.; Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.
   [Daly, Mark J.; Altshuler, David] Harvard Univ, Sch Med, Dept Med, Boston, MA USA.
   [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA.
   [Stoffel, Markus] ETH, Inst Mol Syst Biol, Zurich, Switzerland.
   [Burkhardt, Ralph; Kenny, Eimear E.; Lowe, Jennifer K.; Birkeland, Andrew; Josowitz, Rebecca; Noel, Martha; Breslow, Jan L.] Rockefeller Univ, Biochem Genet & Metab Lab, New York, NY 10065 USA.
C3 Rockefeller University; Howard Hughes Medical Institute; Rockefeller
   University; Harvard University; Massachusetts Institute of Technology
   (MIT); Broad Institute; Massachusetts Institute of Technology (MIT);
   Columbia University; Harvard University; Harvard University Medical
   Affiliates; Massachusetts General Hospital; Harvard University; Harvard
   University Medical Affiliates; Massachusetts General Hospital; Harvard
   University; Harvard Medical School; Harvard University; Harvard Medical
   School; Swiss Federal Institutes of Technology Domain; ETH Zurich;
   Rockefeller University
RP Breslow, JL (corresponding author), Rockefeller Univ, Lab Biochem Genet, 1230 York Ave, New York, NY 10065 USA.
EM breslow@rockefeller.edu
RI Breslow, Jan/B-7544-2008; Daly, Mark/B-2453-2017; Altshuler,
   David/A-4476-2009; Burkhardt, Ralph/F-5221-2013; maller,
   julian/A-9323-2009
OI Stoffel, Markus/0000-0003-1304-5817; Maller, Julian/0000-0002-1565-9559;
   Pe'er, Itsik/0000-0002-6128-7231; Burkhardt, Ralph/0000-0003-1924-1202;
   Altshuler, David/0000-0002-7250-4107
FU Deutsche Forschungsgemeinschaft [DFG Bu2263/1-1]
FX Ralph Burkhardt is a fellow of the Deutsche Forschungsgemeinschaft (DFG
   Bu2263/1-1).
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NR 33
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U1 0
U2 5
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 1079-5642
EI 1524-4636
J9 ARTERIOSCL THROM VAS
JI Arterioscler. Thromb. Vasc. Biol.
PD NOV
PY 2008
VL 28
IS 11
BP 2078
EP U332
DI 10.1161/ATVBAHA.108.172288
PG 18
WC Hematology; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Hematology; Cardiovascular System & Cardiology
GA 363NK
UT WOS:000260273800031
PM 18802019
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Bogdanov, VY
AF Bogdanov, Vladimir Y.
TI Blood coagulation and alternative pre-mRNA splicing: An overview
SO CURRENT MOLECULAR MEDICINE
LA English
DT Review
ID TISSUE-FACTOR PATHWAY; LIPOPROTEIN-ASSOCIATED COAGULATION; PLATELET
   FACTOR-XI; PLASMA THROMBOPLASTIN ANTECEDENT; FACTOR-IX; FACTOR-VII;
   ISLET TRANSPLANTATION; CLINICAL-SIGNIFICANCE; MOLECULAR EVOLUTION;
   THROMBIN GENERATION
AB Throughout the 20th centuary, great advances were made in understanding of how blood coagulation occurs, what physiological and biochemical mechanisms are responsible for its regulationm, and what genes and their protein products comprise the essential components of the hemostatic network. Recently, complete sequencing of the human genome revealed that the structural diversity of higher eukaryotes cannot be solely attributed to the number of protein-encoding genes undergo alternative splicing, a mechanism that enables production of multiple protein-encoding genes undergo alternative splicing, a mechanism that enables production of multiple protein isoforms by a single gene. Research in the field of thrombosis and hemostasis revealed that the genes encoding several critical proteins at various junctures of the coagulation cascade produce alternative spliced protein isoforms with distinct structural and biochemical characteristics, revealing a principally novel dimension in the regulation of blood clotting and, possibly, a few novel therapeutic approaches to treatment of abnormal hemostasis. This review summarizes recently published data pertaining to biosynthesis of the alternatively spliced isoforms of tissue factor (TF, or coagulation factor III), tissue factor pathway inhibitor (TFPI), and coagulation factor XI (FXI), and discusses future directions of this continuously evolving area of biomedical research, with an emphasis on molecular mechanics responsible for regulation of constitutive as well as alternative pre-mRNA splicing.
C1 Mt Sinai Sch Med, Div Hematol & Med Oncol, Samuel Bronfman Dept Med, New York, NY 10029 USA.
C3 Icahn School of Medicine at Mount Sinai
RP Bogdanov, VY (corresponding author), Mt Sinai Sch Med, Div Hematol & Med Oncol, Samuel Bronfman Dept Med, 1 Gustave L Levy Pl,Box 1079, New York, NY 10029 USA.
EM vladimir.bogdanov@mssm.edu
OI Bogdanov, Vladimir/0000-0003-4968-1129
FU NIDDK NIH HHS [DK65752] Funding Source: Medline
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NR 119
TC 12
Z9 13
U1 0
U2 1
PU BENTHAM SCIENCE PUBL LTD
PI SHARJAH
PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB
   EMIRATES
SN 1566-5240
EI 1875-5666
J9 CURR MOL MED
JI Curr. Mol. Med.
PD DEC
PY 2006
VL 6
IS 8
BP 859
EP 869
DI 10.2174/156652406779010821
PG 11
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA 103UO
UT WOS:000241912400004
PM 17168737
DA 2025-04-10
ER

PT J
AU Han, Y
   Wennersten, SA
   Wright, JM
   Ludwig, RW
   Lau, E
   Lam, MPY
AF Han, Yu
   Wennersten, Sara A.
   Wright, Julianna M.
   Ludwig, R. W.
   Lau, Edward
   Lam, Maggie P. Y.
TI Proteogenomics reveals sex-biased aging genes and coordinated splicing
   in cardiac aging
SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
LA English
DT Article
DE aging; alternative splicing; proteoforms; proteogenomics; sex difference
ID R/BIOCONDUCTOR PACKAGE; SAMPLE PREPARATION; HEART-FAILURE; PROTEIN;
   EXPRESSION; PATHWAY; SIGNATURES; MICE; LOCALIZATION; PROTEOMICS
AB The risks of heart diseases are significantly modulated by age and sex, but how these factors influence baseline cardiac gene expression remains incompletely understood. Here, we used RNA sequencing and mass spectrometry to compare gene expres-sion in female and male young adult (4 mo) and early aging (20 mo) mouse hearts, identifying thousands of age-and sex -de-pendent gene expression signatures. Sexually dimorphic cardiac genes are broadly distributed, functioning in mitochondrial metabolism, translation, and other processes. In parallel, we found over 800 genes with differential aging response between male and female, including genes in cAMP and PKA signaling. Analysis of the sex-adjusted aging cardiac transcriptome revealed a widespread remodeling of exon usage patterns that is largely independent from differential gene expression, concomitant with upstream changes in RNA-binding protein and splice factor transcripts. To evaluate the impact of the splicing events on cardiac proteoform composition, we applied an RNA-guided proteomics computational pipeline to analyze the mass spectrometry data and detected hundreds of putative splice variant proteins that have the potential to rewire the cardiac proteome. Taken to-gether, the results here suggest that cardiac aging is associated with 1) widespread sex-biased aging genes and 2) a rewiring of RNA splicing programs, including sex-and age-dependent changes in exon usages and splice patterns that have the potential to influence cardiac protein structure and function. These changes contribute to the emerging evidence for considerable sexual dimorphism in the cardiac aging process that should be considered in the search for disease mechanisms.NEW & NOTEWORTHY Han et al. used proteogenomics to compare male and female mouse hearts at 4 and 20 mo. Sex-biased cardiac genes function in mitochondrial metabolism, translation, autophagy, and other processes. Hundreds of cardiac genes show sex-by-age interactions, that is, sex-biased aging genes. Cardiac aging is accompanied with a remodeling of exon usage in functionally coordinated genes, concomitant with differential expression of RNA-binding proteins and splice factors. These fea-tures represent an underinvestigated aspect of cardiac aging that may be relevant to the search for disease mechanisms.
C1 [Han, Yu; Wennersten, Sara A.; Wright, Julianna M.; Ludwig, R. W.; Lam, Maggie P. Y.] Univ Colorado, Dept Med, Anschutz Med Campus, Sch Med, Aurora, CO 80045 USA.
   [Lam, Maggie P. Y.] Univ Colorado, Dept Biochem & Mol Genet, Anschutz Med Campus, Sch Med, Aurora, CO 80045 USA.
C3 University of Colorado System; University of Colorado Anschutz Medical
   Campus; University of Colorado System; University of Colorado Anschutz
   Medical Campus
RP Lam, MPY (corresponding author), Univ Colorado, Dept Med, Anschutz Med Campus, Sch Med, Aurora, CO 80045 USA.; Lam, MPY (corresponding author), Univ Colorado, Dept Biochem & Mol Genet, Anschutz Med Campus, Sch Med, Aurora, CO 80045 USA.
EM maggie.lam@cuanschutz.edu
OI Lau, Edward/0000-0001-9083-5922; Wennersten, Sara/0000-0002-9846-9530
FU National Institutes of Health [F32-HL149191, R03-OD032666, R00-HL144829,
   R00-HL127302, R01-HL141278, R21-HL150456]; University of Colorado
   Undergraduate Research Opportunities Program mini -grant; University of
   Colorado Consortium; National Heart Lung and Blood Institute
   [R21HL150456, R00HL144829, F32HL149191] Funding Source: NIH RePORTER
FX This study was supported in part by National Institutes of Health Grants
   F32-HL149191 (to Y.H.) , R03-OD032666 and R00-HL144829 (to E.L.) , and
   R00-HL127302, R01-HL141278, and R21-HL150456 (to M.P.Y.L.) ; University
   of Colorado Undergraduate Research Opportunities Program mini -grant (to
   J.W.) ; and University of Colorado Consortium for Fibrosis Research and
   Translation funding (to M.P.Y.L.) .
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NR 104
TC 14
Z9 14
U1 1
U2 4
PU AMER PHYSIOLOGICAL SOC
PI Rockville
PA 6120 Executive Blvd, Suite 600, Rockville, MD, UNITED STATES
SN 0363-6135
EI 1522-1539
J9 AM J PHYSIOL-HEART C
JI Am. J. Physiol.-Heart Circul. Physiol.
PD SEP
PY 2022
VL 323
IS 3
BP H538
EP H558
DI 10.1152/ajpheart.00244.2022
PG 21
WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Physiology
GA 6S3BE
UT WOS:000892865400011
PM 35930447
OA Green Published
DA 2025-04-10
ER

PT J
AU Eisenreichi, A
   Zakrzewicz, A
   Huber, K
   Thierbach, H
   Pepke, W
   Goldin-Lang, P
   Schultheiss, HP
   Pries, A
   Rauch, U
AF Eisenreichi, Andreas
   Zakrzewicz, Andreas
   Huber, Kilian
   Thierbach, Hannes
   Pepke, Wojciech
   Goldin-Lang, Petra
   Schultheiss, Heinz-Peter
   Pries, Axel
   Rauch, Ursula
TI Regulation of pro-angiogenic tissue factor expression in hypoxia-induced
   human lung cancer cells
SO ONCOLOGY REPORTS
LA English
DT Article
DE tissue factor; splicing; angiogenesis; chemokines; A549
ID HUMAN ENDOTHELIAL-CELLS; ACTIVATED FACTOR-VII; DNA TOPOISOMERASE-I;
   INTEGRIN LIGATION; GENE-EXPRESSION; MESSENGER-RNA; BREAST-CANCER;
   UP-REGULATION; GROWTH; BLOOD
AB Alternative splicing is a key regulatory mechanism for cellular metabolism controlling cell proliferation and angiogenesis, both of which are crucial processes for tumorigenesis under hypoxia. Human cells express two tissue factor (TF) isoforms, alternatively spliced TF (asTF) and 'full length' TF (flTF). fITF is the major source of thrombogenicity whereas, the function of soluble asTF, particularly in cancer, is widely unknown. In the present study, we examined the impact of alternative splicing on the pro-angiogenic potential and the TF expression pattern of A549 cells under hypoxia. We focused our efforts toward alternative splicing factors, such as Clk1, and pro-angiogenic proliferation-regulating factors, such as Cyr61. We further examined the influence of asTF overexpression on the expression of MCP-1, Cyr61 and VEGF, as well as on cell number and pro-angiogenic properties of A549 cells. Notably, we found hypoxia to induce the expression of alternative splicing factors (Clk1 and Clk4) as well as proliferation- and angiogenesis-promoting factors (Cyr61 and flTF). asTF overexpression in A549 cells also increased both cell number and tube formation. These effects were mediated by the induction of Cyr61, MCP-1 and VEGF, as well as by integrin alpha(v)beta(3). Taken together, our results suggest that the pro-angiogenic potential of A549 lung cancer cells is modulated under hypoxic conditions via modulation of TF isoform expression which in turn is controlled by alternative splicing.
C1 [Eisenreichi, Andreas; Thierbach, Hannes; Pepke, Wojciech; Goldin-Lang, Petra; Schultheiss, Heinz-Peter; Rauch, Ursula] Charite, Centrum Herz & Kreislaufmed, D-12200 Berlin, Germany.
   [Zakrzewicz, Andreas; Pries, Axel] Charite, Inst Physiol, D-14195 Berlin, Germany.
   [Huber, Kilian] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria.
C3 Berlin Institute of Health; Free University of Berlin; Humboldt
   University of Berlin; Charite Universitatsmedizin Berlin; Berlin
   Institute of Health; Free University of Berlin; Humboldt University of
   Berlin; Charite Universitatsmedizin Berlin; Austrian Academy of
   Sciences; CeMM Research Center for Molecular Medicine of the Austrian
   Academy of Sciences
RP Rauch, U (corresponding author), Charite, Centrum Herz & Kreislaufmed, Campus Benjamin Franklin, D-12200 Berlin, Germany.
EM andreas.eisenreich@charite.de; ursula.rauch@charite.de
RI Schultheiss, Heinz-Peter/HMP-2467-2023; Huber, Kilian/L-6921-2015
OI Eisenreich, Andreas/0000-0002-0615-7901; Eisenreich,
   Andreas/0000-0001-7169-3615; Huber, Kilian/0000-0002-1103-5300
FU Deutsche Forschungsgemeinschaft (DFG) [SFB-TR19]; Else
   Kroner-Fresenius-Stiftung [P09/08//A129/07]
FX This study was supported by grants from the Deutsche
   Forschungsgemeinschaft (DFG) (SFB-TR19 to U.R. and H.-P.S.), and the
   Else Kroner-Fresenius-Stiftung (P09/08//A129/07 to U.R).
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NR 39
TC 40
Z9 48
U1 0
U2 6
PU SPANDIDOS PUBL LTD
PI ATHENS
PA POB 18179, ATHENS, 116 10, GREECE
SN 1021-335X
J9 ONCOL REP
JI Oncol. Rep.
PD JUL
PY 2013
VL 30
IS 1
BP 462
EP 470
DI 10.3892/or.2013.2413
PG 9
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 173KD
UT WOS:000321077500065
PM 23604472
OA Bronze
DA 2025-04-10
ER

PT J
AU Caines, R
   Cochrane, A
   Kelaini, S
   Vila-Gonzalez, M
   Yang, CB
   Eleftheriadou, M
   Moez, A
   Stitt, AW
   Zeng, LF
   Grieve, DJ
   Margariti, A
AF Caines, Rachel
   Cochrane, Amy
   Kelaini, Sophia
   Vila-Gonzalez, Marta
   Yang, Chunbo
   Eleftheriadou, Magdalini
   Moez, Arya
   Stitt, Alan W.
   Zeng, Lingfang
   Grieve, David J.
   Margariti, Andriana
TI The RNA-binding protein QKI controls alternative splicing in vascular
   cells, producing an effective model for therapy
SO JOURNAL OF CELL SCIENCE
LA English
DT Article
DE Vascular smooth muscle cell; Cellular reprogramming; Cell signalling;
   Stem cells; Revascularisation
ID SMOOTH-MUSCLE-CELLS; STEM-CELLS; ENDOTHELIAL-CELLS; QUAKING;
   DIFFERENTIATION; MECHANISMS; REGULATOR; HDAC7; PROLIFERATION;
   ANGIOGENESIS
AB Dysfunction of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) leads to ischaemia, the central pathology of cardiovascular disease. Stem cell technology will revolutionise regenerative medicine, but a need remains to understand key mechanisms of vascular differentiation. RNA-binding proteins have emerged as novel post-transcriptional regulators of alternative splicing and we have previously shown that the RNA-binding protein Quaking (QKI) plays roles in EC differentiation. In this study, we decipher the role of the alternative splicing isoform Quaking 6 (QKI-6) to induce VSMC differentiation from induced pluripotent stem cells (iPSCs). PDGF-BB stimulation induced QKI-6, which bound to HDAC7 intron 1 via the QKI-binding motif, promoting HDAC7 splicing and iPS-VSMC differentiation. Overexpression of QKI-6 transcriptionally activated SM22 (also known as TAGLN), while QKI-6 knockdown diminished differentiation capability. VSMCs overexpressing QKI-6 demonstrated greater contractile ability, and upon combination with iPS-ECs-overexpressing the alternative splicing isoform Quaking 5 (QKI-5), exhibited higher angiogenic potential in vivo than control cells alone. This study demonstrates that QKI-6 is critical for modulation of HDAC7 splicing, regulating phenotypically and functionally robust iPS-VSMCs. These findings also highlight that the QKI isoforms hold key roles in alternative splicing, giving rise to cells which can be used in vascular therapy or for disease modelling.
   This article has an associated First Person interview with the first author of the paper.
C1 [Caines, Rachel; Cochrane, Amy; Kelaini, Sophia; Vila-Gonzalez, Marta; Yang, Chunbo; Eleftheriadou, Magdalini; Moez, Arya; Stitt, Alan W.; Grieve, David J.; Margariti, Andriana] Queens Univ Belfast, Wellcome Wolfson Inst Expt Med, 97 Lisburn Rd, Belfast BT9 7BL, Antrim, North Ireland.
   [Zeng, Lingfang] Kings Coll London, Cardiovasc Div, London SE5 9NU, England.
C3 Queens University Belfast; University of London; King's College London
RP Margariti, A (corresponding author), Queens Univ Belfast, Wellcome Wolfson Inst Expt Med, 97 Lisburn Rd, Belfast BT9 7BL, Antrim, North Ireland.
EM a.margariti@qub.ac.uk
RI Vila-Gonzalez, Marta/JZT-7482-2024; Grieve, David/F-5035-2010;
   Margariti, Andriana/AAH-5318-2019; Stitt, Alan/A-9842-2009
OI Zeng, Lingfang/0000-0002-0390-4561; Stitt, Alan/0000-0002-8647-9918;
   Caines, Rachel/0000-0001-9006-1015; Vila Gonzalez,
   Marta/0000-0002-7463-1046
FU British Heart Foundation [FS/15/23/31435, PG/16/8/31985,
   PG/18/29/33731]; Biotechnology and Biological Sciences Research Council
   (BBSRC) [BB/M003221/1]; BBSRC [BB/M003221/1] Funding Source: UKRI
FX This work was supported by grants from the British Heart Foundation
   (FS/15/23/31435, PG/16/8/31985 and PG/18/29/33731) and Biotechnology and
   Biological Sciences Research Council (BBSRC) (BB/M003221/1).
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NR 59
TC 24
Z9 25
U1 0
U2 7
PU COMPANY BIOLOGISTS LTD
PI CAMBRIDGE
PA BIDDER BUILDING, STATION RD, HISTON, CAMBRIDGE CB24 9LF, ENGLAND
SN 0021-9533
EI 1477-9137
J9 J CELL SCI
JI J. Cell Sci.
PD AUG
PY 2019
VL 132
IS 16
AR jcs230276
DI 10.1242/jcs.230276
PG 13
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA IV1FT
UT WOS:000484023400009
PM 31331967
OA Green Published, Bronze
DA 2025-04-10
ER

PT J
AU Pang, PD
   Alsina, KM
   Cao, SY
   Koushik, AB
   Wehrens, XHT
   Cooper, TA
AF Pang, Paul D.
   Alsina, Katherina M.
   Cao, Shuyi
   Koushik, Amrita B.
   Wehrens, Xander H. T.
   Cooper, Thomas A.
TI CRISPR-Mediated Expression of the Fetal Scn5a Isoform in Adult
   Mice Causes Conduction Defects and Arrhythmias
SO JOURNAL OF THE AMERICAN HEART ASSOCIATION
LA English
DT Article
DE alternative splicing; arrhythmia; conduction; myotonic dystrophy
   cardiomyopathy; SCN5A
ID SODIUM-CHANNEL MUTATIONS; MYOTONIC-DYSTROPHY; VENTRICULAR-TACHYCARDIA;
   SUDDEN-DEATH; EPIDEMIOLOGY; PATHOGENESIS; INVOLVEMENT; DYSFUNCTION
AB Background-The sodium channel, Nav1.5, encoded by SCN5A, undergoes developmentally regulated splicing from inclusion of exon 6A in the fetal heart to exon 6B in adults. These mutually exclusive exons differ in 7 amino acids altering the electrophysiological properties of the Nav1.5 channel. In myotonic dystrophy type 1, SCN5A is mis-spliced such that the fetal pattern of exon 6A inclusion is detected in adult hearts. Cardiac manifestations of myotonic dystrophy type 1 include conduction defects and arrhythmias and are the second-leading cause of death.
   Methods and Results-This work aimed to determine the impact of SCN5A mis-splicing on cardiac function. We used clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) to delete Scn5a exon 6B in mice, thereby redirecting splicing toward exon 6A. These mice exhibit prolonged PR and QRS intervals, slowed conduction velocity, extended action potential duration, and are highly susceptible to arrhythmias.
   Conclusions-Our findings highlight a nonmutational pathological mechanism of arrhythmias and conduction defects as a result of mis-splicing of the predominant cardiac sodium channel. Animals homozygous for the deleted exon express only the fetal isoform and have more-severe phenotypes than heterozygotes that also express the adult isoform. This observation is directly relevant to myotonic dystrophy type 1, and possibly pathological arrhythmias, in which individuals differ with regard to the ratios of the isoforms expressed.
C1 [Pang, Paul D.; Alsina, Katherina M.; Cao, Shuyi; Wehrens, Xander H. T.; Cooper, Thomas A.] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA.
   [Pang, Paul D.; Koushik, Amrita B.; Cooper, Thomas A.] Baylor Coll Med, Dept Pathol & Immunol, One Baylor Plaza,Rm 268B,Mail Stop BCM315, Houston, TX 77030 USA.
   [Cooper, Thomas A.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
   [Wehrens, Xander H. T.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA.
   [Wehrens, Xander H. T.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA.
   [Pang, Paul D.; Alsina, Katherina M.; Wehrens, Xander H. T.; Cooper, Thomas A.] Baylor Coll Med, Integrat Mol & Biomed Sci Program, Houston, TX 77030 USA.
   [Wehrens, Xander H. T.] Baylor Coll Med, Ctr Space Med, Houston, TX 77030 USA.
   [Wehrens, Xander H. T.; Cooper, Thomas A.] Baylor Coll Med, Cardiovasc Res Inst, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Baylor College of Medicine; Baylor College
   of Medicine; Baylor College of Medicine; Baylor College of Medicine;
   Baylor College of Medicine; Baylor College of Medicine; Baylor College
   of Medicine
RP Cooper, TA (corresponding author), Baylor Coll Med, Dept Pathol & Immunol, One Baylor Plaza,Rm 268B,Mail Stop BCM315, Houston, TX 77030 USA.
EM tcooper@bcm.edu
RI Wehrens, Xander/AAQ-9574-2020; cao, shuyi/LEN-1501-2024
OI Wehrens, Xander/0000-0001-5044-672X
FU NIH [R01HL045565, R01AR045653, R01AR060733, T32HL07676, F31HL140879,
   R01HL089598, R01HL091947, R01HL117641]; Muscular Dystrophy Foundation;
   American Heart Association [13EIA 14560061]; Saving Tiny Hearts
   Foundation
FX Pang is funded by the NIH (T32HL07676, F31HL140879). Cooper is funded by
   the NIH (R01HL045565, R01AR045653, and R01AR060733) and the Muscular
   Dystrophy Foundation. Wehrens is funded by the NIH (R01HL089598,
   R01HL091947, and R01HL117641), American Heart Association (13EIA
   14560061), and Saving Tiny Hearts Foundation.
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NR 36
TC 24
Z9 26
U1 0
U2 3
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 2047-9980
J9 J AM HEART ASSOC
JI J. Am. Heart Assoc.
PD OCT 2
PY 2018
VL 7
IS 19
AR e010393
DI 10.1161/JAHA.118.010393
PG 10
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA HD8QG
UT WOS:000452823000041
PM 30371314
OA gold, Green Submitted, Green Published
DA 2025-04-10
ER

PT J
AU Xiao, QL
   Ford, AL
   Xu, J
   Yan, P
   Lee, KY
   Gonzales, E
   West, T
   Holtzman, DM
   Lee, JM
AF Xiao, Qingli
   Ford, Andria L.
   Xu, Jan
   Yan, Ping
   Lee, Kuang-Yung
   Gonzales, Ernesto
   West, Tim
   Holtzman, David M.
   Lee, Jin-Moo
TI Bcl-x Pre-mRNA Splicing Regulates Brain Injury after Neonatal
   Hypoxia-Ischemia
SO JOURNAL OF NEUROSCIENCE
LA English
DT Article
ID CEREBRAL ENDOTHELIAL-CELLS; MYOTONIC-DYSTROPHY; BINDING-PROTEIN;
   ANTISENSE OLIGONUCLEOTIDES; SELECTIVE VULNERABILITY; BH3 DOMAIN;
   DENN-SV; APOPTOSIS; DEATH; MICE
AB The bcl-x gene appears to play a critical role in regulating apoptosis in the developing and mature CNS and following CNS injury. Two isoforms of Bcl-x are produced as a result of alternative pre-mRNA splicing: Bcl-x(L) (the long form) is anti-apoptotic, while Bcl-x(S) (short form) is pro-apoptotic. Despite the antagonistic activities of these two isoforms, little is known about how regulation of alternative splicing of bcl-x may mediate neural cell apoptosis. Here, we report that apoptotic stimuli (staurosporine or C2-ceramide) reciprocally altered Bcl-x splicing in neural cells, decreasing Bcl-x(L) while increasing Bcl-x(S). Specific knockdown of Bcl-x(S) attenuated apoptosis. To further define regulatory elements that influenced Bcl-x splicing, a Bcl-x minigene was constructed. Deletional analysis revealed several consensus sequences within intron 2 that altered splicing. We found that the splicing factor, CUG-binding-protein-1 (CUGBP1), bound to a consensus sequence close to the Bcl-x(L) 5' splice site, altering the Bcl-x(L)/Bcl-x(S) ratio and influencing cell death. In vivo, neonatal hypoxia-ischemia reciprocally altered Bcl-x pre-mRNA splicing, similar to the in vitro studies. Manipulation of the splice isoforms using viral gene transfer of Bcl-x(S) shRNA into the hippocampus of rats before neonatal hypoxia-ischemia decreased vulnerability to injury. Moreover, alterations in nuclear CUGBP1 preceded Bcl-x splicing changes. These results suggest that alternative pre-mRNA splicing may be an important regulatory mechanism for cell death after acute neurological injury and may potentially provide novel targets for intervention.
C1 [Lee, Jin-Moo] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA.
   Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA.
C3 Washington University (WUSTL); Washington University (WUSTL)
RP Lee, JM (corresponding author), 660 S Euclid Ave,Campus Box 8111, St Louis, MO 63110 USA.
EM leejm@neuro.wustl.edu
RI Ford, Andria/AAI-2786-2021; Lee, Jin-Moo/K-2024-2015
OI Lee, Jin-Moo/0000-0002-3979-0906
FU National Institutes of Health [R01 NS48283, R01 NS67905, P01 NS32636,
   P01 NS35902]; American Heart Association [0720035Z]; NIH Neuroscience
   Blueprint Center [P30 NS057105]; Hope Center for Neurological Disorders;
   American Heart Association (AHA) [0720035Z] Funding Source: American
   Heart Association (AHA)
FX This work was supported by the National Institutes of Health Grants R01
   NS48283, R01 NS67905, and P01 NS32636 (to J.M.L.), P01 NS35902 (to
   D.M.H.), American Heart Association Grant 0720035Z (to Q.X), NIH
   Neuroscience Blueprint Center Core Grant P30 NS057105, and a grant from
   the Hope Center for Neurological Disorders.
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NR 46
TC 16
Z9 17
U1 0
U2 3
PU SOC NEUROSCIENCE
PI WASHINGTON
PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA
SN 0270-6474
J9 J NEUROSCI
JI J. Neurosci.
PD SEP 26
PY 2012
VL 32
IS 39
BP 13587
EP 13596
DI 10.1523/JNEUROSCI.2617-12.2012
PG 10
WC Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 016GR
UT WOS:000309506300028
PM 23015448
OA Green Accepted, Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Martino, F
   Varadarajan, NM
   Perestrelo, AR
   Hejret, V
   Durikova, H
   Vukic, D
   Horvath, V
   Cavalieri, F
   Caruso, F
   Albihlal, WS
   Gerber, AP
   O'Connell, MA
   Vanacova, S
   Pagliari, S
   Forte, G
AF Martino, Fabiana
   Varadarajan, Nandan Mysore
   Perestrelo, Ana Rubina
   Hejret, Vaclav
   Durikova, Helena
   Vukic, Dragana
   Horvath, Vladimir
   Cavalieri, Francesca
   Caruso, Frank
   Albihlal, Waleed S.
   Gerber, Andre P.
   O'Connell, Mary A.
   Vanacova, Stepanka
   Pagliari, Stefania
   Forte, Giancarlo
TI The mechanical regulation of RNA binding protein hnRNPC in the failing
   heart
SO SCIENCE TRANSLATIONAL MEDICINE
LA English
DT Article
ID GENE-EXPRESSION; QUALITY-CONTROL; MESSENGER-RNAS; STEM-CELLS; WEB
   SERVER; KINASE-C; MATRIX; TRANSLATION; TRANSCRIPTOME; CYTOSCAPE
AB Cardiac pathologies are characterized by intense remodeling of the extracellular matrix (ECM) that eventually leads to heart failure. Cardiomyocytes respond to the ensuing biomechanical stress by reexpressing fetal contractile proteins via transcriptional and posttranscriptional processes, such as alternative splicing (AS). Here, we demonstrate that the heterogeneous nuclear ribonucleoprotein C (hnRNPC) is up-regulated and relocates to the sarcomeric Z-disc upon ECM pathological remodeling. We show that this is an active site of localized translation, where the ribonucleoprotein associates with the translation machinery. Alterations in hnRNPC expression, phosphorylation, and localization can be mechanically determined and affect the AS of mRNAs involved in mechanotransduction and cardiovascular diseases, including Hippo pathway effector Yes-associated protein 1. We propose that cardiac ECM remodeling serves as a switch in RNA metabolism by affecting an associated regulatory protein of the spliceosome apparatus. These findings offer new insights on the mechanism of mRNA homeostatic mechanoregulation in pathological conditions.
C1 [Martino, Fabiana; Perestrelo, Ana Rubina; Durikova, Helena; Horvath, Vladimir; Pagliari, Stefania; Forte, Giancarlo] St Annes Univ Hosp, Int Clin Res Ctr ICRC, CZ-65691 Brno, Czech Republic.
   [Martino, Fabiana] Masaryk Univ, Dept Biol, Fac Med, CZ-62500 Brno, Czech Republic.
   [Martino, Fabiana; Pagliari, Stefania; Forte, Giancarlo] Competence Ctr Me chanobiol Regenerat Med, INTERREG ATCZ133, CZ-62500 Brno, Czech Republic.
   [Martino, Fabiana] Imperial Coll London, Natl Heart & Lung Inst NHLI, Cardiac Sect, Fac Med, London W12 0NN, England.
   [Varadarajan, Nandan Mysore; Hejret, Vaclav; Vukic, Dragana; O'Connell, Mary A.; Vanacova, Stepanka] Masaryk Univ, Cent European Inst Technol CEITEC, CZ-62500 Brno, Czech Republic.
   [Hejret, Vaclav] Masaryk Univ, Natl Ctr Biomol Res, CZ-62500 Brno, Czech Republic.
   [Horvath, Vladimir; Caruso, Frank] Ctr Cardiovasc & Transplant Surg, CZ-60200 Brno, Czech Republic.
   [Cavalieri, Francesca] Univ Melbourne, Dept Chem Engn, Parkville, Vic 3010, Australia.
   [Cavalieri, Francesca] Univ Roma Tor Vergata, Dipartimento Sci & Tecnol Chim, I-00133 Rome, Italy.
   [Albihlal, Waleed S.] Francis Crick Inst, London NW1 1AT, England.
   [Gerber, Andre P.] Univ Surrey, Fac Hlth & Med Sci, Dept Microbial Sci, Guildford GU2 7XH, Surrey, England.
   [Forte, Giancarlo] Kings Coll London, Sch Cardiovasc & Metab Med & Sci, London WC2R 2LS, England.
C3 St. Anne's University Hospital Brno (FNUSA); Masaryk University Brno;
   Imperial College London; Masaryk University Brno; Masaryk University
   Brno; University of Melbourne; University of Rome Tor Vergata; Francis
   Crick Institute; University of Surrey; University of London; King's
   College London
RP Pagliari, S; Forte, G (corresponding author), St Annes Univ Hosp, Int Clin Res Ctr ICRC, CZ-65691 Brno, Czech Republic.; Pagliari, S; Forte, G (corresponding author), Competence Ctr Me chanobiol Regenerat Med, INTERREG ATCZ133, CZ-62500 Brno, Czech Republic.; Forte, G (corresponding author), Kings Coll London, Sch Cardiovasc & Metab Med & Sci, London WC2R 2LS, England.
EM stefania.pagliari@f-nusa.cz; giancarlo.forte@fnusa.cz
RI Albihlal, Waleed/GOE-5427-2022; Iadevaia, Valentina/J-8613-2017;
   Cavalieri, Francesca/AAH-8644-2020; Martino, Fabiana/AAY-2170-2021;
   O'Connell, Mary/U-7693-2019; Vanacova, Stepanka/AGO-9953-2022; Forte,
   Giancarlo/M-1447-2017; Caruso, Frank/A-9587-2011
OI Forte, Giancarlo/0000-0002-1341-1023; Caruso, Frank/0000-0002-0197-497X;
   Martino, Fabiana/0000-0001-9667-6184; Vukic,
   Dragana/0000-0001-9272-728X; Durikova, Helena/0000-0001-6613-9177;
   O'Connell, Mary Anne/0000-0003-3844-6174; Gerber,
   Andre/0000-0002-2398-6592
FU European Regional Development Fund-Project ENOCH
   [CZ.02.1.01/0.0/0.0/16_019/0000868]; European Social Fund; European
   Regional Development Fund-Project MAGNET
   [CZ.02.1.01/0.0/0.0/15_003/0000492]; National Health and Medical
   Research Council Senior Principal Research Fellowship [GNT1135806];
   Australian Research Council (ARC) Future Fellowship scheme
   [FT140100873]; European Union [690901]; BBSRC [BB/N008820/1]; Royal
   SocietyWolfson Research Merit Award [WM170036]; Czech Science Foundation
   [20-19617S]; GACR [20-11101S]; Ministry of Education, Youth, and Sports
   within programme INTER-COST [LTC18052]; CEITEC [LQ1601]; Marie Curie
   Actions (MSCA) [690901] Funding Source: Marie Curie Actions (MSCA);
   BBSRC [BB/N008820/1] Funding Source: UKRI
FX F.M. was supported by the European Regional Development Fund-Project
   ENOCH (no. CZ.02.1.01/0.0/0.0/16_019/0000868). A.R.P., G.F., and S.P.
   were supported by the European Social Fund and European Regional
   Development Fund-Project MAGNET (CZ.02.1.01/0.0/0.0/15_003/0000492). F.
   Caruso acknowledges the award of a National Health and Medical Research
   Council Senior Principal Research Fellowship (GNT1135806). F. Cavalieri
   acknowledges the award of an Australian Research Council (ARC) Future
   Fellowship scheme (FT140100873) and the European Union's Horizon 2020
   Research and Innovation Program under grant agreement no. 690901
   (NANOSUPREMI). W.S.A. and A.P.G. were supported by the BBSRC
   (BB/N008820/1) and a Royal SocietyWolfson Research Merit Award
   (WM170036) to A.P.G. S.V. and N.M.V. were supported by the Czech Science
   Foundation (20-19617S) and the institutional support CEITEC 2020
   (LQ1601). D.V. was supported by GACR 20-11101S. M.A.O. was supported by
   the Ministry of Education, Youth, and Sports within programme INTER-COST
   (LTC18052).
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   2010, P NATL ACAD SCI US, V107
NR 110
TC 18
Z9 20
U1 3
U2 24
PU AMER ASSOC ADVANCEMENT SCIENCE
PI WASHINGTON
PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA
SN 1946-6234
EI 1946-6242
J9 SCI TRANSL MED
JI Sci. Transl. Med.
PD NOV 23
PY 2022
VL 14
IS 672
AR eabo5715
DI 10.1126/scitranslmed.abo5715
PG 17
WC Cell Biology; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Research & Experimental Medicine
GA 6R5TM
UT WOS:000892365400001
PM 36417487
OA Green Accepted, Green Submitted
DA 2025-04-10
ER

PT J
AU Zheng, XX
   Reho, JJ
   Wirth, B
   Fisher, SA
AF Zheng, Xiaoxu
   Reho, John J.
   Wirth, Brunhilde
   Fisher, Steven A.
TI TRA2β controls Mypt1 exon 24 splicing in the developmental maturation of
   mouse mesenteric artery smooth muscle
SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
LA English
DT Article
DE smooth muscle; development; alternative splicing; myosin phosphatase;
   cGMP
ID MYOSIN PHOSPHATASE ISOFORMS; DROSOPHILA-MELANOGASTER; DIFFERENTIATION;
   HYPERTENSION; SEX; INNERVATION; RELAXATION; EXPRESSION; DIVERSITY;
   PROTEIN
AB Diversity of smooth muscle within the vascular system is generated by alternative splicing of exons, yet there is limited understanding of its timing or control mechanisms. We examined splicing of myosin phosphatase regulatory subunit (Mypt1) exon 24 (E24) in relation to smooth muscle myosin heavy chain (Smmhc) and smoothelin (Smtn) alternative exons (Smmhc E6 and Smtn E20) during maturation of mouse mesenteric artery (MA) smooth muscle. The role of transformer 2 beta (Tra2 beta), a master regulator of splicing in flies, in maturation of arterial smooth muscle was tested through gene inactivation. Splicing of alternative exons in bladder smooth muscle was examined for comparative purposes. MA smooth muscle maturation began after postnatal week 2 and was complete at maturity, as indicated by switching to Mypt1 E24(+) and Smtn E20-splice variants and 11-fold induction of Smmhc. Similar changes in bladder were complete by postnatal day 3. Splicing of Smmhc E6 was temporally dissociated from Mypt1 E24 and Smtn E20 and discordant between arteries and bladder. Tamoxifen-induced smooth muscle-specific inactivation of Tra2 beta within the first week of life but not in maturity reduced splicing of Mypt1 E24 in MAs. Inactivation of Tra2 beta causing a switch to the isoform of MYPT1 containing the COOH-terminal leucine zipper motif (E24(-)) increased arterial sensitivity to cGMP-mediated relaxation. In conclusion, maturation of mouse MA smooth muscle begins postnatally and continues until sexual maturity. TRA2 beta is required for specification during this period of maturation, and its inactivation alters the contractile properties of mature arterial smooth muscle.
C1 [Zheng, Xiaoxu; Reho, John J.; Fisher, Steven A.] Univ Maryland, Sch Med, Div Cardiovasc Med, Baltimore, MD 21201 USA.
   [Wirth, Brunhilde] Univ Cologne, Inst Human Genet, D-50931 Cologne, Germany.
   [Wirth, Brunhilde] Univ Cologne, Inst Genet, Cologne, Germany.
   [Wirth, Brunhilde] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany.
C3 University System of Maryland; University of Maryland Baltimore;
   University of Cologne; University of Cologne; University of Cologne
RP Fisher, SA (corresponding author), Univ Maryland, Sch Med, Div Cardiovasc Med, HSFII, S012a,20 Penn St, Baltimore, MD 21201 USA.
EM sfisher1@medicine.umaryland.edu
RI Wirth, Brunhilde/H-3192-2019
OI Wirth, Brunhilde/0000-0003-4051-5191; Reho, John/0000-0003-0981-3027
FU National Institutes of Health [R01 HL-066171, T32 HL-072751, T32
   AR-007592]
FX This work was supported by National Institutes of Health Grant R01
   HL-066171 (to S. A. Fisher) and Grants T32 HL-072751 and T32 AR-007592
   (to J. Reho).
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NR 33
TC 14
Z9 15
U1 0
U2 3
PU AMER PHYSIOLOGICAL SOC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0363-6143
EI 1522-1563
J9 AM J PHYSIOL-CELL PH
JI Am. J. Physiol.-Cell Physiol.
PD FEB 15
PY 2015
VL 308
IS 4
BP C289
EP C296
DI 10.1152/ajpcell.00304.2014
PG 8
WC Cell Biology; Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Physiology
GA CD1EU
UT WOS:000350818000002
PM 25428883
OA Green Published
DA 2025-04-10
ER

PT J
AU Buyon, JP
   Tseng, CE
   DiDonato, F
   Rashbaum, W
   Morris, A
   Chan, EKL
AF Buyon, JP
   Tseng, CE
   DiDonato, F
   Rashbaum, W
   Morris, A
   Chan, EKL
TI Cardiac expression of 52 beta, an alternative transcript of the
   congenital heart block-associated 52-kd SS-A/Ro autoantigen, is maximal
   during fetal development
SO ARTHRITIS AND RHEUMATISM
LA English
DT Article
ID SYSTEMIC LUPUS-ERYTHEMATOSUS; CULTURED HUMAN KERATINOCYTES;
   ESTROGEN-RECEPTORS; NUCLEAR ANTIGENS; ANTIBODIES; PROTEIN;
   IDENTIFICATION; AUTOANTIBODIES; MOTHERS; BINDING
AB Objective. Congenital heart block (CHB), associated with antibodies to SS-A/Ro and SS-B/La, is most often detected between 18 and 24 weeks of gestation, yet the maternal heart is unaffected, We recently described an alternatively spliced 52-kd SS-A/Ro messenger RNA (mRNA) derived from the skipping of exon 4 which encodes a smaller protein, 52 beta (MW 45 kd), recognized by CHB maternal antisera, This study was designed to identify whether cardiac expression of 52 beta and full-length 52 alpha relates to the development of CHB.
   Methods. Reverse transcriptase-polymerase chain reaction was performed using primers flanking exon 4 and mRNA from 22 human fetal hearts (age 11-25 weeks) and 3 adult hearts, The brain, kidney, liver, lung, and spleen were similarly evaluated in a 15-week, an 18-week, and a 24-week fetus.
   Results. Expression of 52 beta was greatest and 52 alpha lowest between 14 and 16 weeks of gestation, In fetal hearts ages 22-25 weeks and adult heart, the 52 beta transcript was markedly diminished and 52 alpha clearly dominated. The 52 beta mRNA was observed in a 15-week brain, kidney, lung, and spleen; however, its expression relative to 52 alpha was greatest in the heart.
   Conclusion. Since expression of the alternative product 52 beta is maximal at the time of cardiac ontogeny when maternal antibodies gain access to the fetal circulation, just prior to the clinical detection of bradyarrhythmia, a role for 52 beta in the development of CHB is implicated, Although other fetal tissues express 52 beta, there may be differences in accessibility of antigen or regenerative capacities.
C1 NYU, SCH MED, NEW YORK, NY USA.
   BETH ISRAEL MED CTR, NEW YORK, NY 10003 USA.
   SCRIPPS RES INST, LA JOLLA, CA USA.
C3 New York University; Harvard University; Harvard University Medical
   Affiliates; Beth Israel Deaconess Medical Center; Scripps Research
   Institute
RP HOSP JOINT DIS & MED CTR, DEPT RHEUMATOL, ROOM 1608, 301 E 17TH ST, NEW YORK, NY 10003 USA.
RI ; Chan, Edward/B-5671-2009
OI Buyon, Jill/0000-0002-3852-7129; Chan, Edward/0000-0003-3938-9503
FU NIAMS NIH HHS [AR-41803, AR-42455] Funding Source: Medline
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NR 32
TC 53
Z9 54
U1 0
U2 0
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0004-3591
EI 1529-0131
J9 ARTHRITIS RHEUM-US
JI Arthritis Rheum.
PD APR
PY 1997
VL 40
IS 4
BP 655
EP 660
DI 10.1002/art.1780400410
PG 6
WC Rheumatology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Rheumatology
GA WR366
UT WOS:A1997WR36600009
PM 9125247
DA 2025-04-10
ER

PT J
AU Lara-Pezzi, E
   Dopazo, A
   Manzanares, M
AF Lara-Pezzi, Enrique
   Dopazo, Ana
   Manzanares, Miguel
TI Understanding cardiovascular disease: a journey through the genome (and
   what we found there)
SO DISEASE MODELS & MECHANISMS
LA English
DT Review
ID CORONARY-ARTERY-DISEASE; INDEPENDENT RISK-FACTOR; LONG NONCODING RNAS;
   CARDIAC-HYPERTROPHY; WIDE ASSOCIATION; HEART-FAILURE;
   MYOCARDIAL-INFARCTION; EPIGENETIC REGULATION; MISSING HERITABILITY;
   HISTONE DEACETYLASES
AB Cardiovascular disease (CVD) is a major cause of mortality and hospitalization worldwide. Several risk factors have been identified that are strongly associated with the development of CVD. However, these explain only a fraction of cases, and the focus of research into the causes underlying the unexplained risk has shifted first to genetics and more recently to genomics. A genetic contribution to CVD has long been recognized; however, with the exception of certain conditions that show Mendelian inheritance, it has proved more challenging than anticipated to identify the precise genomic components responsible for the development of CVD. Genome-wide association studies (GWAS) have provided information about specific genetic variations associated with disease, but these are only now beginning to reveal the underlying molecular mechanisms. To fully understand the biological implications of these associations, we need to relate them to the exquisite, multilayered regulation of protein expression, which includes chromatin remodeling, regulatory elements, microRNAs and alternative splicing. Understanding how the information contained in, the DNA relates to the operation of these regulatory layers will allow us not only to better predict the development of CVD but also to develop more effective therapies.
C1 [Lara-Pezzi, Enrique; Manzanares, Miguel] Cardiovasc CNIC, Ctr Nacl Invest, Cardiovasc Dev & Repair Dept, Madrid 28029, Spain.
   [Dopazo, Ana] Cardiovasc CNIC, Ctr Nacl Invest, Genom Unit, Madrid 28029, Spain.
C3 Centro Nacional de Investigaciones Cardiovasculares (CNIC); Centro
   Nacional de Investigaciones Cardiovasculares (CNIC)
RP Lara-Pezzi, E (corresponding author), Cardiovasc CNIC, Ctr Nacl Invest, Cardiovasc Dev & Repair Dept, Melchor Fernandez Almagro 3, Madrid 28029, Spain.
EM elara@cnic.es; adopazo@cnic.es; mmanzanares@cnic.es
RI Manzanares, Miguel/AAZ-8305-2021; Manzanares, Miguel/E-1702-2015;
   Dopazo, Ana/N-1159-2014; Lara-Pezzi, Enrique/E-2350-2015
OI Manzanares, Miguel/0000-0003-4849-2836; Dopazo, Ana/0000-0002-4910-1684;
   Lara-Pezzi, Enrique/0000-0002-2743-1033
FU European Union [ERG-239158, ITN-289600]; Spanish Ministry of Science and
   Innovation [BFU2009-10016, CP08/00144, FIS PI10/01124, BFU2011-23083];
   Regional Government of Madrid [S2010/BMD-2321, S2010/BMD-2315]; CNIC
   Translational Grant [CNIC-08-2009]; Spanish Government; Pro-CNIC
   Foundation
FX EL-P. was supported by grants from the European Union [ERG-239158,
   ITN-289600], the Spanish Ministry of Science and Innovation
   [BFU2009-10016, CP08/00144] and the Regional Government of Madrid
   [S2010/BMD-2321]; A.D. by a grant from the Spanish Ministry of Science
   and Innovation [FIS PI10/01124]; and M.M. by grants from the Spanish
   Ministry of Science and Innovation [BFU2011-23083], the Regional
   Government of Madrid [S2010/BMD-2315] and a CNIC Translational Grant
   [CNIC-08-2009]. The CNIC is supported by the Spanish Government and the
   Pro-CNIC Foundation.
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NR 109
TC 31
Z9 34
U1 0
U2 15
PU COMPANY BIOLOGISTS LTD
PI CAMBRIDGE
PA BIDDER BUILDING, STATION RD, HISTON, CAMBRIDGE CB24 9LF, ENGLAND
SN 1754-8403
EI 1754-8411
J9 DIS MODEL MECH
JI Dis. Model. Mech.
PD JUL
PY 2012
VL 5
IS 4
BP 434
EP 443
DI 10.1242/dmm.009787
PG 10
WC Cell Biology; Medicine, Research & Experimental; Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Research & Experimental Medicine; Pathology
GA 978VL
UT WOS:000306773800004
PM 22730474
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU James, V
   Nizamudeen, ZA
   Lea, D
   Dottorini, T
   Holmes, TL
   Johnson, BB
   Arkill, KP
   Denning, C
   Smith, JGW
AF James, Victoria
   Nizamudeen, Zubair A.
   Lea, Daniel
   Dottorini, Tania
   Holmes, Terri L.
   Johnson, Benjamin B.
   Arkill, Kenton P.
   Denning, Chris
   Smith, James G. W.
TI Transcriptomic Analysis of Cardiomyocyte Extracellular Vesicles in
   Hypertrophic Cardiomyopathy Reveals Differential snoRNA Cargo
SO STEM CELLS AND DEVELOPMENT
LA English
DT Article
DE cardiomyocytes; hypertrophic; pluripotent stem cells; extracellular
   vesicles
ID SMALL-NUCLEOLAR RNAS; EXOSOMES; PREVALENCE; PHENOTYPES; MUTATIONS;
   FIBROSIS
AB Hypertrophic cardiomyopathy (HCM) is characterized by increased left ventricular wall thickness that can lead to devastating conditions such as heart failure and sudden cardiac death. Despite extensive study, the mechanisms mediating many of the associated clinical manifestations remain unknown and human models are required. To address this, human-induced pluripotent stem cell (hiPSC) lines were generated from patients with a HCM-associated mutation (c.ACTC1(G301A)) and isogenic controls created by correcting the mutation using CRISPR/Cas9 gene editing technology. Cardiomyocytes (hiPSC-CMs) were differentiated from these hiPSCs and analyzed at baseline, and at increased contractile workload (2Hz electrical stimulation). Released extracellular vesicles (EVs) were isolated and characterized after a 24-h culture period and transcriptomic analysis performed on both hiPSC-CMs and released EVs. Transcriptomic analysis of cellular mRNA showed the HCM mutation caused differential splicing within known HCM pathways, and disrupted metabolic pathways. Analysis at increasing contraction frequency showed further disruption of metabolic gene expression, with an additive effect in the HCM background. Intriguingly, we observed differences in snoRNA cargo within HCM released EVs that specifically altered when HCM hiPSC-CMs were subjected to increased workload. These snoRNAs were predicted to have roles in post-translational modifications and alternative splicing, processes differentially regulated in HCM. As such, the snoRNAs identified in this study may unveil mechanistic insight into unexplained HCM phenotypes and offer potential future use as HCM biomarkers or as targets in future RNA-targeting therapies.
C1 [James, Victoria; Nizamudeen, Zubair A.; Lea, Daniel; Dottorini, Tania] Univ Nottingham, Sch Vet Med & Sci, Nottingham NG7 2RD, England.
   [Holmes, Terri L.; Johnson, Benjamin B.; Smith, James G. W.] Univ East Anglia, Fac Med & Hlth Sci, Norwich Med Sch, Norwich NR4 7UQ, Norfolk, England.
   [Arkill, Kenton P.] Univ Nottingham, Sch Med, Nottingham, England.
   [Denning, Chris] Univ Nottingham, Biodiscovery Inst, Nottingham, England.
C3 University of Nottingham; University of East Anglia; University of
   Nottingham; University of Nottingham
RP James, V (corresponding author), Univ Nottingham, Sch Vet Med & Sci, Nottingham NG7 2RD, England.; Smith, JGW (corresponding author), Univ East Anglia, Fac Med & Hlth Sci, Norwich Med Sch, Norwich NR4 7UQ, Norfolk, England.
EM victoria.james@nottingham.ac.uk; j.g.smith@uea.ac.uk
RI denning, chris/D-4777-2013; Arkill, Kenton/F-6955-2012
OI Smith, James/0000-0003-0427-8678; Arkill, Kenton/0000-0002-3360-6055;
   Johnson, Benjamin/0000-0002-6280-8385; Holmes,
   Terri-Lea/0000-0002-8480-0755; Nizamudeen, Zubair/0000-0002-5552-3656;
   Dottorini, Tania/0000-0001-7733-906X; James,
   Victoria/0000-0002-9926-2953
FU Academy of Medical Sciences/theWellcome Trust/the Government Department
   of Business, Energy and Industrial Strategy/the British Heart
   Foundation/Diabetes UK Springboard Award [SBF005\1057]; MRC
   [MR/P003214/1]; British Heart Foundation [SP/15/9/31605, RG/15/6/31436,
   04BX14CDLG, PG/14/59/31000, RG/14/1/30588, P47352]; National Centre for
   the Replacement, Refinement and Reduction of Animals in Research [NC3R:
   NC/C013202/1, NC3R: NC/K000225/1]; MRC [MR/L012618/1, MR/P003214/1]
   Funding Source: UKRI
FX J.G.W.S. is supported by the Academy ofMedical Sciences/theWellcome
   Trust/the Government Department of Business, Energy and Industrial
   Strategy/the British Heart Foundation/Diabetes UK Springboard Award
   [SBF005\1057]. K.A is supported by the MRC [MR/P003214/1]; CD is funded
   by British Heart Foundation (SP/15/9/31605; RG/15/6/31436; 04BX14CDLG;
   PG/14/59/31000; RG/14/1/30588; P47352), National Centre for the
   Replacement, Refinement and Reduction of Animals in Research (NC3Rs:
   NC/C013202/1; NC/K000225/1).
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NR 56
TC 17
Z9 18
U1 0
U2 6
PU MARY ANN LIEBERT, INC
PI NEW ROCHELLE
PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA
SN 1547-3287
EI 1557-8534
J9 STEM CELLS DEV
JI Stem Cells Dev.
PD DEC 15
PY 2021
VL 30
IS 24
BP 1215
EP 1227
DI 10.1089/scd.2021.0202
PG 13
WC Cell & Tissue Engineering; Hematology; Medicine, Research &
   Experimental; Transplantation
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Hematology; Research & Experimental Medicine;
   Transplantation
GA E4AP8
UT WOS:000974990000003
PM 34806414
OA Green Published, Green Accepted, hybrid
DA 2025-04-10
ER

PT J
AU Nakagawa, N
   Hoshijima, M
   Oyasu, M
   Saito, N
   Tanizawa, K
   Kuroda, S
AF Nakagawa, N
   Hoshijima, M
   Oyasu, M
   Saito, N
   Tanizawa, K
   Kuroda, S
TI ENH, containing PDZ and LIM domains, heart/skeletal muscle-specific
   protein, associates with cytoskeletal proteins through the PDZ domain
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE LIM; PDZ; protein kinase C; heart; cardiomyocytes; alternative splicing;
   Z-disk; scaffold protein; cytoskeletal protein
ID KINASE-C; GENE-EXPRESSION; HEART-FAILURE; BETA; ENIGMA; CARDIOMYOPATHY;
   PATTERNS; MOTIFS; CELLS; MICE
AB The <(En)under bar>igma (h) under bar omologue protein (ENH), containing an N-terminal PDZ domain and three C-terminal LIM domains, is a heart and skeletal muscle-specific protein that has been shown to preferentially interact with protein kinase C beta (PKC beta) through the LIM domains (Kuroda et al. J. Biol. Chem. 271, 31029-31032, 1996). We here demonstrate that ENH is colocalized with a cytoskeletal protein alpha-actinin in the Z-disk region of rat neonatal cardiomyocytes. Pull-down assays using the glutathione-S-transferase-fusion system also showed the interaction of the PDZ domain of ENH with actin and alpha-actinin. Furthermore, by combined use of the in silico and conventional cDNA cloning methods, we have isolated three END-related clones from a mouse heart-derived cDNA library: mENH1 (591 amino acid residues) corresponding to rat ENH, mENH2 (337 residues), and mENH3 (239 residues); the latter two containing only a single PDZ domain, Deciphering their cDNA sequences, these mENH1-3 mRNAs appear to be generated from a single mENH gene by alternative splicing. Northern blot analyses using human cancer cells and mouse embryos have shown expression of each mENH mRNA to vary considerably among the cell types and during the developmental stage. Together with a recent finding that PKC beta is markedly activated in the cardiac hypertrophic signaling, these results suggest that ENH1 plays an important role in the heart development by scaffolding PKC beta to the Z-disk region and that ENH2 and ENH3 negatively modulate the scaffolding activity of ENH1. (C) 2000 Academic Press.
C1 Osaka Univ, Inst Sci & Ind Res, Dept Struct Mol Biol, Osaka 5670047, Japan.
   Univ Calif San Diego, Dept Med, UCSD Salk Program Mol Med, La Jolla, CA 92093 USA.
   Univ Calif San Diego, Ctr Mol Genet, La Jolla, CA 92093 USA.
   Kobe Univ, Biosignal Res Ctr, Kobe, Hyogo 6578501, Japan.
C3 The University of Osaka; University of California System; University of
   California San Diego; University of California System; University of
   California San Diego; Kobe University
RP Kuroda, S (corresponding author), Osaka Univ, Inst Sci & Ind Res, Dept Struct Mol Biol, 8-1 Mihogaoka, Osaka 5670047, Japan.
RI KURODA, SHINYA/G-4961-2014
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NR 20
TC 86
Z9 117
U1 0
U2 17
PU ACADEMIC PRESS INC
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD JUN 7
PY 2000
VL 272
IS 2
BP 505
EP 512
DI 10.1006/bbrc.2000.2787
PG 8
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA 327HC
UT WOS:000087787600034
PM 10833443
DA 2025-04-10
ER

PT J
AU Grubb, DR
   Crook, B
   Ma, Y
   Luo, JT
   Qian, HW
   Gao, XM
   Kiriazis, H
   Du, XJ
   Gregorevic, P
   Woodcock, EA
AF Grubb, David R.
   Crook, Bryony
   Ma, Yi
   Luo, Jieting
   Qian, Hong Wei
   Gao, Xiao-Ming
   Kiriazis, Helen
   Du, Xiao-Jun
   Gregorevic, Paul
   Woodcock, Elizabeth A.
TI The atypical 'b' splice variant of phospholipase Cβ1 promotes cardiac
   contractile dysfunction
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Article
DE Cardiac contractility; Signaling pathways; AAV; Gene therapy
ID PROTEIN-KINASE-C; G-ALPHA-Q; HEART-FAILURE; DILATED CARDIOMYOPATHY;
   THERAPEUTIC TARGET; PRESSURE-OVERLOAD; GENE-THERAPY; 2 FORMS;
   HYPERTROPHY; CARDIOMYOCYTES
AB The activity of the early signaling enzyme, phospholipase C beta 1b (PLC beta 1b), is selectively elevated in diseased myocardium and activity increases with disease progression. We aimed to establish the contribution of heightened PLC beta 1b activity to cardiac pathology. PLC beta 1b, the alternative splice variant, PLC beta 1a, and a blank virus were expressed in mouse hearts using adeno-associated viral vectors (rAAV6-FLAG-PLC beta 1b, rAAV6-FLAG-PLC beta 1a, or rAAV6-blank) delivered intravenously (IV). Following viral delivery, FLAG-PLC beta 1b was expressed in all of the chambers of the mouse heart and was localized to the sarcolemma. Heightened PLC beta 1b expression caused a rapid loss of contractility, 4-6 weeks, that was fully reversed, within 5 days, by inhibition of protein kinase C alpha (PKC alpha). PLC beta 1a did not localize to the sarcolemma and did not affect contractile function. Expression of PLC beta 1b, but not PLC beta 1a, caused downstream dephosphorylation of phospholamban and depletion of the Ca2+ stores of the sarcoplasmic reticulum. We conclude that heightened PLC beta 1b activity observed in diseased myocardium contributes to pathology by PKC alpha-mediated contractile dysfunction. PLC beta 1b is a cardiac-specific signaling system, and thus provides a potential therapeutic target for the development of well-tolerated inotropic agents for use in failing myocardium. (C) 2015 Elsevier Ltd. All rights reserved.
C1 [Grubb, David R.; Crook, Bryony; Ma, Yi; Luo, Jieting; Qian, Hong Wei; Gao, Xiao-Ming; Kiriazis, Helen; Du, Xiao-Jun; Gregorevic, Paul; Woodcock, Elizabeth A.] Baker IDI Heart & Diabet Inst, Melbourne, Vic 3004, Australia.
C3 Baker Heart and Diabetes Institute
RP Woodcock, EA (corresponding author), Baker IDI Heart & Diabet Inst, Mol Cardiol Lab, 75 Commercial Rd, Melbourne, Vic 3004, Australia.
EM liz.woodcock@bakeridi.edu.au
RI Gregorevic, Paul/AAH-6040-2021
OI Gregorevic, Paul/0000-0002-7418-8945; Ma, Yi/0000-0002-7226-8327;
   Woodcock, ELizabeth/0000-0001-7323-6784
FU Australian National Health and Medical Research Council (NHMRC)
   [1002328, 10007712, 1022678]; Victorian Government's Operational
   Infrastructure Support Program; Baker IDI Heart and Diabetes Institute
FX None of the authors has any conflicts of interest in relation to the
   work described. This work was supported by Grants from the Australian
   National Health and Medical Research Council (NHMRC) #1002328,
   #10007712, #1022678. EAW, XJD and PG are Fellows of the NHMRC #586621,
   #1043026, #1046782 respectively. Support was received from the Victorian
   Government's Operational Infrastructure Support Program, and from a
   Commercialization Grant provided by the Baker IDI Heart and Diabetes
   Institute.
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NR 54
TC 10
Z9 12
U1 0
U2 2
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD JUL
PY 2015
VL 84
BP 95
EP 103
DI 10.1016/j.yjmcc.2015.04.016
PG 9
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA CL3GU
UT WOS:000356839200012
PM 25918049
DA 2025-04-10
ER

PT J
AU Kadota, Y
   Jam, FA
   Yukiue, H
   Terakado, I
   Morimune, T
   Tano, A
   Tanaka, Y
   Akahane, S
   Fukumura, M
   Tooyama, I
   Mori, M
AF Kadota, Yosuke
   Jam, Faidruz Azura
   Yukiue, Haruka
   Terakado, Ichiro
   Morimune, Takao
   Tano, Ayami
   Tanaka, Yuya
   Akahane, Sayumi
   Fukumura, Mayu
   Tooyama, Ikuo
   Mori, Masaki
TI Srsf7 Establishes the Juvenile Transcriptome through Age-Dependent
   Alternative Splicing in Mice
SO ISCIENCE
LA English
DT Article
ID MESSENGER-RNAS; SENESCENCE; GENE; SR; REPRESSION; REGULATORS; EXPORT;
   SRP20; SEX; 9G8
AB The juvenile phase is characterized by continuously progressing physiological processes such as growth and maturation, which are accompanied by transitions in gene expression. The contribution of transcriptome dynamics to the establishment of juvenile properties remains unclear. Here, we investigated alternative splicing (AS) events in postnatal growth and elucidated the landscape of age-dependent alternative splicing (ADAS) in C57BL/6 mice. Our analysis of ADAS in the cerebral cortex, cardiomyocytes, and hepatocytes revealed numerous juvenile-specific splicing isoforms that shape the juvenile transcriptome, which in turn functions as a basis for the highly anabolic status of juvenile cells. Mechanistically, the juvenile-expressed splicing factor Srsf7 mediates ADAS, as exemplified by switching from juvenile to adult forms of anabolism-associated genes Eif4a2 and Rbm7. Suppression of Srsf7 results in "fast-forwarding'' of this transcriptome transition, causing impaired anabolism and growth in mice. Thus, juvenile-specific AS is indispensable for the anabolic state of juveniles and differentiates juveniles from adults.
C1 [Kadota, Yosuke; Jam, Faidruz Azura; Yukiue, Haruka; Morimune, Takao; Tano, Ayami; Tanaka, Yuya; Akahane, Sayumi; Fukumura, Mayu; Tooyama, Ikuo; Mori, Masaki] Shiga Univ Med Sci, MNRC, Seta Tsukinowa Cho, Otsu, Shiga 5202192, Japan.
   [Terakado, Ichiro] Shiga Univ Med Sci, RCALS, Seta Tsukinowa Cho, Otsu, Shiga 5202192, Japan.
   [Morimune, Takao] Shiga Univ Med Sci, Dept Pediat, Seta Tsukinowa Cho, Otsu, Shiga 5202192, Japan.
C3 Shiga University of Medical Science; Shiga University of Medical
   Science; Shiga University of Medical Science
RP Mori, M (corresponding author), Shiga Univ Med Sci, MNRC, Seta Tsukinowa Cho, Otsu, Shiga 5202192, Japan.
EM morim@belle.shiga-med.ac.jp
RI Jam, faidruz/AAQ-8304-2020; MORI, MASAKI/AFU-9866-2022
OI Mori, Masaki/0000-0001-7632-3875; Tanaka, Yuya/0000-0003-0260-0424;
   Kadota, Yosuke/0000-0001-7335-561X; azura, faidruz/0000-0003-0870-8444
FU Sumitomo Foundation; Kato Memorial Bioscience Foundation; Japan Epilepsy
   Research Foundation; Houston Foundation; MSD Life Science Foundation;
   Ichiro Kanehara Foundation for the Promotion of Medical Sciences and
   Medical Care; Japan Brain Foundation; MEXT KAKENHI [15K15387]; JSPS
   KAKENHI [15K15387, 15H01486, 18K07788, 19H04774]; Leading Initiative for
   Excellent Young Researchers (LEADER) [5013323]; Japan Agency for Medical
   Research and Development (AMED); Grants-in-Aid for Scientific Research
   [19H04774, 18K07788, 15K15387, 15H01486] Funding Source: KAKEN
FX We would like to thank all the laboratory members of the Molecular
   Neuroscience Research Center (MNRC) for the helpful discussion and
   sincere cooperation. We would like to especially thank Jean-Pierre
   Bellier for repeated critical readings. This research was cooperated by
   the Central Research Laboratory at Shiga University of Medical Science
   (SUMS). M.M. is supported by a research grant from the Sumitomo
   Foundation, the Kato Memorial Bioscience Foundation, the Japan Epilepsy
   Research Foundation (JERF), the Houston Foundation, the MSD Life Science
   Foundation, the Ichiro Kanehara Foundation for the Promotion of Medical
   Sciences and Medical Care, and the Japan Brain Foundation. This study
   was supported by MEXT KAKENHI Grant Number 15K15387; JSPS KAKENHI Grant
   Numbers 15K15387, 15H01486, 18K07788, 19H04774; the Leading Initiative
   for Excellent Young Researchers (LEADER) 5013323; and Japan Agency for
   Medical Research and Development (AMED).
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NR 56
TC 20
Z9 20
U1 0
U2 7
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
EI 2589-0042
J9 ISCIENCE
JI iScience
PD MAR 27
PY 2020
VL 23
IS 3
AR 100929
DI 10.1016/j.isci.2020.100929
PG 28
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA LG8QR
UT WOS:000528358900048
PM 32146325
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Dery, KJ
   Najjar, SM
   Beauchemin, N
   Shively, JE
   Kupiec-Weglinski, JW
AF Dery, Kenneth J.
   Najjar, Sonia M.
   Beauchemin, Nicole
   Shively, John E.
   Kupiec-Weglinski, Jerzy W.
TI Mechanism and function of CEACAM1 splice isoforms
SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
LA English
DT Review
DE alternative splicing; CEACAM1; exons; inflammation; ischemia-reperfusion
   injury; phosphorodiamidate morpholinos
ID CELL-ADHESION MOLECULE; TUMOR-SUPPRESSOR CEACAM1; SHORT CYTOPLASMIC
   DOMAIN; BILIARY GLYCOPROTEIN; C-CAM; TYROSINE PHOSPHORYLATION;
   3-DIMENSIONAL MODEL; HEPATIC CEACAM1; T-CELLS; RNA
AB BackgroundAlternative splicing is a fundamental mechanism in the post-transcriptional regulation of genes. The multifunctional transmembrane glycoprotein receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) undergoes extensive alternative splicing to allow for tunable functions in cell signalling, adhesion and modulation of immune and metabolic responses. Splice isoforms that differ in their ectodomain and short or long cytoplasmic tail (CEACAM1-S/CEACAM1-L) have distinct functional roles. The mechanisms that regulate CEACAM1 RNA splicing remain elusive.MethodsThis narrative review summarizes the current knowledge of the mechanism and function of CEACAM1 splice isoforms. Historical perspectives address the biological significance of the glycosylated Ig domains, the variable exon 7, and phosphorylation events that dictate its signal transduction pathways. The use of small antisense molecules to target mis-spliced variable exon 7 is discussed.ResultsThe Ig variable-like N domain mediates cell adhesion and immune checkpoint inhibitory functions. Gly and Tyr residues in the transmembrane (TM) domain are essential for dimerization. Calmodulin, Calcium/Calmodulin-dependent protein kinase II delta (CamK2D), Actin and Annexin A2 are binding partners of CEACAM1-S. Homology studies of the muCEACAM1-S and huCEACAM1-S TM predict differences in their signal transduction pathways. Hypoxia-inducible factor 1-alpha (HIF-1-alpha) induces alternative splicing to produce CEACAM1-S under limited oxygen conditions. Antisense small molecules directed to exon 7 may correct faulty expression of the short and long cytoplasmic tail splicing isoforms.ConclusionMore pre-clinical and clinical studies are needed to elucidate the precise mechanisms by which CEACAM1 RNA splicing may be exploited to develop targeted interventions towards novel therapeutic strategies.
C1 [Dery, Kenneth J.; Kupiec-Weglinski, Jerzy W.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90095 USA.
   [Najjar, Sonia M.] Ohio Univ, Heritage Coll Osteopath Med, Dept Biomed Sci, Athens, OH USA.
   [Beauchemin, Nicole] McGill Univ, Rosalind & Morris Goodman Canc Inst, Montreal, PQ, Canada.
   [Shively, John E.] Arthur D Riggs Diabet & Metab Res Inst, Beckman Res Inst, City Hope Natl Med Ctr, Dept Theranost & Immunol, Duarte, CA USA.
C3 University of California System; University of California Los Angeles;
   University System of Ohio; Ohio University; McGill University; City of
   Hope; Beckman Research Institute of City of Hope
RP Dery, KJ (corresponding author), Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90095 USA.
EM kdery@mednet.ucla.edu
RI Najjar, Sonia/GXW-2217-2022
OI Shively, John/0000-0002-7763-770X; Dery, Kenneth/0000-0003-4238-4092
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NR 104
TC 0
Z9 0
U1 0
U2 0
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0014-2972
EI 1365-2362
J9 EUR J CLIN INVEST
JI Eur. J. Clin. Invest.
PD DEC
PY 2024
VL 54
SU 2
SI SI
AR e14350
DI 10.1111/eci.14350
PG 16
WC Medicine, General & Internal; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC General & Internal Medicine; Research & Experimental Medicine
GA P5J8X
UT WOS:001378281100005
PM 39674874
OA hybrid
DA 2025-04-10
ER

PT J
AU Cao, Z
   Yan, LL
   Shen, ZF
   Chen, Y
   Shi, Y
   He, XB
   Zhou, NM
AF Cao, Zheng
   Yan, Lili
   Shen, Zhangfei
   Chen, Yu
   Shi, Ying
   He, Xiaobai
   Zhou, Naiming
TI A novel splice variant of Gaq-coupled Bombyx CAPA-PVK receptor 1
   functions as a specific Gai/o-linked receptor for CAPA-PK
SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
LA English
DT Article
DE GPCR; Alternative splicing; CAPA-PK; Gai/o; ERK1/2
ID CARDIOACCELERATORY PEPTIDES; DROSOPHILA-MELANOGASTER; CONSTITUTIVE
   ACTIVITY; SIGNAL-TRANSDUCTION; TOBACCO HAWKMOTH; PROTEIN;
   IDENTIFICATION; NEUROPEPTIDES; ACTIVATION; EXPRESSION
AB Alternative splicing enables G protein-coupled receptor (GPCR) genes to greatly increase the number of structurally and functionally distinct receptor isoforms. However, the functional role and relevance of the individual GPCR splice variants in regulating physiological processes are still to be assessed. A naturally occurring alternative splice variant of Bombyx CAPA-PVK receptor, BomCAPA-PVK-R1-Delta 341, has been shown to act as a dominant-negative protein to regulate cell surface expression and function of the canonical CAPA-PVK receptor. Herein, using functional assays, we identify the splice variant Delta 341 as a specific receptor for neuropeptide CAPA-PK, and upon activation, Delta 341 signals to ERK1/2 pathway. Further characterization demonstrates that Delta 341 couples to Gai/o, distinct from the Gaq-coupled canonical CAPA-PVK receptor, triggering ERK1/2 phosphorylation through G beta gamma-PI3K-PKC. signaling cascade. Moreover, our ELISA data show that the ligand-dependent internalization of the splice variant Delta 341 is significantly impaired due to lack of GRKs-mediated phosphorylation sites. Our findings highlight the potential of this knowledge for molecular, pharmacological and physiological studies on GPCR splice variants in the future.
C1 [Cao, Zheng; Yan, Lili; Chen, Yu; Shi, Ying; Zhou, Naiming] Zhejiang Univ, Coll Life Sci, Inst Biochem, Zijingang Campus, Hangzhou 310058, Zhejiang, Peoples R China.
   [Shen, Zhangfei] Zhejiang Univ, Dept Econ Zool, Coll Anim Sci, Zijingang Campus, Hangzhou 310058, Zhejiang, Peoples R China.
   [He, Xiaobai] Jiangsu Univ Sci & Technol, Coll Biotechnol, Zhenjiang 212018, Jiangsu, Peoples R China.
C3 Zhejiang University; Zhejiang University; Jiangsu University of Science
   & Technology
RP Zhou, NM (corresponding author), Zhejiang Univ, Coll Life Sci, Inst Biochem, Zijingang Campus, Hangzhou 310058, Zhejiang, Peoples R China.
EM zhounaiming@zju.edu.cn
RI shen, zhangfei/LFS-1896-2024; Cao, Zheng/AAB-7910-2022; Zhou,
   Naiming/AHC-1121-2022
OI Cao, Zheng/0000-0002-4934-0888; shen, zhangfei/0000-0002-3707-2265
FU National Natural Science Foundation of China [31771543, 31502017];
   Ministry of Science and Technology of People's Republic of China
   [012CB910402]
FX We would like to thank Drs. Jin O-Uchi and Naoaki Sato for providing us
   the plasmids of PKC-isoforms. We thank Hanmin Chen for assistance with
   confocal microscopy. This work was supported by grants from the National
   Natural Science Foundation of China, 31771543 (N.Z.) and 31502017
   (X.H.), the Ministry of Science and Technology of People's Republic of
   China, 012CB910402 (N.Z.).
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NR 69
TC 4
Z9 4
U1 2
U2 14
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29a, 1043 NX AMSTERDAM, NETHERLANDS
SN 0167-4889
EI 1879-2596
J9 BBA-MOL CELL RES
JI Biochim. Biophys. Acta-Mol. Cell Res.
PD AUG
PY 2020
VL 1867
IS 8
AR 118718
DI 10.1016/j.bbamcr.2020.118718
PG 16
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA LT0IN
UT WOS:000536760800002
PM 32289337
OA Bronze
DA 2025-04-10
ER

PT J
AU Ito, J
   Iijima, M
   Yoshimoto, N
   Niimi, T
   Kuroda, S
   Maturana, AD
AF Ito, Jumpei
   Iijima, Masumi
   Yoshimoto, Nobuo
   Niimi, Tomoaki
   Kuroda, Shun'ichi
   Maturana, Andres D.
TI RBM20 and RBM24 cooperatively promote the expression of short enh
   splice variants
SO FEBS LETTERS
LA English
DT Article
DE alternative splicing; PDZ-LIM; scaffold protein
ID PDZ-LIM PROTEIN; ENIGMA HOMOLOG; DOMAIN; GENE; CARDIOMYOPATHY;
   SEQUESTRATION; CYPHER/ZASP; ACTIVATION; MUTATIONS; INSIGHTS
AB PDZ-LIM protein ENH1 is a scaffold protein for protein kinases and transcriptional regulators. While ENH1 promotes the hypertrophic growth of cardiomyocytes, its short splice variant (ENH3) prevents the hypertrophic growth. The mechanism underlying the alternative splicing of enh mRNA between ENH short and long isoforms has remained unknown. Here, we found that two splicing factors, RNA-binding motif 20 (RBM20) and RNA-binding motif 24 (RBM24) together promoted the expression of short enh splice variants and bound the 50 intronic region of exon 11 containing an in-phase stop codon. In addition, expression of both RBMs is repressed by hypertrophic stimulations. Collectively, our results suggest that, in healthy conditions, RBM20 and RBM24 cooperate to promote the expression of short ENH isoforms.
C1 [Ito, Jumpei; Niimi, Tomoaki; Kuroda, Shun'ichi; Maturana, Andres D.] Nagoya Univ, Grad Sch Bioagr Sci, Nagoya, Aichi 4648601, Japan.
   [Ito, Jumpei] Japan Soc Promot Sci, Tokyo, Japan.
   [Iijima, Masumi; Yoshimoto, Nobuo; Kuroda, Shun'ichi] Osaka Univ, Inst Sci & Ind Res, Osaka, Japan.
C3 Nagoya University; Japan Society for the Promotion of Science; The
   University of Osaka
RP Maturana, AD (corresponding author), Nagoya Univ, Grad Sch Bioagr Sci, Chikusa Ku, Nagoya, Aichi 4648601, Japan.
EM maturana@agr.nagoya-u.ac.jp
RI Kuroda, Shun'Ichi/KVY-1906-2024
OI Ito, Jumpei/0000-0001-5149-9962
FU Japanese Society for the Promotion of Science (JSPS) [24570150,
   26002967]; Grants-in-Aid for Scientific Research [16K04888, 15K21068,
   24570150] Funding Source: KAKEN
FX We thank Dr. Sebastien Walchli for his critical comments on the
   manuscript. This work was supported by the Japanese Society for the
   Promotion of Science (JSPS), Grant-in-Aid for Scientific Research (C)
   (24570150) to ADM and Grant-in-Aid for JSPS Fellows (26002967) to JI.
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NR 38
TC 25
Z9 26
U1 0
U2 1
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0014-5793
EI 1873-3468
J9 FEBS LETT
JI FEBS Lett.
PD JUL
PY 2016
VL 590
IS 14
BP 2262
EP 2274
DI 10.1002/1873-3468.12251
PG 13
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA DS4OT
UT WOS:000380761100022
PM 27289039
OA Bronze
DA 2025-04-10
ER

PT J
AU Chang, RL
   Nithiyanantham, S
   Huang, CY
   Pai, PY
   Chang, TT
   Hu, LC
   Chen, RJ
   VijayaPadma, V
   Kuo, WW
   Huang, CY
AF Chang, Ruey-Lin
   Nithiyanantham, Srinivasan
   Huang, Chih-Yang
   Pai, Pei-Ying
   Chang, Tung-Ti
   Hu, Lai-Chin
   Chen, Ray-Jade
   VijayaPadma, V.
   Kuo, Wei-Wen
   Huang, Chih-Yang
TI Synergistic cardiac pathological hypertrophy induced by high-salt diet
   in IGF-IIRα cardiac-specific transgenic rats
SO PLOS ONE
LA English
DT Article
ID LEFT-VENTRICULAR MASS; GROWTH-FACTOR-II; SIGNALING PATHWAYS; TYPE-1
   RECEPTOR; ANGIOTENSIN-II; HEART-FAILURE; ACTIVATION; APOPTOSIS;
   EXPRESSION; SODIUM
AB Stress-induced cardiac hypertrophy leads to heart failure. Our previous studies demonstrate that insulin-like growth factor-II receptor (IGF-IIR) signaling is pivotal to hypertrophy regulation. In this study, we show a novel IGF-IIR alternative spliced transcript, IGF-IIR alpha (150 kDa) play a key role in high-salt induced hypertrophy mechanisms. Cardiac overexpression of IGF-IIR alpha and high-salt diet influenced cardiac dysfunction by increasing pathophysiological changes with up-regulation of hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). We found that, cardiac hypertrophy under high-salt conditions were amplified in the presence of IGF-IIR alpha overexpression. Importantly, high-salt induced angiotensin II type I receptor (AT1R) up regulation mediated IGF-IIR expressions via upstream mitogen activated protein kinase (MAPK)/silent mating type information regulation 2 homolog 1 (SIRT1)/heat shock factor 1 (HSF1) pathway. Further, G-coupled receptors (G alpha q) activated calcineurin/nuclear factor of activated T-cells, cytoplasmic 3 (NFATc3)/protein kinase C (PKC) signaling was significantly up regulated under high-salt conditions. All these effects were observed to be dramatically over-regulated in IGF-IIR alpha transgenic rats fed with a high-salt diet. Altogether, from the findings, we demonstrate that IGF-IIR alpha plays a crucial role during high-salt conditions leading to synergistic cardiac hypertrophy.
C1 [Chang, Ruey-Lin] China Med Univ, Sch Postbaccalaureate Chinese Med, Coll Chinese Med, Taichung, Taiwan.
   [Nithiyanantham, Srinivasan] China Med Univ, Grad Inst Basic Med Sci, Taichung, Taiwan.
   [Huang, Chih-Yang] China Med Univ, China Med Univ Hosp, Translat Res Core, Taichung, Taiwan.
   [Pai, Pei-Ying] China Med Univ Hosp, Div Cardiol, Taichung, Taiwan.
   [Chang, Tung-Ti] China Med Univ, Sch Chinese Med, Taichung, Taiwan.
   [Hu, Lai-Chin] Armed Forces Taichung Gen Hosp, Div Cardiol, Dept Internal Med, Taichung, Taiwan.
   [Chen, Ray-Jade] Taipei Med Univ, Sch Med, Dept Surg, Coll Med, Taipei, Taiwan.
   [VijayaPadma, V.] Bharathiar Univ, Dept Biotechnol, Coimbatore, Tamil Nadu, India.
   [Kuo, Wei-Wen] China Med Univ, Dept Biol Sci & Technol, Taichung, Taiwan.
   [Huang, Chih-Yang] Tzu Chi Univ, Hualien Tzu Chi Hosp, Buddhist Tzu Chi Med Fdn, Coll Med, Hualien, Taiwan.
   [Huang, Chih-Yang] China Med Univ, Dept Med Res, China Med Univ Hosp, Taichung, Taiwan.
   [Huang, Chih-Yang] Asia Univ, Dept Biotechnol, Taichung, Taiwan.
C3 China Medical University Taiwan; China Medical University Taiwan; China
   Medical University Taiwan; China Medical University Hospital - Taiwan;
   China Medical University Taiwan; China Medical University Hospital -
   Taiwan; China Medical University Taiwan; Taipei Medical University;
   Bharathiar University; China Medical University Taiwan; Tzu Chi
   University; Buddhist Tzu Chi General Hospital; Hualien Tzu Chi Hospital;
   China Medical University Taiwan; China Medical University Hospital -
   Taiwan; Asia University Taiwan
RP Huang, CY (corresponding author), Tzu Chi Univ, Hualien Tzu Chi Hosp, Buddhist Tzu Chi Med Fdn, Coll Med, Hualien, Taiwan.; Huang, CY (corresponding author), China Med Univ, Dept Med Res, China Med Univ Hosp, Taichung, Taiwan.; Huang, CY (corresponding author), Asia Univ, Dept Biotechnol, Taichung, Taiwan.
EM cyhuang@mail.cmu.edu.tw
RI Huang, Kevin Chih-Yang/Q-4862-2016; Chen, Ray/GRJ-6736-2022
OI Huang, Chih-Yang/0000-0003-2347-0411
FU China Medical University, Taiwan; China Medical University and Hospital,
   Taiwan; Asia University, Taiwan
FX This study was supported by China Medical University - 105-S-07, Taiwan;
   China Medical University and Hospital -02, Taiwan; Asia University -
   106, Taiwan. The funders had no role in study design, data collection
   and analysis, decision to publish, or preparation of the manuscript.
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NR 42
TC 10
Z9 10
U1 0
U2 2
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD JUN 18
PY 2019
VL 14
IS 6
AR e0216285
DI 10.1371/journal.pone.0216285
PG 16
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA IW3OQ
UT WOS:000484891700004
PM 31211784
OA Green Published, Green Submitted, gold
DA 2025-04-10
ER

PT J
AU Meshorer, E
   Bryk, B
   Toiber, D
   Cohen, J
   Podoly, E
   Dori, A
   Soreq, H
AF Meshorer, E
   Bryk, B
   Toiber, D
   Cohen, J
   Podoly, E
   Dori, A
   Soreq, H
TI SC35 promotes sustainable stress-induced alternative splicing of
   neuronal acetylcholinesterase mRNA
SO MOLECULAR PSYCHIATRY
LA English
DT Article
DE SC35; stress; acetylcholinesterase; alternative splicing; ASF/SF2
ID AMYOTROPHIC-LATERAL-SCLEROSIS; PREFRONTAL CORTEX; HNRNP A1; IN-VIVO;
   GENE-EXPRESSION; SR PROTEINS; CELLS; BINDING; TRANSCRIPTION; HIPPOCAMPUS
AB Long-lasting alternative splicing of neuronal acetylcholinesterase (AChE) pre-mRNA occurs during neuronal development and following stress, altering synaptic properties. To explore the corresponding molecular events, we sought to identify mRNAs encoding for abundant splicing factors in the prefrontal cortex (PFC) following stress. Here we show elevated levels of the splicing factor SC35 in stressed as compared with naive mice. In cotransfections of COS-1 and HEK293 cells with an AChE minigene allowing 30 splice variations, SC35 facilitated a shift from the primary AChE-S to the stress-induced AChE-R variant, while ASF/SF2 caused the opposite effect. Transfection with chimeric constructs comprising of SC35 and ASF/SF2 RRM/RS domains identified the SC35 RRM as responsible for AChE mRNA's alternative splicing. In poststress PFC neurons, increased SC35 mRNA and protein levels coincided with selective increase in AChE-R mRNA. In the developing mouse embryo, cortical progenitor cells in the ventricular zone displayed transient SC35 elevation concomitant with dominance of AChE-R over AChE-S mRNA. Finally, transgenic mice overexpressing human AChE-R, but not those overexpressing AChE-S, showed significant elevation in neuronal SC35 levels, suggesting a reciprocal reinforcement process. Together, these findings point to an interactive relationship of SC35 with cholinergic signals in the long-lasting consequences of stress on nervous system plasticity and development.
C1 Hebrew Univ Jerusalem, Dept Biol Chem, Jerusalem, Israel.
   Soroka Univ Med Ctr, Dept Neurol, Beer Sheva, Israel.
   Hebrew Univ Jerusalem, Wolfson Ctr Struct Biol, Jerusalem, Israel.
C3 Hebrew University of Jerusalem; Ben Gurion University; Soroka Medical
   Center; Hebrew University of Jerusalem
RP NCI, NIH, 41 Lib Dr, Bethesda, MD 20892 USA.
EM meshoree@mail.nih.gov; soreq@cc.huji.ac.il
RI Dori, Amir/JCD-7507-2023; Soreq, Hermona/AFM-0869-2022
OI Dori, Amir/0000-0003-4633-1481; Toiber, Deborah/0000-0002-1465-0130;
   Meshorer, Eran/0000-0003-4777-986X; Cohen, Jonathan/0000-0001-8120-3827;
   Soreq, Hermona/0000-0002-0955-526X
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NR 59
TC 73
Z9 79
U1 0
U2 4
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1359-4184
EI 1476-5578
J9 MOL PSYCHIATR
JI Mol. Psychiatr.
PD NOV
PY 2005
VL 10
IS 11
BP 985
EP 997
DI 10.1038/sj.mp.4001735
PG 13
WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry
GA 977WA
UT WOS:000232833000005
PM 16116489
DA 2025-04-10
ER

PT J
AU Sandoval-Castellanos, AM
   Bhargava, A
   Zhao, M
   Xu, J
   Ning, K
AF Sandoval-Castellanos, Ana M.
   Bhargava, Anushka
   Zhao, Min
   Xu, Jun
   Ning, Ke
TI Serine and arginine rich splicing factor 1: a potential target for
   neuroprotection and other diseases
SO NEURAL REGENERATION RESEARCH
LA English
DT Review
DE alternative splicing; autoimmune disorders; cancer; hypertension; mRNA;
   neuroprotection;; plicing factors;; RSF1
ID HEPATOCELLULAR-CARCINOMA; FACTOR SRSF1; RNA; PROLIFERATION; MECHANISM;
   EXPRESSION; PROMOTES; INVASION; CANCER
AB Alternative splicing is the process of producing variably spliced mRNAs by choosing distinct combinations of splice sites within a messenger RNA precursor. This splicing enables mRNA from a single gene to synthesize different proteins, which have different cellular properties and functions and yet arise from the same single gene. A family of splicing factors, Serine-arginine rich proteins, are needed to initiate the assembly and activation of the spliceosome. Serine and arginine rich splicing factor 1, part of the arginine/serine-rich splicing factor protein family, can either activate or inhibit the splicing of mRNAs, depending on the phosphorylation status of the protein and its interaction partners. Considering that serine and arginine rich splicing factor 1 is either an activator or an inhibitor, this protein has been studied widely to identify its various roles in different diseases. Research has found that serine and arginine rich splicing factor 1 is a key target for neuroprotection, showing its promising potential use in therapeutics for neurodegenerative disorders. Furthermore, serine and arginine rich splicing factor 1 might be used to regulate cancer development and autoimmune diseases. In this review, we highlight how serine and arginine rich splicing factor 1 has been studied concerning neuroprotection. In addition, we draw attention to how serine and arginine rich splicing factor 1 is being studied in cancer and immunological disorders, as well as how serine and arginine rich splicing factor 1 acts outside the central or peripheral nervous system.
C1 [Sandoval-Castellanos, Ana M.; Bhargava, Anushka; Ning, Ke] Univ Sheffield, Sheffield Inst Translat Neurosci, SITraN, Sheffield, England.
   [Sandoval-Castellanos, Ana M.; Zhao, Min] Univ Calif Davis, Inst Regenerat Cures, Sch Med, Dept Ophthalmol & Vis Sci, Sacramento, CA USA.
   [Sandoval-Castellanos, Ana M.; Zhao, Min] Univ Calif Davis, Inst Regenerat Cures, Sch Med, Dept Dermatol, Sacramento, CA USA.
   [Xu, Jun; Ning, Ke] Tongji Univ, Sch Med, East Hosp, Shanghai, Peoples R China.
C3 University of Sheffield; University of California System; University of
   California Davis; University of California System; University of
   California Davis; Tongji University
RP Ning, K (corresponding author), Univ Sheffield, Sheffield Inst Translat Neurosci, SITraN, Sheffield, England.; Ning, K (corresponding author), Tongji Univ, Sch Med, East Hosp, Shanghai, Peoples R China.
EM k.ning@sheffield.ac.uk
RI Zhao, Min/JGM-3156-2023; Ning, Ke/E-7837-2010
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NR 66
TC 6
Z9 7
U1 4
U2 21
PU WOLTERS KLUWER MEDKNOW PUBLICATIONS
PI MUMBAI
PA WOLTERS KLUWER INDIA PVT LTD , A-202, 2ND FLR, QUBE, C T S  NO 1498A-2
   VILLAGE MAROL, ANDHERI EAST, MUMBAI, Maharashtra, INDIA
SN 1673-5374
EI 1876-7958
J9 NEURAL REGEN RES
JI Neural Regen. Res.
PD JUL
PY 2023
VL 18
IS 7
BP 1411
EP 1416
DI 10.4103/1673-5374.360243
PG 6
WC Cell Biology; Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Neurosciences & Neurology
GA 9C8CU
UT WOS:000935639600003
PM 36571335
OA Green Submitted, gold, Green Published, Green Accepted
DA 2025-04-10
ER

PT J
AU Wei, B
   Jin, JP
AF Wei, Bin
   Jin, J. -P.
TI TNNTI, TNNT2, and TNNT3: Isoform genes, regulation, and
   structure-function relationships
SO GENE
LA English
DT Review
DE Troponin; Striated muscle; Isoform; Evolution; Alternative splicing;
   Restrictive proteolysis; Cardiac function; Myopathy
ID CARDIAC-TROPONIN-T; FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; NH2-TERMINAL
   VARIABLE REGION; FAST SKELETAL-MUSCLE; PROTEIN-KINASE-C; METAL-BINDING
   CLUSTER; COMPLETE NUCLEOTIDE-SEQUENCE; GLU(180) NONSENSE MUTATION;
   ALPHA-TROPOMYOSIN; RESTRICTIVE CARDIOMYOPATHY
AB Troponin T (TnT) is a central player in the calcium regulation of actin thin filament function and is essential for the contraction of striated muscles. Three homologous genes have evolved in vertebrates to encode three muscle type-specific TnT isoforms: TNNT1 for slow skeletal musde TnT, TNNT2 for cardiac muscle TnT, and TNNT3 for fast skeletal muscle TnT. Alternative splicing and posttranslational modifications confer additional structural and functional variations of TnT during development and muscle adaptation to various physiological and pathological conditions. This review focuses on the TnT isoform genes and their molecular evolution, alternative splicing, developmental regulation, structure-function relationships of TnT proteins, posttranslational modifications, and myopathic mutations and abnormal splicing. The goal is to provide a concise summary of the current knowledge and some perspectives for future research and translational applications. (C) 2016 Elsevier B.V. All rights reserved.
C1 [Wei, Bin; Jin, J. -P.] Wayne State Univ, Sch Med, Dept Physiol, 540 E Canfield St, Detroit, MI 48201 USA.
C3 Wayne State University
RP Jin, JP (corresponding author), Wayne State Univ, Sch Med, Dept Physiol, 540 E Canfield St, Detroit, MI 48201 USA.
EM jjin@med.wayne.edu
RI Jin, Jian-Ping/AAD-1149-2020
OI Jin, JP/0000-0001-9932-1063
FU National Institutes of Health [GM089820, GM114833, AR048816, HL-078773,
   HL098945]; Elsevier
FX This review and the corresponding Gene Wiki article are written as part
   of the Cardiac Gene Wiki Review series a series resulting from a
   collaboration between the journal GENE, the Gene Wiki Initiative, and
   the BD2K initiative. The Cardiac Gene Wiki Initiative is supported by
   the National Institutes of Health (GM089820 and GM114833). Additional
   support for Gene Wild Reviews is provided by Elsevier, the publisher of
   GENE.The authors would like to thank Dr. Rong Liu for the sequence
   analysis and construction of phylogenetic tree shown in Fig. 3. The
   outstanding contributions of the present and past members of the Jin
   laboratory have formed the foundation of our troponin research. Our
   research on TnT was supported by grants from the National Institutes of
   Health (AR048816, HL-078773 and HL098945 to J.-P.J).
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NR 148
TC 158
Z9 178
U1 6
U2 37
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0378-1119
EI 1879-0038
J9 GENE
JI Gene
PD MAY 10
PY 2016
VL 582
IS 1
BP 1
EP 13
DI 10.1016/j.gene.2016.01.006
PG 13
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA DG9AV
UT WOS:000372376100001
PM 26774798
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Hopitzan, AA
   Baines, AJ
   Ludosky, MA
   Recouvreur, M
   Kordeli, E
AF Hopitzan, AA
   Baines, AJ
   Ludosky, MA
   Recouvreur, M
   Kordeli, E
TI Ankyrin-G in skeletal muscle: Tissue-specific alternative splicing
   contributes to the complexity of the sarcolemmal cytoskeleton
SO EXPERIMENTAL CELL RESEARCH
LA English
DT Article
DE ankyrin-G; Ank3; alternative splicing; cytoskeleton; skeletal muscle;
   costamere; sarcolemma; bioinformatics; gene structure; direct gene
   transfer
ID SARCOPLASMIC-RETICULUM; NEUROMUSCULAR-JUNCTION; CARDIAC-ARRHYTHMIA;
   REGULATORY DOMAIN; MEMBRANE; GENE; SPECTRIN; IDENTIFICATION; EXPRESSION;
   ISOFORM
AB Ankyrins are versatile adaptor proteins that join the spectrin-based cytoskeleton to transmembrane proteins, and have roles in organizing the microstructure of cell membranes. Molecular diversity of ankyrins in mammals arises from extensive alternative splicing of the products of three genes. There has been no systematic analysis of the diversity of expression of ankyrins-G, the widely expressed Ank3 gene products, in a complex tissue. We previously described Ank(G107), the first muscle-specific ankyrin-G. Here, we combined cDNA and database analyses to gain novel insight into the ankyrins-G of skeletal muscle. We find: (i) that Ank3 is composed of at least 53 exons, many of which are subject to tissue-specific splicing; (ii) five novel full-length cDNAs encoding two canonical (Ank(G197), Ank(G217)) and three small isoforms (Ank(G109), Ank(G128), Ank(G130)) bring to six the number of ankyrins-G expressed in skeletal muscle; (iii) a 76-residue insert in the C-terminal domain is a 'signature' for muscle ankyrins; (iv) variably spliced sequences of 17/18 and 195 residues increase diversity in the C-terminal domains. Comparison of endogenous ankyrins-G with in vitro translated cDNAs revealed that small ankyrins account for the majority of the immunoreactivity for ankyrin-G in soleus muscle. The small ankyrins, when expressed in vivo in the rat muscle, are all targeted to sarcolemmal costameres. Our results demonstrate the tissue-dependent alternative splicing of Ank3 in skeletal muscle and point to novel functions of small ankyrins-G in organizing microdomains of the plasma membrane. (c) 2005 Elsevier Inc. All rights reserved.
C1 Univ Paris 06, CNRS, Inst Jacques Monod, F-75251 Paris, France.
   Univ Paris 07, CNRS, Inst Jacques Monod, F-75251 Paris, France.
   Univ Kent, Dept Biosci, Canterbury CT2 7NJ, Kent, England.
C3 Sorbonne Universite; Universite Paris Cite; Centre National de la
   Recherche Scientifique (CNRS); Universite Paris Cite; Centre National de
   la Recherche Scientifique (CNRS); University of Kent
RP Univ Paris 06, CNRS, Inst Jacques Monod, 2 Pl Jussieu, F-75251 Paris, France.
EM kordeli@ijm.jussieu.fr
OI Kordeli, Ekaterini/0000-0002-5115-2202; Baines,
   Anthony/0000-0003-3068-7811
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NR 53
TC 29
Z9 37
U1 0
U2 3
PU ELSEVIER INC
PI SAN DIEGO
PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0014-4827
EI 1090-2422
J9 EXP CELL RES
JI Exp. Cell Res.
PD SEP 10
PY 2005
VL 309
IS 1
BP 86
EP 98
DI 10.1016/j.yexcr.2005.04.013
PG 13
WC Oncology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Cell Biology
GA 963DC
UT WOS:000231782500009
PM 15953600
OA Green Submitted
DA 2025-04-10
ER

PT J
AU Gualandi, F
   Rimessi, P
   Cardazzo, B
   Toffolatti, L
   Dunckley, MG
   Calzolari, E
   Patarnello, T
   Muntoni, F
   Ferlini, A
AF Gualandi, F
   Rimessi, P
   Cardazzo, B
   Toffolatti, L
   Dunckley, MG
   Calzolari, E
   Patarnello, T
   Muntoni, F
   Ferlini, A
TI Genomic definition of a pure intronic dystrophin deletion responsible
   for an XLDC splicing mutation: in vitro mimicking and antisense
   modulation of the splicing abnormality
SO GENE
LA English
DT Article
DE dystrophin; dilated cardiomyopathy; breakpoint definition; splicing
   regulation; mobile elements
ID MESSENGER-RNA; GENE; ENHANCER; FAMILY; EXON; INCLUSION; MUSCLE; REGION
AB We characterised a dystrophin gene rearrangement in a previously described family with X-linked dilated cardiomyopathy and we demonstrated that it represents an 11 kb deletion occurring within intron 11. This unique deletion joined two physiologically distant intronic regions and brought adjacent two crytpic splice sites, generating a 159 bp sequence recognised as a novel alternative exon and spliced into the dystrophin transcript. Comparative analysis of the intronic region involved in the breakpoint revealed the presence of a LINE1 element (LIP_MA2). containing a 5' unconventional region (LIM1_5). This region provides the 5' cryptic splice site utilised by the novel exon, includes part of the region spliced into the dystrophin transcript and contains two short GA rich regions compatible with splicing motifs. We performed an in vitro splicing assay by using a minigene containing the patient minimal genomic rearrangement and we reproduced the inclusion of the novel alternative exon seen in the patient tissues. Antisense splicing modulation targeting the 3' cryptic splice site succeeded in restoring the canonical splicing. This represents a novel intronic mutational mechanism affecting the dystrophin gene and generating a splicing pathology. The definition of this mechanism might open perspectives in unravelling splicing regulatory motifs and their involvement in human genetic diseases. (C) 2003 Elsevier Science B.V. All rights reserved.
C1 Univ Ferrara, Dipartimento Sperimentale & Diagnost, Sez Genet Med, I-44100 Ferrara, Italy.
   Univ Padua, Dipartimento Biol, Padua, Italy.
   Univ London Imperial Coll Sci Technol & Med, Fac Med, Dept Paediat, Dubowitz Neuromusc Ctr, London, England.
C3 University of Ferrara; University of Padua; Imperial College London
RP Univ Ferrara, Dipartimento Sperimentale & Diagnost, Sez Genet Med, Via L Borsari 46, I-44100 Ferrara, Italy.
EM fla@unife.it
RI ; FERLINI, ALESSANDRA/K-7532-2016; Gualandi, Francesca/K-7513-2016
OI PATARNELLO, Tomaso/0000-0003-1794-5791; FERLINI,
   ALESSANDRA/0000-0001-8385-9870; Gualandi, Francesca/0000-0001-9551-057X
FU Telethon [GGP02311] Funding Source: Medline
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NR 26
TC 10
Z9 10
U1 0
U2 2
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0378-1119
EI 1879-0038
J9 GENE
JI Gene
PD JUN 5
PY 2003
VL 311
BP 25
EP 33
DI 10.1016/S0378-1119(03)00527-4
PG 9
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 702XV
UT WOS:000184250800003
PM 12853135
DA 2025-04-10
ER

PT J
AU Zhang, Z
   Shen, M
   Gresch, PJ
   Ghamari-Langroudi, M
   Rabchevsky, AG
   Emeson, RB
   Stamm, S
AF Zhang, Zhaiyi
   Shen, Manli
   Gresch, Paul J.
   Ghamari-Langroudi, Masoud
   Rabchevsky, Alexander G.
   Emeson, Ronald B.
   Stamm, Stefan
TI Oligonucleotide-induced alternative splicing of serotonin 2C receptor
   reduces food intake
SO EMBO MOLECULAR MEDICINE
LA English
DT Article
DE alternative splicing; brain function; food uptake; obesity; pre-mRNA
   processing
ID SMALL NUCLEOLAR RNAS; ANTISENSE OLIGONUCLEOTIDES; MODULATION;
   EXPRESSION; AGONISTS; SNORNAS; OBESITY; CLONING; GENE
AB The serotonin 2C receptor regulates food uptake, and its activity is regulated by alternative pre-mRNA splicing. Alternative exon skipping is predicted to generate a truncated receptor protein isoform, whose existence was confirmed with a new antiserum. The truncated receptor sequesters the full-length receptor in intracellular membranes. We developed an oligonucleotide that promotes exon inclusion, which increases the ratio of the full-length to truncated receptor protein. Decreasing the amount of truncated receptor results in the accumulation of full-length, constitutively active receptor at the cell surface. After injection into the third ventricle of mice, the oligonucleotide accumulates in the arcuate nucleus, where it changes alternative splicing of the serotonin 2C receptor and increases pro-opiomelanocortin expression. Oligonucleotide injection reduced food intake in both wild-type and ob/ob mice. Unexpectedly, the oligonucleotide crossed the blood-brain barrier and its systemic delivery reduced food intake in wild-type mice. The physiological effect of the oligonucleotide suggests that a truncated splice variant regulates the activity of the serotonin 2C receptor, indicating that therapies aimed to change pre-mRNA processing could be useful to treat hyperphagia, characteristic for disorders like Prader-Willi syndrome.
C1 [Zhang, Zhaiyi; Shen, Manli; Stamm, Stefan] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40506 USA.
   [Gresch, Paul J.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA.
   [Ghamari-Langroudi, Masoud; Emeson, Ronald B.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA.
   [Rabchevsky, Alexander G.] Univ Kentucky, Res Ctr, Spinal Cord & Brain Injury, Lexington, KY USA.
C3 University of Kentucky; Vanderbilt University; Vanderbilt University;
   University of Kentucky
RP Stamm, S (corresponding author), Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40506 USA.
EM stefan@stamms-lab.net
RI Rabchevsky, Alexander/AAQ-2451-2021
OI Rabchevsky, Alexander/0000-0002-1991-0915; Emeson,
   Ronald/0000-0002-4585-1648
FU NIMH/Vanderbilt Silvio O. Conte Center [P50 MH096972]; National
   Institutes of Health [RO1 GM083187, R21HD080035, P20RR020171];
   Foundation for Prader-Willi Research; Institutional Development Award
   (IDeA) from the National Institute of General Medical Sciences of the
   National Institutes of Health [8 P20 GM103527-06]
FX We are very grateful to the NIMH/Vanderbilt Silvio O. Conte Center for
   support of these studies (P50 MH096972). This work also was supported by
   National Institutes of Health RO1 GM083187, R21HD080035, and P20RR020171
   to S. S and the Foundation for Prader-Willi Research, and by an
   Institutional Development Award (IDeA) from the National Institute of
   General Medical Sciences of the National Institutes of Health (8 P20
   GM103527-06).
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NR 50
TC 18
Z9 18
U1 2
U2 9
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1757-4676
EI 1757-4684
J9 EMBO MOL MED
JI EMBO Mol. Med.
PD AUG
PY 2016
VL 8
IS 8
BP 878
EP 894
DI 10.15252/emmm.201506030
PG 17
WC Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Research & Experimental Medicine
GA DW4SO
UT WOS:000383633500005
PM 27406820
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Uzumcu, A
   Norgett, EE
   Dindar, A
   Uyguner, O
   Nisli, K
   Kayserili, H
   Sahin, SE
   Dupont, E
   Severs, NJ
   Leigh, IM
   Yuksel-Apak, M
   Kelsell, DP
   Wollnik, B
AF Uzumcu, A
   Norgett, EE
   Dindar, A
   Uyguner, O
   Nisli, K
   Kayserili, H
   Sahin, SE
   Dupont, E
   Severs, NJ
   Leigh, IM
   Yuksel-Apak, M
   Kelsell, DP
   Wollnik, B
TI Loss of desmoplakin isoform I causes early onset cardiomyopathy and
   heart failure in a Naxos-like syndrome
SO JOURNAL OF MEDICAL GENETICS
LA English
DT Article
ID RIGHT-VENTRICULAR CARDIOMYOPATHY; INTERMEDIATE-FILAMENT NETWORKS;
   PALMOPLANTAR KERATODERMA; DESMOSOMAL PLAQUE; WOOLLY HAIR; RECESSIVE
   MUTATION; PLAKOGLOBIN; HAPLOINSUFFICIENCY; CONNECTION; STRENGTH
AB Background: Desmosomes are cellular junctions important for intercellular adhesion and anchoring the intermediate filament ( IF) cytoskeleton to the cell membrane. Desmoplakin (DSP) is the most abundant desmosomal protein with 2 isoforms produced by alternative splicing.
   Methods: We describe a patient with a recessively inherited arrhythmogenic dilated cardiomyopathy with left and right ventricular involvement, epidermolytic palmoplantar keratoderma, and woolly hair. The patient showed a severe heart phenotype with an early onset and rapid progression to heart failure at 4 years of age.
   Results: A homozygous nonsense mutation, R1267X, was found in exon 23 of the desmoplakin gene, which results in an isoform specific truncation of the larger DSPI isoform. The loss of most of the DSPI specific rod domain and C-terminal area was confirmed by Western blotting and immunofluorescence. We further showed that the truncated DSPI transcript is unstable, leading to a loss of DSPI. DSPI is reported to be an obligate constituent of desmosomes and the only isoform present in cardiac tissue. To address this, we reviewed the expression of DSP isoforms in the heart. Our data suggest that DSPI is the major cardiac isoform but we also show that specific compartments of the heart have detectable DSPII expression.
   Conclusions: This is the first description of a phenotype caused by a mutation affecting only one DSP isoform. Our findings emphasise the importance of desmoplakin and desmosomes in epidermal and cardiac function and additionally highlight the possibility that the different isoforms of desmoplakin may have distinct functional properties within the desmosome.
C1 Univ Cologne, CMMC, Inst Human Genet, D-50931 Cologne, Germany.
   Istanbul Univ, Inst Child Hlth, Div Med Genet, Istanbul, Turkey.
   Univ London, Barts & London Queen Marys Sch Med & Dent, Ctr Cutaneous Res, Inst Cell & Mol Sci, London, England.
   Istanbul Fac Med, Dept Pediat Cardiol, Istanbul, Turkey.
   Univ London Imperial Coll Sci Technol & Med, NHLI, London, England.
C3 University of Cologne; Istanbul University; University of London; Queen
   Mary University London; Istanbul University; Imperial College London
RP Univ Cologne, CMMC, Inst Human Genet, Kerpener Str 34, D-50931 Cologne, Germany.
EM bwollnik@uni-koeln.de
RI Wollnik, Bernd/GRY-6062-2022; nişli, kemal/AAT-6434-2020; Kelsell,
   David/F-8767-2011; UYGUNER, ZEHRA/Y-3899-2018; Kayserili,
   Hulya/AAA-5593-2021
OI Kayserili, Hulya/0000-0003-0376-499X; Kelsell,
   David/0000-0002-9910-7144; Wollnik, Bernd/0000-0003-2589-0364; Dupont,
   Emmanuel/0000-0002-9529-4202
FU Wellcome Trust Funding Source: Medline
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NR 24
TC 96
Z9 110
U1 1
U2 7
PU BMJ PUBLISHING GROUP
PI LONDON
PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND
SN 0022-2593
EI 1468-6244
J9 J MED GENET
JI J. Med. Genet.
PD FEB
PY 2006
VL 43
IS 2
AR e5
DI 10.1136/jmg.2005.032904
PG 8
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 010IZ
UT WOS:000235182900019
PM 16467215
OA Green Published
DA 2025-04-10
ER

PT J
AU Nagel, RJ
   Lancaster, AM
   Zahler, AM
AF Nagel, RJ
   Lancaster, AM
   Zahler, AM
TI Specific binding of an exonic splicing enhancer by the pre-mRNA splicing
   factor SRp55
SO RNA
LA English
DT Article
DE SR proteins; troponin T; alternative splicing; splicing factors; exonic
   splicing enhancers
ID SMALL NUCLEAR RIBONUCLEOPROTEIN; T ALTERNATIVE EXON; MESSENGER-RNA;
   SR-PROTEINS; PREMESSENGER RNA; SITE SELECTION; 5'-SPLICE-SITE
   RECOGNITION; DISTINCT FUNCTIONS; CONSERVED FAMILY; PRIMER EXTENSION
AB Purine-rich exonic splicing enhancers (ESEs) have been identified in many alternatively spliced exons. Alternative splicing of several ESE-containing exons has been shown to depend on subsets of the SR protein family of pre-mRNA splicing factors. In this report, we show that purified SR protein family member SRp55 by itself binds a 30-nt ESE-containing exon, the alternatively spliced exon 5 of avian cardiac troponin T. We show that purified SRp55 binds specifically to this RNA sequence with an apparent K-d of 60 nM as assayed by gel mobility retardation experiments. Mutations in the exon 5 sequence that increase or decrease exon 5 inclusion in vivo and in vitro have correspondingly different affinities for SRp55 in our assays. The exon 5 sequence contains two purine-rich motifs, common to many ESEs, and both are required for SRp55 binding. Hill plot analysis of binding titration reactions indicates that there is a cooperative binding of at least two SRp55 proteins to the exon sequence. Chemical modification interference studies using kethoxal show that SRp55 binding to exon 5 requires the N1 and/or the N2 of almost every G residue in the exon. Dimethylsulfate modification interference studies indicate that none of the N1 positions of A residues in the er:on are important for binding. We postulate that SRp55 may recognize both primary sequence and RNA secondary structural elements within pre-mRNA.
C1 Univ Calif Santa Cruz, Dept Biol, Santa Cruz, CA 95064 USA.
   Univ Calif Santa Cruz, Sinsheimer Labs, Ctr Mol Biol RNA, Santa Cruz, CA 95064 USA.
C3 University of California System; University of California Santa Cruz;
   University of California System; University of California Santa Cruz
RP Univ Calif Santa Cruz, Dept Biol, Santa Cruz, CA 95064 USA.
EM zahler@biology.ucsc.edu
OI Zahler, Alan/0000-0003-0027-1647
FU NIGMS NIH HHS [1R01GM52848] Funding Source: Medline
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NR 56
TC 33
Z9 35
U1 0
U2 1
PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
PI COLD SPRING HARBOR
PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA
SN 1355-8382
EI 1469-9001
J9 RNA
JI RNA
PD JAN
PY 1998
VL 4
IS 1
BP 11
EP 23
PG 13
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA YY818
UT WOS:000072188600002
PM 9436904
DA 2025-04-10
ER

PT J
AU Montañés-Agudo, P
   van der Made, I
   Aufiero, S
   Tijsen, AJ
   Pinto, YM
   Creemers, EE
AF Montanes-Agudo, Pablo
   van der Made, Ingeborg
   Aufiero, Simona
   Tijsen, Anke J.
   Pinto, Yigal M.
   Creemers, Esther E.
TI Quaking regulates circular RNA production in cardiomyocytes
SO JOURNAL OF CELL SCIENCE
LA English
DT Article
DE circRNAs; Alternative splicing; RNA-binding proteins; Quaking;
   Cardiomyocytes
ID EXPRESSION; RBM20; GENE; TRANSLATION; LANDSCAPE
AB Circular RNAs (circRNAs) are a class of non-coding RNA molecules that are gaining increasing attention for their roles in various pathophysiological processes. The RNA-binding protein quaking (QKI) has been identified as a regulator of circRNA formation. In this study, we investigate the role of QKI in the formation of circRNAs in the heart by performing RNA-sequencing on Qki-knockout mice. Loss of QKI resulted in the differential expression of 17% of the circRNAs in adult mouse hearts. Interestingly, the majority of the QKIregulated circRNAs (58%) were derived from genes undergoing QKIdependent splicing, indicating a relationship between back-splicing and linear splicing. We compared these QKI-dependent circRNAs with those regulated by RBM20, another cardiac splicing factor essential for circRNA formation. We found that QKI and RBM20 regulate the formation of a distinct, but partially overlapping set of circRNAs in the heart. Strikingly, many shared circRNAs were derived from the Ttn gene, and they were regulated in an opposite manner. Our findings indicate that QKI not only regulates alternative splicing in the heart but also the formation of circRNAs.
C1 [Montanes-Agudo, Pablo; van der Made, Ingeborg; Aufiero, Simona; Tijsen, Anke J.; Pinto, Yigal M.; Creemers, Esther E.] Amsterdam UMC Locat Univ Amsterdam, Amsterdam Cardiovasc Sci, Dept Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands.
RP Creemers, EE (corresponding author), Amsterdam UMC Locat Univ Amsterdam, Amsterdam Cardiovasc Sci, Dept Expt Cardiol, NL-1105 AZ Amsterdam, Netherlands.
EM e.e.creemers@amsterdamumc.nl
OI Creemers, Esther/0000-0002-9001-3854; Tijsen, Anke/0000-0002-8030-8894
FU Rembrandt Institute of Cardiovascular Science; Netherlands
   Cardiovascular Research Initiative CVON (CVON-ARENA-PRIME); University
   of Amsterdam
FX This work was supported by grants from the Rembrandt Institute of
   Cardiovascular Science (2017) to E.E.C. and from the Netherlands
   Cardiovascular Research Initiative CVON (CVON-ARENA-PRIME) to Y.M.P.
   Open Access funding provided by University of Amsterdam. Deposited in
   PMC for immediate release.
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NR 37
TC 11
Z9 11
U1 1
U2 2
PU COMPANY BIOLOGISTS LTD
PI CAMBRIDGE
PA BIDDER BUILDING, STATION RD, HISTON, CAMBRIDGE CB24 9LF, ENGLAND
SN 0021-9533
EI 1477-9137
J9 J CELL SCI
JI J. Cell Sci.
PD JUL
PY 2023
VL 136
IS 13
AR jcs261120
DI 10.1242/jcs.261120
PG 10
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA O6IN7
UT WOS:001044823500010
PM 37272356
OA hybrid, Green Published
DA 2025-04-10
ER

PT J
AU Qian, JN
   Zhang, JJ
   Cao, J
   Wang, X
   Zhang, W
   Chen, XF
AF Qian, Jianan
   Zhang, Jingjing
   Cao, Ji
   Wang, Xue
   Zhang, Wei
   Chen, Xiangfan
TI The Regulatory Effect of Receptor-Interacting Protein Kinase 3 on
   CaMKIIδ in TAC-Induced Myocardial Hypertrophy
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Article
DE RIPK3; CaMKII delta; necroptosis; myocardial hypertrophy; alternative
   splicing
ID CARDIAC-HYPERTROPHY; NECROPTOSIS; OVEREXPRESSION; INFLAMMATION;
   INHIBITION; ACTIVATION; MECHANISMS
AB Necroptosis is a newly discovered mechanism of cell death, and its key regulatory role is attributed to the interaction of receptor-interacting protein kinases (RIPKs) RIPK1 and RIPK3. Ca2+/calmodulin-dependent protein kinase (CaMKII) is a newly discovered RIPK3 substrate, and its alternative splicing plays a fundamental role in cardiovascular diseases. In the present study, we aimed to explore the role and mechanism of necroptosis and alternative splicing of CaMKII delta in myocardial hypertrophy. Transverse aortic constriction (TAC) was performed on wild-type and knockout mice to establish the model of myocardial hypertrophy. After 3 weeks, echocardiography, cardiac index, cross-sectional area of myocardial cells, hypertrophic gene expression, myocardial damage, and fibers were assessed. Moreover, we detected the levels of inflammatory factors (IL-6 and TNF-alpha) and examined the expressions of necroptosis-related proteins RIPK3, RIPK1, and phosphorylated MLKL. Meanwhile, we tested the expression levels of splicing factors ASF/SF2 and SC-35 in an attempt to explore CaMKII delta. The relationship between variable splicing disorder and the expression levels of splicing factors ASF/SF2 and SC-35. Further, we also investigated CaMKII activation, oxidative stress, and mitochondrial ultrastructure. In addition, wild-type mice were administered with a recombinant adeno-associated virus (AAV) carrying RIPK3, followed by TAC surgery to construct a model of myocardial hypertrophy, and the above-mentioned indicators were tested after 3 weeks. The results showed that RIPK3 deficiency could alleviate cardiac dysfunction, myocardial injury, aggravation of necrosis, and CaMKII activation induced by TAC surgery in mice with myocardial hypertrophy. Tail vein injection of AAV could reverse cardiac dysfunction, myocardial damage, aggravation of necrosis, and CaMKII activation in mice with myocardial hypertrophy. These results proved that RIPK3 could be used as a molecular intervention target for the prevention and treatment of myocardial hypertrophy.
C1 [Qian, Jianan; Zhang, Jingjing; Cao, Ji; Wang, Xue; Zhang, Wei; Chen, Xiangfan] Nantong Univ, Sch Pharm, Nantong 226001, Peoples R China.
   [Zhang, Jingjing; Zhang, Wei; Chen, Xiangfan] Nantong Univ, Sch Med, Nantong 226001, Peoples R China.
   [Chen, Xiangfan] Nantong Univ, Nantong Peoples Hosp 1, Affiliated Hosp 2, Nantong 226001, Peoples R China.
C3 Nantong University; Nantong University; Nantong University
RP Zhang, W; Chen, XF (corresponding author), Nantong Univ, Sch Pharm, Nantong 226001, Peoples R China.; Zhang, W; Chen, XF (corresponding author), Nantong Univ, Sch Med, Nantong 226001, Peoples R China.
EM jn29103@163.com; zhangjingjing@stmail.ntu.edu.cn;
   019310033@stmail.ntu.edu.cn; w18862936086@163.com; zhangw@ntu.edu.cn;
   cxf8448180@ntu.edu.cn
RI Chen, Xiangfan/M-3719-2016; Zhang, Wei/JKI-3565-2023
FU The RIPK3-/- mice were donated by Wang Xiaodong (National
   Institute of Biological Sciences, Beijing).
FX The RIPK3<SUP>-/-</SUP> mice were donated by Wang Xiaodong (National
   Institute of Biological Sciences, Beijing).
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NR 50
TC 3
Z9 3
U1 2
U2 3
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
SN 1661-6596
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD OCT
PY 2023
VL 24
IS 19
AR 14529
DI 10.3390/ijms241914529
PG 24
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA U5BF3
UT WOS:001084942500001
PM 37833985
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Murphy, LL
   Moon-Grady, AJ
   Cuneo, BF
   Wakai, RT
   Yu, SH
   Kunic, JD
   Benson, DW
   George, AL
AF Murphy, Lisa L.
   Moon-Grady, Anita J.
   Cuneo, Bettina F.
   Wakai, Ronald T.
   Yu, Suhong
   Kunic, Jennifer D.
   Benson, D. Woodrow
   George, Alfred L., Jr.
TI Developmentally regulated SCN5A splice variant potentiates
   dysfunction of a novel mutation associated with severe fetal arrhythmia
SO HEART RHYTHM
LA English
DT Article
DE Arrhythmia; Sodium channel; SCN5A; Sudden death; Long-QT syndrome;
   Magnetocardiography; Alternative splicing
ID LONG-QT SYNDROME; INFANT-DEATH-SYNDROME; CARDIAC SODIUM-CHANNEL;
   PRENATAL-DIAGNOSIS; GENE; LIFE; BRADYCARDIA; EXPRESSION; DEFECTS;
   NEWBORN
AB BACKGROUND Congenital long-QT syndrome (LQTS) may present during fetal development and can be life-threatening. The molecular mechanism for the unusual early onset of LQTS during fetal development is unknown.
   OBJECTIVE We sought to elucidate the molecular basis for severe fetal LQTS presenting at 19 weeks' gestation, the earliest known presentation of this disease.
   METHODS Fetal magnetocardiography was used to demonstrated torsades de pointes and a prolonged rate-corrected QT interval. In vitro electrophysiological studies were performed to determine functional consequences of a novel SCN5A mutation found in the fetus.
   RESULTS The fetus presented with episodes of ventricular ectopy progressing to incessant ventricular tachycardia and hydrops fetalis. Genetic analysis disclosed a novel, de novo heterozygous mutation (L409P) and a homozygous common variant (R558 in SCN5A). In vitro electrophysiological studies demonstrated that the mutation in combination with R558 caused significant depolarized shifts in the voltage dependence of inactivation and activation, faster recovery from inactivation, and a 7-fold higher level of persistent current. When the mutation was engineered in a fetal-expressed SCN5A splice isoform, channel dysfunction was markedly potentiated. Also, R558 alone in the fetal splice isoform evoked a large persistent current, and hence both alleles were dysfunctional.
   CONCLUSION We report the earliest confirmed diagnosis of symptomatic LQTS and present evidence that mutant cardiac sodium channel dysfunction is potentiated by a developmentally regulated alternative splicing event in SCN5A. Our findings provide a plausible mechanism for the unusual severity and early onset of cardiac arrhythmia in fetal LQTS.
C1 [George, Alfred L., Jr.] Vanderbilt Univ, Div Med Genet, Dept Pharmacol, Nashville, TN 37232 USA.
   [Kunic, Jennifer D.; George, Alfred L., Jr.] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA.
   [Moon-Grady, Anita J.] Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA.
   [Cuneo, Bettina F.] Hope Childrens Hosp, Heart Inst Children, Oak Lawn, IL USA.
   [Wakai, Ronald T.; Yu, Suhong] Univ Wisconsin, Dept Med Phys, Madison, WI 53706 USA.
   [Benson, D. Woodrow] Cincinnati Childrens Hosp, Div Cardiol, Med Ctr, Cincinnati, OH USA.
C3 Vanderbilt University; Vanderbilt University; University of California
   System; University of California San Francisco; University of Wisconsin
   System; University of Wisconsin Madison; Cincinnati Children's Hospital
   Medical Center
RP George, AL (corresponding author), Vanderbilt Univ, Div Med Genet, Dept Pharmacol, 529 Light Hall,2215 Garland Ave, Nashville, TN 37232 USA.
EM al.george@vanderbilt.edu
RI YU, SUHONG/G-7532-2015
OI Wakai, Ronald/0000-0002-9894-0484; Moon-Grady, Anita/0000-0003-3822-693X
FU National Institutes of Health [HL083374, HL063174, HL69712]
FX This work was supported by grants from the National Institutes of Health
   (HL083374 to A.L.G., HL063174 to R.T.W., and HL69712 to D.W.B.). First
   two authors contributed equally. Alfred L. George, Jr, MD, Division of
   Genetic Medicine, Vanderbilt University, 529 Light Hall, 2215 Garland
   Avenue, Nashville, TN 37232-0275. E-mail address:
   al.george@vanderbilt.edu.
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NR 34
TC 42
Z9 50
U1 0
U2 7
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 1547-5271
EI 1556-3871
J9 HEART RHYTHM
JI Heart Rhythm
PD APR
PY 2012
VL 9
IS 4
BP 590
EP 597
DI 10.1016/j.hrthm.2011.11.006
PG 8
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 918NY
UT WOS:000302258100025
PM 22064211
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Conboy, JG
AF Conboy, John G.
TI Developmental regulation of RNA processing by Rbfox proteins
SO WILEY INTERDISCIPLINARY REVIEWS-RNA
LA English
DT Review
ID AUTISM SPECTRUM DISORDER; COPY NUMBER VARIATIONS; SPLICING FACTORS;
   IN-VIVO; CELL DIFFERENTIATION; ALTERNATIVE EXONS; BRAIN-DEVELOPMENT;
   MAMMALIAN BRAIN; BINDING MOTIFS; CANDIDATE GENE
AB The Rbfox genes encode an ancient family of sequence-specific RNA binding proteins (RBPs) that are critical developmental regulators in multiple tissues including skeletal muscle, cardiac muscle, and brain. The hallmark of Rbfox proteins is a single high-affinity RRM domain, highly conserved from insects to humans, that binds preferentially to UGCAUG motifs at diverse regulatory sites in pre-mRNA introns, mRNA 3'UTRs, and pre-miRNAs hairpin structures. Versatile regulatory circuits operate on Rbfox pre-mRNA and mRNA to ensure proper expression of Rbfox1 protein isoforms, which then act on the broader transcriptome to regulate alternative splicing networks, mRNA stability and translation, and microRNA processing. Complex Rbfox expression is encoded in large genes encompassing multiple promoters and alternative splicing options that govern spatiotemporal expression of structurally distinct and tissue-specific protein isoforms with different classes of RNA targets. Nuclear Rbfox1 is a candidate master regulator that binds intronic UGCAUG elements to impact splicing efficiency of target alternative exons, many in transcripts for other splicing regulators. Tissue-specificity of Rbfox-mediated alternative splicing is executed by combinatorial regulation through the integrated activity of Rbfox proteins and synergistic or antagonistic splicing factors. Studies in animal models show that Rbfox1-related genes are critical for diverse developmental processes including germ cell differentiation and memory in Drosophila, neuronal migration and function in mouse brain, myoblast fusion and skeletal muscle function, and normal heart function. Finally, genetic and biochemical evidence suggest that aberrations in Rbfox-regulated circuitry are risk factors for multiple human disorders, especially neurodevelopmental disorders including epilepsy and autism, and cardiac hypertrophy. (C) 2016 Wiley Periodicals, Inc.
C1 [Conboy, John G.] Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA.
C3 United States Department of Energy (DOE); Lawrence Berkeley National
   Laboratory
RP Conboy, JG (corresponding author), Lawrence Berkeley Natl Lab, Biol Syst & Engn Div, Berkeley, CA 94720 USA.
EM jgconboy@lbl.gov
FU National Institutes of Health [DK094699]
FX This work was supported by National Institutes of Health [DK094699] and
   Director, Office of Science and Office of Biological & Environmental
   Research of the US Department of Energy [DE-AC02-05CH1123].
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NR 89
TC 90
Z9 104
U1 0
U2 40
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1757-7004
EI 1757-7012
J9 WIRES RNA
JI Wiley Interdiscip. Rev.-RNA
PD MAR-APR
PY 2017
VL 8
IS 2
AR e1398
DI 10.1002/wrna.1398
PG 17
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA EP3KP
UT WOS:000397281500009
PM 27748060
OA Green Published, Green Accepted, Green Submitted
DA 2025-04-10
ER

PT J
AU Stormo, C
   Kringen, MK
   Grimholt, RM
   Berg, JP
   Piehler, AP
AF Stormo, Camilla
   Kringen, Marianne K.
   Grimholt, Runa M.
   Berg, Jens P.
   Piehler, Armin P.
TI A novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)
   splice variant with an alternative exon 1 potentially encoding an
   extended N-terminus
SO BMC MOLECULAR BIOLOGY
LA English
DT Article
DE 3-hydroxy-3-methylglutaryl-coenzyme A reductase; HMG-CoA; Transcription;
   Alternative splicing; Statin; Cholesterol
ID COENZYME-A REDUCTASE; COA REDUCTASE; GENE-EXPRESSION;
   ENDOPLASMIC-RETICULUM; CHOLESTEROL; PEROXISOMES; LIVER; LOCALIZATION;
   POLYMORPHISM; PROMOTERS
AB Background: The major rate-limiting enzyme for de novo cholesterol synthesis is 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). HMGCR is sterically inhibited by statins, the most commonly prescribed drugs for the prevention of cardiovascular events. Alternative splicing of HMGCR has been implicated in the control of cholesterol homeostasis. The aim of this study was to identify novel alternatively spliced variants of HMGCR with potential physiological importance.
   Results: Bioinformatic analyses predicted three novel HMGCR transcripts containing an alternative exon 1 (HMGCR-1b, -1c, -1d) compared with the canonical transcript (HMGCR-1a). The open reading frame of the HMGCR-1b transcript potentially encodes 20 additional amino acids at the N-terminus, compared with HMGCR-1a. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to examine the mRNA levels of HMGCR in different tissues; HMGCR-1a was the most highly expressed variant in most tissues, with the exception of the skin, esophagus, and uterine cervix, in which HMGCR-1b was the most highly expressed transcript. Atorvastatin treatment of HepG2 cells resulted in increased HMGCR-1b mRNA levels, but unaltered proximal promoter activity compared to untreated cells. In contrast, HMGCR-1c showed a more restricted transcription pattern, but was also induced by atorvastatin treatment.
   Conclusions: The gene encoding HMGCR uses alternative, mutually exclusive exon 1 sequences. This contributes to an increased complexity of HMGCR transcripts. Further studies are needed to investigate whether HMGCR splice variants identified in this study are physiologically functional.
C1 [Stormo, Camilla; Grimholt, Runa M.; Berg, Jens P.; Piehler, Armin P.] Univ Oslo, Dept Med Biochem, N-0424 Oslo, Norway.
   [Kringen, Marianne K.] Oslo Univ Hosp, Dept Pharmacol, N-0424 Oslo, Norway.
   [Berg, Jens P.] Univ Oslo, Fac Med, Inst Clin Med, N-0318 Oslo, Norway.
   [Piehler, Armin P.] Furst Med Lab, NO-1051 Oslo, Norway.
C3 University of Oslo; University of Oslo; University of Oslo
RP Stormo, C (corresponding author), Univ Oslo, Dept Med Biochem, POB 4956, N-0424 Oslo, Norway.
EM camilla.stormo@medisin.uio.no
RI Berg, Jens/IZQ-0634-2023
OI Berg, Jens P/0000-0003-0157-5888
FU Division of Diagnostics and Intervention, Oslo University Hospital,
   Norway; South-Eastern Norway Regional Health Authority
FX We give special thanks to Daniel Sachse for technical assistance with
   figure illustrations and statistical analysis. We thank Dr. Bernd Thiede
   for help with protein bioinformatics. This work was funded by the
   Division of Diagnostics and Intervention, Oslo University Hospital,
   Norway and South-Eastern Norway Regional Health Authority.
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NR 32
TC 11
Z9 16
U1 1
U2 21
PU BIOMED CENTRAL LTD
PI LONDON
PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND
SN 1471-2199
J9 BMC MOL BIOL
JI BMC Mol. Biol.
PD SEP 18
PY 2012
VL 13
AR 29
DI 10.1186/1471-2199-13-29
PG 10
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 060TM
UT WOS:000312801000001
PM 22989091
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Dlamini, Z
   Hull, R
   Makhafola, TJ
   Mbele, M
AF Dlamini, Zodwa
   Hull, Rodney
   Makhafola, Tshepiso J.
   Mbele, Mzwandile
TI Regulation of alternative splicing in obesity-induced hypertension
SO DIABETES METABOLIC SYNDROME AND OBESITY-TARGETS AND THERAPY
LA English
DT Review
DE obesity; hypertension; weight loss; angiogenesis; alternative splicing;
   gene regulation
ID BODY-MASS INDEX; ANGIOTENSIN-ALDOSTERONE SYSTEM; SYMPATHETIC NEURAL
   ACTIVATION; CARDIOVASCULAR RISK-FACTORS; ADIPOSE-TISSUE; BLOOD-PRESSURE;
   RESISTANT HYPERTENSION; MYOCARDIAL-INFARCTION; FUNCTIONAL-ANALYSIS;
   INSULIN-RESISTANCE
AB Obesity is the result of genetics which predisposes an individual to obesity and environmental factors, resulting in excessive weight gain. A well-established linear relationship exists between hypertension and obesity. The combined burden of hypertension and obesity poses significant health and economic challenges. Many environmental factors and genetic traits interact to contribute to obesity-linked hypertension. These include excess sodium re-absorption or secretion by the kidneys, a hypertensive shift of renal-pressure and activation of the sympathetic nervous system. Most individuals suffering from hypertension need drugs in order to treat their raised blood pressure, and while a number of antihypertensive therapeutic agents are currently available, 50% of cases remain uncontrolled. In order to develop new and effective therapeutic agents combating obesity-induced hypertension, a thorough understanding of the molecular events leading to adipogenesis is critical. With the advent of whole genome and exome sequencing techniques, new genes and variants which can be used as markers for obesity and hypertension are being identified. This review examines the role played by alternative splicing (AS) as a contributing factor to the metabolic regulation of obesity-induced hypertension. Splicing mutations constitute at least 14% of the disease-causing mutations, thus implicating polymorphisms that effect splicing as indicators of disease susceptibility. The unique transcripts resulting from the alternate splicing of mRNA encoding proteins that play a key role in contributing to obesity would be vital to gain a proper understanding of the genetic causes of obesity. A greater knowledge of the genetic basis for obesity-linked hypertension will assist in the development of appropriate diagnostic tests as well as the identification of new personalized therapeutic targets against obesity-induced hypertension.
C1 [Dlamini, Zodwa; Hull, Rodney; Makhafola, Tshepiso J.; Mbele, Mzwandile] Univ Pretoria, Fac Hlth Sci, PACRI, South African Med Res Council,PPNDTHAC Extramural, ZA-0028 Hatfield, South Africa.
C3 University of Pretoria; South African Medical Research Council
RP Dlamini, Z (corresponding author), Univ Pretoria, Fac Hlth Sci, PACRI, South African Med Res Council,PPNDTHAC Extramural, ZA-0028 Hatfield, South Africa.
EM Zodwa.dlamini@up.ac.za
RI makhafola, Tshepiso/AAR-2556-2020; Dlamini, Zodwa/HNB-6090-2023; Hull,
   Rodney/HJP-0275-2023; Stefanadis, Christodoulos/ABH-2232-2020;
   Makhafola, Tshepiso Jan/N-1607-2015
OI Dlamini, Zodwa/0000-0002-8012-3646; Hull, Rodney/0000-0002-2001-3453;
   Stefanadis, Christodoulos/0000-0001-5974-6454; Makhafola, Tshepiso
   Jan/0000-0002-8335-9611
FU South African Medical Research Council (SAMRC); National Research
   Foundation (NRF)
FX We would like to thank the South African Medical Research Council
   (SAMRC) and the National Research Foundation (NRF) for funding this
   work.
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NR 146
TC 6
Z9 7
U1 0
U2 8
PU DOVE MEDICAL PRESS LTD
PI ALBANY
PA PO BOX 300-008, ALBANY, AUCKLAND 0752, NEW ZEALAND
SN 1178-7007
J9 DIABETES METAB SYNDR
JI Diabetes Metab. Syndr. Obes.
PY 2019
VL 12
BP 1597
EP 1615
DI 10.2147/DMSO.S188680
PG 19
WC Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Endocrinology & Metabolism
GA IU3PD
UT WOS:000483497900002
PM 31695458
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Vancheri, C
   Morini, E
   Prandi, FR
   Alkhoury, E
   Celotto, R
   Romeo, F
   Novelli, G
   Amati, F
AF Vancheri, Chiara
   Morini, Elena
   Prandi, Francesca Romana
   Alkhoury, Elie
   Celotto, Roberto
   Romeo, Francesco
   Novelli, Giuseppe
   Amati, Francesca
TI Two RECK Splice Variants (Long and Short) Are Differentially
   Expressed in Patients with Stable and Unstable Coronary Artery Disease:
   A Pilot Study
SO GENES
LA English
DT Article
DE RECK; alternative splicing event; splicing variants; biomarkers;
   coronary artery disease
ID CYSTEINE-RICH PROTEIN; MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASES;
   CULPRIT LESION; KAZAL MOTIFS; REGULATOR; IMPACT; GENES; ROLES; RISK
AB Primary prevention is crucial for coronary heart disease (CAD) and the identification of new reliable biomarkers might help risk stratification or predict adverse coronary events. Alternative splicing (AS) is a less investigated genetic factors implicated in CAD etiology. We performed an RNA-seq study on PBMCs from CAD patients and control subjects (CTR) and observed 113 differentially regulated AS events (24 up and 89 downregulated) in 86 genes. The RECK (Reversion-inducing-cysteine-rich protein with Kazal motifs) gene was further analyzed in a larger case study (24 CTR subjects, 72 CAD and 32 AMI patients) for its Splicing-Index FC (FC = -2.64; p = 0.0217), the AS event involving an exon (exon 18), and its role in vascular inflammation and remodeling. We observed a significant downregulation of Long RECK splice variant (containing exon 18) in PBMCs of AMI compared to CTR subjects (FC = -3.3; p < 0.005). Interestingly, the Short RECK splice variant (lacking exon 18) was under-expressed in AMI compared to both CTR (FC = -4.5; p < 0.0001) and CAD patients (FC = -4.2; p < 0.0001). A ROC curve, constructed combining Long and Short RECK expression data, shows an AUC = 0.81 (p < 0.001) to distinguish AMI from stable CAD patients. A significant negative correlation between Long RECK and triglycerides in CTR group and a positive correlation in the AMI group was found. The combined evaluation of Long and Short RECK expression levels is a potential genomic biomarker for the discrimination of AMI from CAD patients. Our results underline the relevance of deeper studies on the expression of these two splice variants to elucidate their functional role in CAD development and progression.
C1 [Vancheri, Chiara; Morini, Elena; Novelli, Giuseppe; Amati, Francesca] Univ Roma Tor Vergata, Dept Biomed & Prevent, Genet Unit, I-00133 Rome, Italy.
   [Prandi, Francesca Romana; Alkhoury, Elie; Celotto, Roberto; Romeo, Francesco] Univ Hosp Tor Vergata, Unit Cardiol, I-00133 Rome, Italy.
   [Romeo, Francesco] Unicamillus Int Med Univ, I-00131 Rome, Italy.
   [Novelli, Giuseppe] Tor Vergata Univ Hosp, PTV, Med Genet Labs, I-00133 Rome, Italy.
   [Novelli, Giuseppe] Neuromed IRCCS Inst, I-86077 Pozzilli, Italy.
   [Novelli, Giuseppe] Reno Univ Nevada, Sch Med, Reno, NV USA.
   [Amati, Francesca] Univ San Raffaele, Dept Promot Human Sci & Qual Life, I-00166 Rome, Italy.
C3 University of Rome Tor Vergata; University of Rome Tor Vergata; Policlin
   Tor Vergata; University of Rome Tor Vergata; Policlin Tor Vergata;
   Universita Telematica San Raffaele
RP Amati, F (corresponding author), Univ Roma Tor Vergata, Dept Biomed & Prevent, Genet Unit, I-00133 Rome, Italy.; Amati, F (corresponding author), Univ San Raffaele, Dept Promot Human Sci & Qual Life, I-00166 Rome, Italy.
EM chiara.vancheri88@gmail.com; morinielena.em@gmail.com;
   francescaromanaprandi@gmail.com; elie.alkhoury22@gmail.com;
   celott.roberto@yahoo.it; romeocerabino@gmail.com; gnovelli@me.com;
   amati@med.uniroma2.it
RI Morini, Elena/JNE-6567-2023; Romeo, Francesco/IRZ-6637-2023; Novelli,
   Giuseppe/A-5195-2013; Amati, Francesca/J-8439-2012
OI Celotto, Roberto/0000-0003-1837-5997; Novelli,
   Giuseppe/0000-0002-7781-602X; Amati, Francesca/0000-0003-2209-2156;
   Prandi, Francesca Romana/0000-0003-1878-8871
FU Fondazione Roma [Sn.NCDS-2013-00000333]; Bandi Ateneo "Consolidate
   Foundations" [AmiRNAE82F16000570005]
FX This research was funded by "Fondazione Roma" (Sn.NCDS-2013-00000333 to
   G.N. and F.R.) and Bandi Ateneo "Consolidate Foundations"
   (AmiRNAE82F16000570005 to F.A.).
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NR 63
TC 4
Z9 5
U1 2
U2 9
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2073-4425
J9 GENES-BASEL
JI Genes
PD JUN
PY 2021
VL 12
IS 6
AR 939
DI 10.3390/genes12060939
PG 20
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA SY8NG
UT WOS:000666137100001
PM 34205376
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Stark, JM
   Cooper, TA
   Roth, MB
AF Stark, JM
   Cooper, TA
   Roth, MB
TI The relative strengths of SR protein-mediated associations of
   alternative and constitutive exons can influence alternative splicing
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID PRE-MESSENGER-RNA; TROPONIN-T-GENE; ENHANCER; MUSCLE; RECOGNITION;
   COMPLEX; BINDING; INTRON; SITES
AB We have characterized the functional role of SR protein-mediated exon/exon associations in the alternative splicing of exon 5 of chicken cardiac troponin T (cTnT). We have previously shown that SR proteins can promote the association of the alternative exon 5 with the flanking constitutive exon 6 of this pre-mRNA. In this study, we have shown that when exons 2, 3, and 4 of the cTnT pre-mRNA are spliced together, the composite exon 2/3/4 contains an additional SR protein binding site. Furthermore, we have found that SR proteins can also promote interactions between the pairs of exons 2/3/4-5 and 2/3/ 4-6. We then asked whether the SR protein binding sites in these exons play a role in cTnT alternative splicing in vivo. We found that the SR protein binding sites in exons 2/3/4 and 6 promote exon 5 skipping, and it has previously been shown that the SR protein binding site in exon 5 promotes exon 5 inclusion. Consistent with these results, we find that the SR protein-mediated association of exon 2/3/4 with 6 is preferred over associations involving exon 5, in that exons 2/3/4 and 6 are more efficient than exon 5 in competing an SR protein-mediated exon/exon association. We suggest that the relative strengths of SR protein-mediated associations of alternative and constitutive exons play a role in determining alternative splicing patterns.
C1 Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98104 USA.
   Fred Hutchinson Canc Res Ctr, Mol & Cellular Biol Program, Seattle, WA 98104 USA.
   Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA.
   Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA.
C3 Fred Hutchinson Cancer Center; Fred Hutchinson Cancer Center; Baylor
   College of Medicine; Baylor College of Medicine
RP Roth, MB (corresponding author), Fred Hutchinson Canc Res Ctr, Div Basic Sci, 1124 Columbia St, Seattle, WA 98104 USA.
FU NHLBI NIH HHS [HL45565] Funding Source: Medline; NIGMS NIH HHS [GM48435,
   T32 GM07270] Funding Source: Medline
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NR 25
TC 7
Z9 10
U1 0
U2 0
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0021-9258
J9 J BIOL CHEM
JI J. Biol. Chem.
PD OCT 15
PY 1999
VL 274
IS 42
BP 29838
EP 29842
DI 10.1074/jbc.274.42.29838
PG 5
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 246QQ
UT WOS:000083176400042
PM 10514463
OA hybrid
DA 2025-04-10
ER

PT J
AU Giudice, J
   Jiang, H
AF Giudice, Jimena
   Jiang, Hao
TI Splicing regulation through biomolecular condensates and membraneless
   organelles
SO NATURE REVIEWS MOLECULAR CELL BIOLOGY
LA English
DT Review
ID LIQUID PHASE-SEPARATION; RNA-BINDING PROTEINS; PRE-MESSENGER-RNAS;
   NUCLEAR SPECKLES; SEQUENCE DETERMINANTS; HNRNP PROTEINS; SC-35 DOMAINS;
   GENE; TDP-43; ORGANIZATION
AB Biomolecular condensates, sometimes also known as membraneless organelles (MLOs), can form through weak multivalent intermolecular interactions of proteins and nucleic acids, a process often associated with liquid-liquid phase separation. Biomolecular condensates are emerging as sites and regulatory platforms of vital cellular functions, including transcription and RNA processing. In the first part of this Review, we comprehensively discuss how alternative splicing regulates the formation and properties of condensates, and conversely the roles of biomolecular condensates in splicing regulation. In the second part, we focus on the spatial connection between splicing regulation and nuclear MLOs such as transcriptional condensates, splicing condensates and nuclear speckles. We then discuss key studies showing how splicing regulation through biomolecular condensates is implicated in human pathologies such as neurodegenerative diseases, different types of cancer, developmental disorders and cardiomyopathies, and conclude with a discussion of outstanding questions pertaining to the roles of condensates and MLOs in splicing regulation and how to experimentally study them.
   Biomolecular condensates are emerging as hubs of splicing regulation. This Review discusses the modulation of condensate functions through alternative splicing, regulation of (co-transcriptional) splicing at condensates and the involvement of these condensates in human diseases.
C1 [Giudice, Jimena] Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA.
   [Giudice, Jimena] Univ N Carolina, McAllister Heart Inst, Sch Med, Chapel Hill, NC 27599 USA.
   [Jiang, Hao] Univ Virginia, Dept Biochem & Mol Genet, Sch Med, Charlottesville, VA 22908 USA.
C3 University of North Carolina; University of North Carolina Chapel Hill;
   University of North Carolina; University of North Carolina Chapel Hill;
   University of North Carolina School of Medicine; University of Virginia
RP Giudice, J (corresponding author), Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA.; Giudice, J (corresponding author), Univ N Carolina, McAllister Heart Inst, Sch Med, Chapel Hill, NC 27599 USA.; Jiang, H (corresponding author), Univ Virginia, Dept Biochem & Mol Genet, Sch Med, Charlottesville, VA 22908 USA.
EM jimena_giudice@med.unc.edu; hj8d@virginia.edu
RI Giudice, Jimena/N-5156-2016
OI Giudice, Jimena/0000-0002-3330-7784
FU Department of Defense Breast Cancer Research Program (Breakthrough
   Award) [BC190343]; University of North Carolina at Chapel Hill; National
   Institutes of Health (NIH) [R01-GM130866]; National Science Foundation
   (NSF) [2239056]
FX The work by H.J. on AKAP95 condensates was supported by the Department
   of Defense Breast Cancer Research Program (Breakthrough Award BC190343).
   J.G. is supported by The University of North Carolina at Chapel Hill
   (start-up funds and Jefferson Pilot Award), the National Institutes of
   Health (NIH) (R01-GM130866) and the National Science Foundation (NSF)
   (CAREER award 2239056).
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NR 214
TC 10
Z9 10
U1 14
U2 32
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 1471-0072
EI 1471-0080
J9 NAT REV MOL CELL BIO
JI Nat. Rev. Mol. Cell Biol.
PD SEP
PY 2024
VL 25
IS 9
BP 683
EP 700
DI 10.1038/s41580-024-00739-7
EA MAY 2024
PG 18
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA D6F6E
UT WOS:001228496600001
PM 38773325
DA 2025-04-10
ER

PT J
AU Suzuki, N
   Idogawa, M
   Tange, S
   Ohashi, T
   Sasaki, Y
   Nakase, H
   Tokino, T
AF Suzuki, Natsumi
   Idogawa, Masashi
   Tange, Shoichiro
   Ohashi, Tomoko
   Sasaki, Yasushi
   Nakase, Hiroshi
   Tokino, Takashi
TI p53-induced ARVCF modulates the splicing landscape and supports the
   tumor suppressive function of p53
SO ONCOGENE
LA English
DT Article
ID TRANSCRIPTIONAL TARGET; APOPTOSIS
AB p53 is one of the most important tumor suppressor genes, and the exploration of p53-target genes is important for elucidation of its functional mechanisms. In this study, we identified Armadillo Repeat gene deleted in Velo-Cardio-Facial syndrome (ARVCF) as a direct target of p53 through ChIP-sequencing analysis. Activated p53 protein was found to bind to two distinct sites in the ARVCF gene, resulting in induction of ARVCF expression at both the mRNA and protein levels. We revealed that the knockdown of ARVCF inhibited p53-induced apoptosis. Interestingly, ARVCF interacted with hnRNPH2, which is involved in pre-mRNA splicing, and ARVCF knockdown induced dynamic changes in alternative splicing patterns. These results suggest that p53-induced ARVCF indirectly, but not directly, regulates p53 target selectivity through splicing alterations of specific genes. Thus, we demonstrated that the induction of ARVCF expression contributed to the tumor suppressive function of p53. Recently, it has been reported that many tumors have thousands of alternative splicing events that are not detectable in normal samples. ARVCF may play a role in alternative splicing events in cancer and may provide clues to explore novel approaches for cancer diagnosis and therapy.
C1 [Suzuki, Natsumi; Idogawa, Masashi; Tange, Shoichiro; Ohashi, Tomoko; Tokino, Takashi] Sapporo Med Univ, Res Inst Frontier Med, Dept Med Genome Sci, Sch Med, Sapporo, Hokkaido, Japan.
   [Idogawa, Masashi; Nakase, Hiroshi] Sapporo Med Univ, Dept Gastroenterol & Hepatol, Sch Med, Sapporo, Hokkaido, Japan.
   [Sasaki, Yasushi] Sapporo Med Univ, Ctr Med Educ, Dept Liberal Arts & Sci, Biol, Sapporo, Hokkaido, Japan.
C3 Sapporo Medical University; Sapporo Medical University; Sapporo Medical
   University
RP Idogawa, M; Tokino, T (corresponding author), Sapporo Med Univ, Res Inst Frontier Med, Dept Med Genome Sci, Sch Med, Sapporo, Hokkaido, Japan.; Idogawa, M (corresponding author), Sapporo Med Univ, Dept Gastroenterol & Hepatol, Sch Med, Sapporo, Hokkaido, Japan.
EM idogawa@sapmed.ac.jp; tokino@sapmed.ac.jp
RI Tange, Shoichiro/AAJ-5265-2020; Nakase, Hiroshi/AAZ-4425-2020; Tokino,
   Takashi/AAI-9887-2021; Idogawa, Masashi/B-5208-2008; Sasaki,
   Yasushi/AAA-3079-2019
OI Idogawa, Masashi/0000-0002-8507-1726; Tange,
   Shoichiro/0000-0002-2126-6938; Sasaki, Yasushi/0000-0002-3500-8059
FU JSPS KAKENHI [19K08372, 19K07645, 16K09285, 16K07122]; Takeda Science
   Foundation; Grants-in-Aid for Scientific Research [16K09285, 16K07122,
   19K08372, 19K07645] Funding Source: KAKEN
FX This work was supported by JSPS KAKENHI (grant numbers: 19K08372,
   19K07645, 16K09285, and 16K07122) and Takeda Science Foundation.
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NR 21
TC 6
Z9 6
U1 0
U2 1
PU NATURE PUBLISHING GROUP
PI LONDON
PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 0950-9232
EI 1476-5594
J9 ONCOGENE
JI Oncogene
PD MAR
PY 2020
VL 39
IS 10
BP 2202
EP 2211
DI 10.1038/s41388-019-1133-7
PG 10
WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics &
   Heredity
GA KS8UR
UT WOS:000518584000013
PM 31827232
DA 2025-04-10
ER

PT J
AU Liu, J
   Wang, K
   Liu, XY
   Pan, L
   Zhou, WL
   Huang, JR
   Liu, HL
   Su, ZY
   Xu, XQ
AF Liu, Jing
   Wang, Ke
   Liu, Xingyang
   Pan, Lei
   Zhou, Wanlu
   Huang, Jingru
   Liu, Hongli
   Su, Zhiying
   Xu, Xiu Qin
TI RBM24 controls cardiac QT interval through CaMKIIδ splicing
SO CELLULAR AND MOLECULAR LIFE SCIENCES
LA English
DT Article
DE RNA binding motif 24; Calmodulin-dependent protein kinase II delta;
   Alternative splicing; Calcium; Arrhythmia
ID KINASE-II; ISOFORM; CARDIOMYOPATHY; HYPERTROPHY; EXPRESSION; MUTATION
AB Calcium/calmodulin-dependent kinase II delta (CaMKII delta) is the predominant cardiac isoform and it is alternatively spliced to generate multiple variants. Variable variants allow for distinct localization and potentially different functions in the heart. Dysregulation of CaMKII delta splicing has been demonstrated to be involved in the pathogenesis of heart diseases, such as cardiac hypertrophy, arrhythmia, and diastolic dysfunction. However, the mechanisms that regulate CaMKII delta are incompletely understood. Here, we show that RNA binding motif protein 24 (RBM24) is a key splicing regulator of CaMKII delta. RBM24 ablation leads to the aberrant shift of CaMKII delta towards the delta-C isoform, which is known to activate the L-type Ca current. In line with this, we found marked alteration in Ca2+ handling followed by prolongation of the ventricular cardiac action potential and QT interval in RBM24 knockout mice, and these changes could be attenuated by treatment with an inhibitor of CaMKII delta. Importantly, knockdown of RBM24 in human embryonic stem cell-derived cardiomyocytes showed similar electrophysiological abnormalities, suggesting the important role of RBM24 in the human heart. Thus, our data suggest that RBM24 is a critical regulator of CaMKII delta to control the cardiac QT interval, highlighting the key role of splicing regulation in cardiac rhythm.
C1 [Liu, Jing; Wang, Ke; Pan, Lei; Zhou, Wanlu; Huang, Jingru; Liu, Hongli; Su, Zhiying; Xu, Xiu Qin] Xiamen Univ, Inst Stem Cell & Regenerat Med, Sch Med, Xiamen 361100, Fujian, Peoples R China.
   [Liu, Jing; Liu, Hongli; Su, Zhiying; Xu, Xiu Qin] Xiamen Univ, Women & Childrens Hosp, Sch Med, Dept Gynecol, Xiamen 361100, Fujian, Peoples R China.
   [Liu, Jing] Xiamen Univ, Shenzhen Res Inst, Shenzhen 518000, Guangdong, Peoples R China.
   [Liu, Xingyang] Xiamen Univ, Sch Med, Xiamen 361100, Fujian, Peoples R China.
C3 Xiamen University; Xiamen University; Xiamen University; Xiamen
   University
RP Xu, XQ (corresponding author), Xiamen Univ, Inst Stem Cell & Regenerat Med, Sch Med, Xiamen 361100, Fujian, Peoples R China.; Xu, XQ (corresponding author), Xiamen Univ, Women & Childrens Hosp, Sch Med, Dept Gynecol, Xiamen 361100, Fujian, Peoples R China.
EM xuxq@xmu.edu.cn
FU National Key R&D program of China [2018YFA0107304]; National Natural
   Science Foundation of China (NSFC) [82070424, 81871744]; Natural Science
   Foundation of Fujian Province [2021J01011]; Guangdong Natural Science
   Foundation [2017A030313113]; Fundamental Research Funds for the Central
   Universities [20720220058]
FX This work was supported by the National Key R & D program of China
   (2018YFA0107304), National Natural Science Foundation of China (NSFC)
   (82070424 and 81871744), Natural Science Foundation of Fujian Province
   (2021J01011), Guangdong Natural Science Foundation (2017A030313113), and
   the Fundamental Research Funds for the Central Universities
   (20720220058).
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NR 36
TC 6
Z9 6
U1 0
U2 3
PU SPRINGER BASEL AG
PI BASEL
PA PICASSOPLATZ 4, BASEL, 4052, SWITZERLAND
SN 1420-682X
EI 1420-9071
J9 CELL MOL LIFE SCI
JI Cell. Mol. Life Sci.
PD DEC
PY 2022
VL 79
IS 12
AR 613
DI 10.1007/s00018-022-04624-4
PG 17
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 7V5PI
UT WOS:000912865400001
PM 36454480
DA 2025-04-10
ER

PT J
AU Zhang, XM
   Ameer, FS
   Azhar, G
   Wei, JY
AF Zhang, Xiaomin
   Ameer, Fathima S.
   Azhar, Gohar
   Wei, Jeanne Y.
TI Alternative Splicing Increases Sirtuin Gene Family Diversity and
   Modulates Their Subcellular Localization and Function
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Article
DE novel isoforms; exon skipping and inclusion; age-related expression;
   mitochondrial function
ID NUCLEAR-LOCALIZATION; STRUCTURAL BASIS; SIR2 HOMOLOG; PREDICTION;
   PROTEINS; MITOCHONDRIAL; TRANSCRIPTION; EXPRESSION; REGULATOR; DATABASE
AB Alternative splicing generates multiple distinct isoforms that increase transcriptome and proteome diversity. There are seven sirtuin genes in humans, each consists of multiple exons that are likely to undergo alternative splicing. Our aim was to characterize the effect of alternative splicing on the sirtuin genes. Here, we report the identification of 23 human sirtuin isoforms, most of which were not previously reported. Five of the sirtuin genes had more than one isoform, whereas sirtuin-6 had nine isoforms. Exon skipping was the main event. Most of the sirtuin isoforms were deficient in parts of the protein domains, including the catalytic domain, the N- or C-terminus, nuclear localization signal or mitochondrial targeting signal. The domain loss caused potential structural changes. Three SIRT1 isoforms had a differential effect on the mitochondrial oxygen consumption rate. Age-related changes in the expression of SIRT1 isoforms were observed in the human heart in fetus, adults, and very old individuals. We also identified 15 sirtuin isoforms in mice. Our data indicate that alternative splicing increases sirtuin gene diversity and may modulate subcellular localization and function, thereby adding complexity to the gene regulation of mitochondrial respiration, metabolism, and cardiac function during maturation and aging.
C1 [Zhang, Xiaomin; Ameer, Fathima S.; Azhar, Gohar; Wei, Jeanne Y.] Univ Arkansas Med Sci, Donald W Reynolds Dept Geriatr, Little Rock, AR 72205 USA.
   [Ameer, Fathima S.; Azhar, Gohar] Univ Arkansas Med Sci, Inst Aging, Little Rock, AR 72205 USA.
C3 University of Arkansas System; University of Arkansas Medical Sciences;
   University of Arkansas System; University of Arkansas Medical Sciences
RP Zhang, XM; Wei, JY (corresponding author), Univ Arkansas Med Sci, Donald W Reynolds Dept Geriatr, Little Rock, AR 72205 USA.
EM ZhangXiaomin@uams.edu; FSAmeer@uams.edu; AzharGohar@uams.edu;
   WeiJeanne@uams.edu
RI Zhang, Xiaomin/GVT-8927-2022
OI Zhang, Xiaomin/0000-0002-5660-5303
FU Claude D. Pepper Older American Independence Center from National
   Institute on Aging (NIA) [P30AG28718]
FX This study was supported in part by the Claude D. Pepper Older American
   Independence Center grant (P30AG28718) from National Institute on Aging
   (NIA).
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NR 50
TC 22
Z9 22
U1 0
U2 11
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD JAN
PY 2021
VL 22
IS 2
AR 473
DI 10.3390/ijms22020473
PG 15
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA PY2OB
UT WOS:000611887000001
PM 33418837
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Walzik, S
   Schroeter, A
   Benndorf, K
   Zimmer, T
AF Walzik, Stefan
   Schroeter, Annett
   Benndorf, Klaus
   Zimmer, Thomas
TI Alternative Splicing of the Cardiac Sodium Channel Creates Multiple
   Variants of Mutant T1620K Channels
SO PLOS ONE
LA English
DT Article
ID SICK SINUS SYNDROME; LONG-QT SYNDROME; BREAST-CANCER CELLS;
   BRUGADA-SYNDROME; NA+ CHANNEL; SCN5A MUTATION; CONDUCTION DISEASE;
   EXPRESSION; SUBUNIT; POLYMORPHISMS
AB Alternative splicing creates several Na(v)1.5 transcripts in the mammalian myocardium and in various other tissues including brain, dorsal root ganglia, breast cancer cells as well as neuronal stem cell lines. In total nine Na(v)1.5 splice variants have been discovered. Four of them, namely Na(v)1.5a, Na(v)1.5c, Na(v)1.5d, and Na(v)1.5e, generate functional channels in heterologous expression systems. The significance of alternatively spliced transcripts for cardiac excitation, in particular their role in SCN5A channelopathies, is less well understood. In the present study, we systematically investigated electrophysiological properties of mutant T1620K channels in the background of all known functional Na(v)1.5 splice variants in HEK293 cells. This mutation has been previously associated with two distinct cardiac excitation disorders: with long QT syndrome type 3 (LQT3) and isolated cardiac conduction disease (CCD). When investigating the effect of the T1620K mutation, we noticed similar channel defects in the background of hNa(v)1.5, hNa(v)1.5a, and hNa(v)1.5c. In contrast, the hNa(v)1.5d background produced differential effects: In the mutant channel, some gain-of-function features did not emerge, whereas loss-of-function became more pronounced. In case of hNa(v)1.5e, the neonatal variant of hNa(v)1.5, both the splice variant itself as well as the corresponding mutant channel showed electrophysiological properties that were distinct from the wild-type and mutant reference channels, hNa(v)1.5 and T1620K, respectively. In conclusion, our data show that alternative splicing is a mechanism capable of generating a variety of functionally distinct wild-type and mutant hNa(v)1.5 channels. Thus, the cellular splicing machinery is a potential player affecting genotype-phenotype correlations in SCN5A channelopathies.
C1 [Walzik, Stefan; Schroeter, Annett; Benndorf, Klaus; Zimmer, Thomas] Univ Jena, Inst Physiol 2, Univ Hosp Jena, Jena, Germany.
C3 Friedrich Schiller University of Jena
RP Walzik, S (corresponding author), Univ Jena, Inst Physiol 2, Univ Hosp Jena, Jena, Germany.
EM thomas.zimmer@mti.uni-jena.de
RI Zimmer, Thomas/ISU-6303-2023
OI Benndorf, Klaus/0000-0002-0707-4083
FU Friedrich Schiller University of Jena [923409]
FX This work was supported by the Friedrich Schiller University of Jena
   (budget account no. 923409). The funder had no role in study design,
   data collection and analysis, decision to publish, or preparation of the
   manuscript.
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NR 43
TC 18
Z9 18
U1 0
U2 2
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD APR 28
PY 2011
VL 6
IS 4
AR e19188
DI 10.1371/journal.pone.0019188
PG 10
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 756NX
UT WOS:000290020700036
PM 21552533
OA gold, Green Published, Green Submitted
DA 2025-04-10
ER

PT J
AU Chen, XY
   Liu, Y
   Xu, C
   Ba, LN
   Liu, Z
   Li, XY
   Huang, J
   Simpson, E
   Gao, HY
   Cao, DY
   Sheng, W
   Qi, HP
   Ji, HR
   Sanderson, M
   Cai, CL
   Li, XH
   Yang, L
   Na, J
   Yamamura, K
   Liu, YL
   Huang, G
   Shou, WN
   Sun, N
AF Chen, Xinyun
   Liu, Ying
   Xu, Chen
   Ba, Lina
   Liu, Zhuo
   Li, Xiuya
   Huang, Jie
   Simpson, Ed
   Gao, Hongyu
   Cao, Dayan
   Sheng, Wei
   Qi, Hanping
   Ji, Hongrui
   Sanderson, Maria
   Cai, Chen-Leng
   Li, Xiaohui
   Yang, Lei
   Na, Jie
   Yamamura, Kenichi
   Liu, Yunlong
   Huang, Guoying
   Shou, Weinian
   Sun, Ning
TI QKI is a critical pre-mRNA alternative splicing regulator of cardiac
   myofibrillogenesis and contractile function
SO NATURE COMMUNICATIONS
LA English
DT Article
ID BINDING PROTEIN QKI; SYSTEMATIC IDENTIFICATION; EXPRESSION ANALYSIS;
   STEM-CELLS; QUAKING; GENE; HEART; MUTATION; FAMILY; MYELINATION
AB The RNA-binding protein QKI belongs to the hnRNP K-homology domain protein family, a well-known regulator of pre-mRNA alternative splicing and is associated with several neurodevelopmental disorders. Qki is found highly expressed in developing and adult hearts. By employing the human embryonic stem cell (hESC) to cardiomyocyte differentiation system and generating QKI-deficient hESCs (hESCs-QKI(del)) using CRISPR/Cas9 gene editing technology, we analyze the physiological role of QKI in cardiomyocyte differentiation, maturation, and contractile function. hESCs-QKI(del) largely maintain normal pluripotency and normal differentiation potential for the generation of early cardiogenic progenitors, but they fail to transition into functional cardiomyocytes. In this work, by using a series of transcriptomic, cell and biochemical analyses, and the Qki-deficient mouse model, we demonstrate that QKI is indispensable to cardiac sarcomerogenesis and cardiac function through its regulation of alternative splicing in genes involved in Z-disc formation and contractile physiology, suggesting that QKI is associated with the pathogenesis of certain forms of cardiomyopathies. RNA binding protein Quaking (QKI) is known for its broad function in pre-mRNA splicing and modification and its association with several neurodevelopmental disorders. Here the authors reveal that QKI-mediated regulation of RNA splicing is indispensable to cardiac development and contractile physiology.
C1 [Chen, Xinyun; Xu, Chen; Li, Xiuya; Huang, Jie; Sun, Ning] Fudan Univ, Sch BasicMed Sci, Dept Physiol & Pathophysiol, Shanghai, Peoples R China.
   [Chen, Xinyun; Sheng, Wei; Huang, Guoying; Sun, Ning] Fudan Univ, Childrens Hosp, Shanghai Key Lab Birth Defects, Shanghai, Peoples R China.
   [Chen, Xinyun; Liu, Ying; Xu, Chen; Ba, Lina; Liu, Zhuo; Sheng, Wei; Qi, Hanping; Ji, Hongrui; Sanderson, Maria; Cai, Chen-Leng; Yang, Lei; Shou, Weinian] Indiana Univ Sch Med, Dept Pediat, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA.
   [Simpson, Ed; Gao, Hongyu; Liu, Yunlong] Indiana Univ Sch Med, Dept Bioinformat, Indianapolis, IN 46202 USA.
   [Cao, Dayan; Li, Xiaohui] Army Med Univ, Coll Pharm, Inst Mat Med, Chongqing, Peoples R China.
   [Cao, Dayan; Li, Xiaohui] Army Med Univ, Coll Pharm, Ctr Translat Med, Chongqing, Peoples R China.
   [Na, Jie] Tsinghua Univ, Sch Med, Ctr Stem Cell Biol & Regenerat Med, Beijing, Peoples R China.
   [Yamamura, Kenichi] Kumanoto Univ, Inst Resource Dev & Anal, Kumanoto, Japan.
C3 Fudan University; Fudan University; Indiana University System; Indiana
   University Bloomington; Indiana University System; Indiana University
   Bloomington; Army Medical University; Army Medical University; Tsinghua
   University
RP Sun, N (corresponding author), Fudan Univ, Sch BasicMed Sci, Dept Physiol & Pathophysiol, Shanghai, Peoples R China.; Huang, G; Sun, N (corresponding author), Fudan Univ, Childrens Hosp, Shanghai Key Lab Birth Defects, Shanghai, Peoples R China.; Shou, WN (corresponding author), Indiana Univ Sch Med, Dept Pediat, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA.
EM gyhuang@shmu.edu.cn; wshou@iu.edu; sunning@fudan.edu.cn
RI cheng, heping/A-7299-2011; Xu, Chen/AAE-4975-2021; Sun,
   Ning/HLX-6289-2023; Na, Jie/N-3522-2018; liang, YU/IYT-4334-2023;
   Simpson, Edward/G-1912-2015
OI liang, YU/0009-0007-3922-3454; Sun, Ning/0000-0002-7861-3646; Simpson,
   Edward/0000-0001-9015-9864; Xu, Chen/0000-0001-5146-5260; cao,
   dayan/0000-0001-7648-3668
FU National Institute of Health [P01HL134599, R01HL145060]; Riley Children
   Foundation; National Natural Science Foundation of China [81500241,
   31571527]; China Scholarship Council (CSC); CSC; Innovative Research
   Team of High-Level Local Universities in Shanghai; Haiju program of
   National Children's Medical Center [EK1125180102]
FX We thank all members in Shou lab, Sun Lab, and Huang lab for critical
   discussion and proofreading. This work was supported in part by National
   Institute of Health P01HL134599 and R01HL145060, and Riley Children
   Foundation (to W.S.). N.S. was supported by the National Natural Science
   Foundation of China #31571527; X.C. was supported in part by visiting
   scholar fund from China Scholarship Council (CSC); C.X. was supported in
   part by visiting scholar funds from CSC and the Young Investigator Award
   by the National Natural Science Foundation of China (#81500241), and
   fund from the Innovative Research Team of High-Level Local Universities
   in Shanghai; W. Sheng was supported by the fellowship from Haiju program
   of National Children's Medical Center (EK1125180102).
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NR 84
TC 57
Z9 64
U1 1
U2 24
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
EI 2041-1723
J9 NAT COMMUN
JI Nat. Commun.
PD JAN 4
PY 2021
VL 12
IS 1
AR 89
DI 10.1038/s41467-020-20327-5
PG 18
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA SY1EB
UT WOS:000665636000016
PM 33397958
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Lee, JN
   Bae, SH
   Paik, YK
AF Lee, JN
   Bae, SH
   Paik, YK
TI Structure and alternative splicing of the rat 7-dehydrocholesterol
   reductase gene
SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION
LA English
DT Article
DE 7-dehydrocholesterol reductase; cholesterol; lanosterol; alternative
   splicing; isoform; Smith-Lemli-Opitz syndrome
ID LEMLI-OPITZ-SYNDROME; PRE-MESSENGER-RNA; CHOLESTEROL-BIOSYNTHESIS;
   LANOSTEROL; PROTEIN; TRANSLATION; EXPRESSION; MUTATIONS; TOPOLOGY;
   SPECTRUM
AB The enzyme 7-dehydrocholesterol reductase (Dhcr7) catalyzes the reduction of 7-dehydrocholesterol (DHC), the terminal reaction of the pathway of cholesterol biosynthesis. We report the isolation and characterization of the genomic DNA encoding rat Dhcr7 that contains nine exons and eight introns distributed over 15 944 nucleotides (nts) and a consensus GT-AG at each exon/intron junction. Unexpectedly, we have found the occurrence of at least five isoforms of Dhcr7, designated as Dhcr7-AS (alternatively spliced)-1 (1474 nts), -2 (1595 nts), -3 (1602 nts), -4 (1723 nts) and -5 (1287 nts), which was believed to be caused by alternative usage of three 5' noncoding exons. Furthermore, Dhcr7-AS-1 was found to be differentially expressed in six tissues examined while Dhcr7-AS-2 was expressed mainly in liver and brain. Interestingly, human Dhcr7 gene in HepG2 cells produced no detectable isoform while mouse Dhcr7 gene in L929 cells produced three isoforms, suggesting a difference in alternative splicing between species. Thus, regulation of Dhcr7 through the combined mechanisms of tissue-specific transcription and differential alternative splicing appears unique among enzymes characterized from the entire post-lanosterol pathway in cholesterol biosynthesis. (C) 2002 Published by Elsevier Science B.V.
C1 Yonsei Univ, Dept Biochem, Bioprod Res Ctr, Sudaemoon Ku, Seoul 120749, South Korea.
   Yonsei Univ, Yonsei Proteome Res Ctr, Sudaemoon Ku, Seoul 120749, South Korea.
C3 Yonsei University; Yonsei University
RP Paik, YK (corresponding author), Yonsei Univ, Dept Biochem, Bioprod Res Ctr, Sudaemoon Ku, 134 Shinchon Dong, Seoul 120749, South Korea.
RI Bae, Sung-Ho/AAK-7350-2020
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NR 29
TC 13
Z9 15
U1 0
U2 2
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0167-4781
J9 BBA-GENE STRUCT EXPR
JI Biochim. Biophys. Acta-Gene Struct. Expression
PD JUN 7
PY 2002
VL 1576
IS 1-2
BP 148
EP 156
AR PII S0167-4781(02)00285-3
DI 10.1016/S0167-4781(02)00285-3
PG 9
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA 560BE
UT WOS:000176060700018
PM 12031495
DA 2025-04-10
ER

PT J
AU Gawronski, KAB
   Bone, WP
   Park, Y
   Pashos, EE
   Wenz, BM
   Dudek, MF
   Wang, X
   Yang, WL
   Rader, DJ
   Musunuru, K
   Voight, BF
   Brown, CD
AF Gawronski, Katerina A. B.
   Bone, William P.
   Park, YoSon
   Pashos, Evanthia E.
   Wenz, Brandon M.
   Dudek, Max F.
   Wang, Xiao
   Yang, Wenli
   Rader, Daniel J.
   Musunuru, Kiran
   Voight, Benjamin F.
   Brown, Christopher D.
TI Evaluating the Contribution of Cell Type-Specific Alternative Splicing
   to Variation in Lipid Levels
SO CIRCULATION-GENOMIC AND PRECISION MEDICINE
LA English
DT Article
DE alternative splicing; hepatocyte; induced pluripotent stem cells;
   lipids; lipoproteins
ID GENETIC-VARIATION; DISCOVERY; CHOLESTEROL; VARIANTS; REVEALS; PACKAGE;
   SITES; RISK
AB Background:Genome-wide association studies have identified hundreds of loci associated with lipid levels. However, the genetic mechanisms underlying most of these loci are not well-understood. Recent work indicates that changes in the abundance of alternatively spliced transcripts contribute to complex trait variation. Consequently, identifying genetic loci that associate with alternative splicing in disease-relevant cell types and determining the degree to which these loci are informative for lipid biology is of broad interest. Methods:We analyze gene splicing in 83 sample-matched induced pluripotent stem cell (iPSC) and hepatocyte-like cell lines (n=166), as well as in an independent collection of primary liver tissues (n=96) to perform discovery of splicing quantitative trait loci (sQTLs). Results:We observe that transcript splicing is highly cell type specific, and the genes that are differentially spliced between iPSCs and hepatocyte-like cells are enriched for metabolism pathway annotations. We identify 1384 hepatocyte-like cell sQTLs and 1455 iPSC sQTLs at a false discovery rate of <5% and find that sQTLs are often shared across cell types. To evaluate the contribution of sQTLs to variation in lipid levels, we conduct colocalization analysis using lipid genome-wide association data. We identify 19 lipid-associated loci that colocalize either with an hepatocyte-like cell expression quantitative trait locus or sQTL. Only 2 loci colocalize with both a sQTL and expression quantitative trait locus, indicating that sQTLs contribute information about genome-wide association studies loci that cannot be obtained by analysis of steady-state gene expression alone. Conclusions:These results provide an important foundation for future efforts that use iPSC and iPSC-derived cells to evaluate genetic mechanisms influencing both cardiovascular disease risk and complex traits in general.
C1 [Voight, Benjamin F.] Univ Penn, Perelman Sch Med, 10-126 Smilow Ctr Translat Res,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA.
   [Brown, Christopher D.] Univ Penn, Perelman Sch Med, CRB Room 538,415 Curie Blvd, Philadelphia, PA 19104 USA.
   [Gawronski, Katerina A. B.; Wenz, Brandon M.] Univ Penn, Perelman Sch Med, Cell & Mol Biol Grad Grp, Philadelphia, PA USA.
   [Bone, William P.; Dudek, Max F.] Univ Penn, Perelman Sch Med, Genom & Computat Biol Grad Grp, Philadelphia, PA USA.
   [Park, YoSon; Pashos, Evanthia E.; Rader, Daniel J.; Musunuru, Kiran; Voight, Benjamin F.; Brown, Christopher D.] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA USA.
   [Wang, Xiao] Univ Penn, Cardiovasc Inst, Perelman Sch Med, Philadelphia, PA USA.
   [Yang, Wenli] Univ Penn, Inst Regenerat Med, Perelman Sch Med, Philadelphia, PA USA.
   [Rader, Daniel J.; Musunuru, Kiran] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA USA.
   [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Div Translat Med & Human Genet, Philadelphia, PA USA.
   [Voight, Benjamin F.] Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA USA.
   [Voight, Benjamin F.] Univ Penn, Inst Translat Med & Therapeut, Perelman Sch Med, Philadelphia, PA USA.
C3 University of Pennsylvania; University of Pennsylvania; University of
   Pennsylvania; University of Pennsylvania; University of Pennsylvania;
   University of Pennsylvania; University of Pennsylvania; University of
   Pennsylvania; University of Pennsylvania; University of Pennsylvania;
   University of Pennsylvania
RP Voight, BF (corresponding author), Univ Penn, Perelman Sch Med, 10-126 Smilow Ctr Translat Res,3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA.; Brown, CD (corresponding author), Univ Penn, Perelman Sch Med, CRB Room 538,415 Curie Blvd, Philadelphia, PA 19104 USA.
EM kgawro@pennmedicine.upenn.edu; wbone@pennmedicine.upenn.edu;
   yoson.park@gmail.com; evanthia.pashos@pfizer.com; b.wenz91@gmail.com;
   Max.Dudek@pennmedicine.upenn.edu; xiao8@pennmedicine.upenn.edu;
   wenliyan@pennmedicine.upenn.edu; rader@pennmedicine.upenn.edu;
   kiranmusunuru@gmail.com; voight@pennmedicine.upenn.edu;
   chrbro@pennmedicine.upenn.edu
RI Bell, Kim/JPX-3621-2023; Voight, Benjamin/F-1775-2011; Rader,
   Daniel/AFQ-9696-2022; Musunuru, Kiran/JPL-8412-2023
OI Bone, William/0000-0002-9617-4624; Yang, Wenli/0000-0002-1873-2336;
   Wang, Xiao/0000-0001-7502-8292; Rader, Daniel/0000-0002-9245-9876;
   Voight, Benjamin/0000-0002-6205-9994; Musunuru,
   Kiran/0000-0003-3298-0368; Dudek, Max/0000-0001-8521-9543; ,
   YoSon/0000-0002-0465-4744
FU National Institutes of Health (NIH)-National Heart, Lung, and Blood
   Institute [HL133218]; NIH-National Institute of Diabetes and Digestive
   Kidney Diseases [DK101478, DK126194]; NIH-National Institute of General
   Medical Sciences [GM008216]; American Heart Association [19PRE34450081];
   American Heart Association (AHA) [19PRE34450081] Funding Source:
   American Heart Association (AHA)
FX Dr Brown acknowledges support from the National Institutes of Health
   (NIH)-National Heart, Lung, and Blood Institute (HL133218) for the work.
   Dr Voight is grateful for support from the work from the NIH-National
   Institute of Diabetes and Digestive Kidney Diseases (DK101478 and
   DK126194). Dr Gawronski was supported in part from the NIH-National
   Institute of General Medical Sciences (GM008216) and the American Heart
   Association (19PRE34450081).
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NR 45
TC 1
Z9 1
U1 0
U2 2
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 2574-8300
J9 CIRC-GENOM PRECIS ME
JI Circ.-Genom. Precis. Med.
PD JUN
PY 2023
VL 16
IS 3
BP 248
EP 257
DI 10.1161/CIRCGEN.120.003249
PG 10
WC Cardiac & Cardiovascular Systems; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Genetics & Heredity
GA L5HX6
UT WOS:001023584200006
PM 37165871
OA Green Submitted, Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Uversky, VN
AF Uversky, Vladimir N.
TI (Intrinsically disordered) splice variants in the proteome: implications
   for novel drug discovery
SO GENES & GENOMICS
LA English
DT Review
DE Alternative splicing; Drug target; Intrinsic disorder; Intrinsically
   disordered protein; Posttranslational modification; Protein binding;
   Protein-protein interaction; Splice variant
ID ANDROGEN RECEPTOR; FUNCTIONAL DIVERSITY; STRUCTURAL DISORDER;
   POSTTRANSLATIONAL MODIFICATION; CARDIOVASCULAR-DISEASE;
   MYOCARDIAL-INFARCTION; UNSTRUCTURED PROTEINS; ESCHERICHIA-COLI;
   BREAST-CANCER; EXPRESSION
AB In higher eukaryotes, proteomes are typically larger than corresponding genomes mostly due to alternative spicing (AS) which is affecting more than 86 % of human genes. Tissue specificity of many proteins is often determined by the AS of pre-mRNAs that generates multiple proteins from a single gene. Aberrations in AS are found in numerous human diseases. This article shows that AS expanded the classic "one-gene-one-protein" paradigm to the "one-gene-many-proteins" concept. AS is intimately associated with protein intrinsic disorder. There is a tight connection between the altered AS of some key intrinsically disordered proteins and pathogenesis of neurodegenerative diseases, cardiovascular disease, cancer, and diabetes. The development of drugs for splice variants is a challenging endeavor. AS has tremendous influence on the applicability of several drugs developed to affect functions typically attributed to the ordered parts of disease-related proteins. Although there are several means for the differential targeting of splice variants, new approaches are obviously needed. It is expected that better understanding of the molecular mechanisms underlying modulation of biological activities of numerous spliced variants will be achieved and new drug design approaches for proteins with multiple splice variants will be developed.
C1 [Uversky, Vladimir N.] Univ S Florida, Coll Med, Byrd Alzheimers Res Inst, Dept Mol Med, 12901 Bruce B Downs Blvd,MDC07, Tampa, FL 33612 USA.
   [Uversky, Vladimir N.] Russian Acad Sci, Inst Cytol, Lab Struct Dynam Stabil & Folding Prot, St Petersburg 194064, Russia.
   [Uversky, Vladimir N.] King Abdulaziz Univ, Fac Sci, Dept Biol, Jeddah 21589, Saudi Arabia.
C3 State University System of Florida; University of South Florida; Russian
   Academy of Sciences; St. Petersburg Scientific Centre of the Russian
   Academy of Sciences; Institute of Cytology RAS; King Abdulaziz
   University
RP Uversky, VN (corresponding author), Univ S Florida, Coll Med, Byrd Alzheimers Res Inst, Dept Mol Med, 12901 Bruce B Downs Blvd,MDC07, Tampa, FL 33612 USA.; Uversky, VN (corresponding author), Russian Acad Sci, Inst Cytol, Lab Struct Dynam Stabil & Folding Prot, St Petersburg 194064, Russia.; Uversky, VN (corresponding author), King Abdulaziz Univ, Fac Sci, Dept Biol, Jeddah 21589, Saudi Arabia.
EM vuversky@health.usf.edu
RI Uversky, Vladimir/F-4515-2011
FU Russian Science Foundation RSCF [14-24-00131]
FX This work was supported in part by a grant from Russian Science
   Foundation RSCF No 14-24-00131.
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NR 173
TC 12
Z9 12
U1 0
U2 21
PU SPRINGER
PI NEW YORK
PA ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES
SN 1976-9571
EI 2092-9293
J9 GENES GENOM
JI Genes Genom.
PD JUL
PY 2016
VL 38
IS 7
BP 577
EP 594
DI 10.1007/s13258-015-0384-0
PG 18
WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology;
   Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology;
   Genetics & Heredity
GA DO7BO
UT WOS:000377937400002
DA 2025-04-10
ER

PT J
AU Terenzi, F
   Brimacombe, KR
   Penn, MS
   Ladd, AN
AF Terenzi, Fulvia
   Brimacombe, Kyle R.
   Penn, Marc S.
   Ladd, Andrea N.
TI CELF-mediated alternative splicing is required for cardiac function
   during early, but not later, postnatal life
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Article
DE Alternative splicing; CELF proteins; Transgenic mice; Cardiomyopathy;
   Development; Postnatal remodeling
ID RNA-BINDING PROTEINS; TROPONIN-T ISOFORMS; MYOTONIC-DYSTROPHY;
   GENE-EXPRESSION; MOUSE HEART; IN-VIVO; FAMILY; MUSCLE; MICE;
   CARDIOMYOPATHY
AB During the transition from juvenile to adult life, the heart undergoes programmed remodeling at the levels of transcription and alternative splicing. Members of the CUG-BP and ETR-3-like factor (CELF) family have been implicated in driving developmental transitions in alternative splicing of cardiac transcripts during maturation of the heart. Here, we investigated the timing of the requirement for CELF activity in the postnatal heart using a previously described transgenic mouse model (MHC-CELF Delta). In MHC-CELF Delta mice, nuclear CELF activity has been disrupted specifically in the heart by cardiac-specific expression of a dominant negative CELF protein. Longitudinal analyses of two lines of MHC-CELF Delta mice with differing levels of dominant negative protein expression demonstrate that CELF splicing activity is required for healthy cardiac function during juvenile, but not adult, life. Cardiac function, chamber dilation, and heart size all recover with age in the mild line of MHC-CELF Delta mice without a loss of dominant negative protein expression or change in expression of endogenous CELF proteins or known CELF antagonists. This is the first example of a mouse model with genetically induced cardiomyopathy that spontaneously recovers without intervention. Our results suggest that CELF proteins are key players in the integrated gene expression program involved in postnatal cardiac remodeling and maturation. (C) 2008 Elsevier Inc. All rights reserved.
C1 [Terenzi, Fulvia; Brimacombe, Kyle R.; Ladd, Andrea N.] Cleveland Clin Fdn, Dept Cell Biol, Lerner Res Inst, Cleveland, OH 44195 USA.
   [Penn, Marc S.] Cleveland Clin Fdn, Dept Cardiovasc Med, Cleveland, OH 44195 USA.
   [Penn, Marc S.] Cleveland Clin Fdn, Dept Stem Cell Biol & Regenerat Med, Lerner Res Inst, Cleveland, OH 44195 USA.
C3 Cleveland Clinic Foundation; Cleveland Clinic Foundation; Cleveland
   Clinic Foundation
RP Ladd, AN (corresponding author), Cleveland Clin Fdn, Dept Cell Biol, Lerner Res Inst, 9500 Euclid Ave,NC10, Cleveland, OH 44195 USA.
EM ladda@ccf.org
OI Ladd, Andrea/0000-0003-4725-5644
FU Cleveland Clinic
FX We thank Natalie Vajda for maintaining the MHC-CELF Delta mouse colony
   and collecting tissue samples, Dara Berger and Yu Peng for assistance
   with imaging, and Jeanne Drinko and Zoran Popovic for help with
   echocardiography. This work was supported by seed funding to A.N.L. from
   the Cleveland Clinic.
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NR 37
TC 16
Z9 18
U1 0
U2 1
PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
PI LONDON
PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD MAR
PY 2009
VL 46
IS 3
BP 395
EP 404
DI 10.1016/j.yjmcc.2008.10.030
PG 10
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA 411RC
UT WOS:000263666500013
PM 19073192
DA 2025-04-10
ER

PT J
AU Feng, JO
   Yan, Y
   Buzin, CH
   Sommer, SS
   Towbin, JA
AF Feng, JO
   Yan, Y
   Buzin, CH
   Sommer, SS
   Towbin, JA
TI Comprehensive mutation scanning of the dystrophin gene in patients with
   nonsyndromic X-linked dilated cardiomyopathy
SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
LA English
DT Article
ID DREIFUSS-MUSCULAR-DYSTROPHY; BARTH-SYNDROME; DMD GENE; DOVAM-S;
   NONCOMPACTION; HYPOTHESIS; ELEMENT; FAMILY; MUSCLE
AB OBJECTIVES The goal of this study was to perform comprehensive mutation analysis of the dystrophin gene in patients with X-linked dilated cardiomyopathy (XLCM).
   BACKGROUND X-linked dilated cardiomyopathy is a familial disease that is characterized by congestive heart failure without clinical signs of skeletal myopathy. Mutations in the dystrophin gene have been associated with the X-linked form of dilated cardiomyopathy. However, the fraction of XLCM with dystrophin mutations and the distribution of those mutations is not dear. Technical difficulties previously limited comprehensive mutation analysis of this very large gene.
   METHODS The Detection Of Virtually All Mutations-Single Strand Conformation Polymorphism (SSCP) (DOVAM-S), a roboticalty enhanced multiplexed scanning method that is a highly sensitive modification of SSCP, has successfully detected all of 240 mutations and polymorphisms in three blinded analyses of the factor VIII, factor IX, and ATM genes. Utilizing this method all 79 coding exons and splice junctions for the muscle dystrophin gene, along with six alternative exon 1 sequences, were scanned in eight patients with XLCM.
   RESULTS This is the first comprehensive scanning of the dystrophin gene in XLCM. Three of eight patients have putative mutations, including two splicing mutations and a missense mutation at a highly conserved amino acid.
   CONCLUSIONS Mutations within the coding regions and splice junctions in the dystrophin gene only account for some cases of XLCM. Genetic heterogeneity and/or undetected mutations in auxiliary regulatory regions or deep within introns may occur in XLCM.
C1 City Hope Natl Med Ctr, Dept Mol Genet, Beckman Res Inst, Duarte, CA 91010 USA.
   Baylor Coll Med, Dept Pediat Cardiol, Houston, TX 77030 USA.
C3 City of Hope; Beckman Research Institute of City of Hope; Baylor College
   of Medicine
RP Sommer, SS (corresponding author), City Hope Natl Med Ctr, Dept Mol Genet, Beckman Res Inst, 1500 E Duarte Rd, Duarte, CA 91010 USA.
RI Towbin, Jeffrey/J-5595-2019
FU NHLBI NIH HHS [R01 HL62570] Funding Source: Medline
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NR 25
TC 34
Z9 40
U1 0
U2 1
PU ELSEVIER SCIENCE INC
PI NEW YORK
PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA
SN 0735-1097
J9 J AM COLL CARDIOL
JI J. Am. Coll. Cardiol.
PD SEP 18
PY 2002
VL 40
IS 6
BP 1120
EP 1124
AR PII S0735-1097(02)02126-5
DI 10.1016/S0735-1097(02)02126-5
PG 5
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 593TQ
UT WOS:000178009900016
PM 12354438
DA 2025-04-10
ER

PT J
AU Dauksaite, V
   Gotthardt, M
AF Dauksaite, Vita
   Gotthardt, Michael
TI Molecular basis of titin exon exclusion by RBM20 and the novel titin
   splice regulator PTB4
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID TRACT BINDING-PROTEIN; RNA-BINDING; DILATED CARDIOMYOPATHY; DISEASE;
   MUTATIONS; REPRESSOR; GENE
AB RNA-binding motif protein 20 (RBM20) is a cardiac splice regulator that adapts cardiac filling via its diverse substrates-including the sarcomeric protein titin. The molecular basis and regulation of RBM20-dependent exon exclusion are largely unknown. In tissue culture experiments, we show that the combination of RNA recognition motif (RRM) and C-terminus is necessary and sufficient for RBM20 activity, indicating an important function of the ZnF2 domain in splicing repression. Using splice reporter and in vitro binding assays targeting titin exons 241-243, we identified a minimal genomic segment that is necessary for RBM20-mediated splicing repression of the alternative exon. Here, RBM20 binds the cluster containing most RBM20 binding motifs through its RRM domain and represses the upstream and downstream introns. For subsequent exon exclusion, specific regions upstream, downstream and within the alternative exon 242 are required. Regulation of exon exclusion involves PTB4 as a novel titin splice regulator, which counteracts RBM20 repressor activity in HEK293 cells. Together, these mechanistic insights into the regulation and action of RBM20 and PTB4 provide a basis for the future development of RBM20 modulators that adapt titin elasticity in cardiac disease.
C1 [Dauksaite, Vita; Gotthardt, Michael] Max Delbruck Ctr Mol Med, Neuromuscular & Cardiovasc Cell Biol, D-13125 Berlin, Germany.
   [Gotthardt, Michael] German Ctr Cardiovasc Res, Partner Site Berlin DZHK, D-10115 Berlin, Germany.
C3 Helmholtz Association; Max Delbruck Center for Molecular Medicine;
   German Centre for Cardiovascular Research
RP Gotthardt, M (corresponding author), Max Delbruck Ctr Mol Med, Neuromuscular & Cardiovasc Cell Biol, D-13125 Berlin, Germany.; Gotthardt, M (corresponding author), German Ctr Cardiovasc Res, Partner Site Berlin DZHK, D-10115 Berlin, Germany.
EM gotthardt@mdc-berlin.de
RI Gotthardt, Michael/ABE-8274-2021
OI Gotthardt, Michael/0000-0003-1788-3172
FU European Research Council [StG282078]; Deutsche Forschungsgemeinschaft,
   Bonn, Germany [Go865/11-1]; 'Bundesministerium fur Bildung und
   Forschung' [CaRNAtion]; German Center for Cardiovascular Research
   (DZHK), Berlin
FX European Research Council [StG282078]; Deutsche Forschungsgemeinschaft,
   Bonn, Germany [Go865/11-1]; 'Bundesministerium fur Bildung und
   Forschung' [CaRNAtion]; German Center for Cardiovascular Research
   (DZHK), Berlin. Funding for open access charge: Institutional funds.
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NR 27
TC 26
Z9 30
U1 0
U2 3
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0305-1048
EI 1362-4962
J9 NUCLEIC ACIDS RES
JI Nucleic Acids Res.
PD JUN 1
PY 2018
VL 46
IS 10
BP 5227
EP 5238
DI 10.1093/nar/gky165
PG 12
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA GM7AB
UT WOS:000438329100034
PM 29518215
OA Green Published, gold, Green Accepted, Green Submitted
DA 2025-04-10
ER

PT J
AU Gi, WT
   Haas, J
   Sedaghat-Hamedani, F
   Kayvanpour, E
   Tappu, R
   Lehmann, DH
   Samani, OS
   Wisdom, M
   Keller, A
   Katus, HA
   Meder, B
AF Gi, Weng-Tein
   Haas, Jan
   Sedaghat-Hamedani, Farbod
   Kayvanpour, Elham
   Tappu, Rewati
   Lehmann, David Hermann
   Samani, Omid Shirvani
   Wisdom, Michael
   Keller, Andreas
   Katus, Hugo A.
   Meder, Benjamin
TI Epigenetic Regulation of Alternative mRNA Splicing in Dilated
   Cardiomyopathy
SO JOURNAL OF CLINICAL MEDICINE
LA English
DT Article
DE dilated cardiomyopathy; DNA methylation; alternative splicing;
   epigenetics
ID LONG NONCODING RNAS; DNA METHYLATION; HISTONE MODIFICATION; GENETICS;
   HEART; TITIN; VARIANTS; TTN-AS1; ROLES
AB In recent years, the genetic architecture of dilated cardiomyopathy (DCM) has been more thoroughly elucidated. However, there is still insufficient knowledge on the modifiers and regulatory principles that lead to the failure of myocardial function. The current study investigates the association of epigenome-wideDNAmethylation and alternative splicing, both of which are important regulatory principles in DCM. We analyzed screening and replication cohorts of cases and controls and identified distinct transcriptomic patterns in the myocardium that differ significantly, and we identified a strong association of intronic DNA methylation and flanking exons usage (p < 2 x 10(-16)). By combining differential exon usage (DEU) and differential methylation regions (DMR), we found a significant change of regulation in important sarcomeric and other DCM-associated pathways. Interestingly, inverse regulation of Titin antisense non-coding RNA transcript splicing and DNA methylation of a locus reciprocal to TTN substantiate these findings and indicate an additional role for non-protein-coding transcripts. In summary, this study highlights for the first time the close interrelationship between genetic imprinting by DNA methylation and the transport of this epigenetic information towards the dynamic mRNA splicing landscape. This expands our knowledge of the genome-environment interaction in DCM besides simple gene expression regulation.
C1 [Gi, Weng-Tein; Haas, Jan; Sedaghat-Hamedani, Farbod; Kayvanpour, Elham; Tappu, Rewati; Lehmann, David Hermann; Samani, Omid Shirvani; Wisdom, Michael; Katus, Hugo A.; Meder, Benjamin] Heidelberg Univ, Inst Cardiomyopathies Heidelberg ICH, Heart Ctr Heidelberg, D-69121 Heidelberg, Germany.
   [Gi, Weng-Tein; Haas, Jan; Sedaghat-Hamedani, Farbod; Kayvanpour, Elham; Tappu, Rewati; Samani, Omid Shirvani; Wisdom, Michael; Katus, Hugo A.; Meder, Benjamin] DZHK German Ctr Cardiovasc Res, D-69121 Heidelberg, Germany.
   [Gi, Weng-Tein; Haas, Jan; Sedaghat-Hamedani, Farbod; Kayvanpour, Elham; Tappu, Rewati; Lehmann, David Hermann; Samani, Omid Shirvani; Wisdom, Michael; Katus, Hugo A.; Meder, Benjamin] Heidelberg Univ, Dept Med 3, INF 410, D-69120 Heidelberg, Germany.
   [Keller, Andreas] Saarland Univ, Med Fac, Dept Clin Bioinformat, D-66123 Saarbrucken, Germany.
   [Meder, Benjamin] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
C3 Ruprecht Karls University Heidelberg; German Centre for Cardiovascular
   Research; Ruprecht Karls University Heidelberg; Saarland University;
   Stanford University
RP Meder, B (corresponding author), Heidelberg Univ, Inst Cardiomyopathies Heidelberg ICH, Heart Ctr Heidelberg, D-69121 Heidelberg, Germany.; Meder, B (corresponding author), DZHK German Ctr Cardiovasc Res, D-69121 Heidelberg, Germany.; Meder, B (corresponding author), Heidelberg Univ, Dept Med 3, INF 410, D-69120 Heidelberg, Germany.; Meder, B (corresponding author), Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
EM Weng-Tein.Gi@med.uni-heidelberg.de; jan.haas@med.uni-heidelberg.de;
   Farbod.Sedaghat-Hamedani@med.uni-heidelberg.de;
   Elham.Kayvanpour@med.uni-heidelberg.de;
   Rewati.Tappu@med.uni-heidelberg.de;
   DavidHermann.Lehmann@med.uni-heidelberg.de;
   Omid.ShirvaniSamani@med.uni-heidelberg.de;
   Michael.Wisdom@med.uni-heidelberg.de;
   Andreas.Keller@ccb.uni-saarland.de; hugo.katus@med.uni-heidelberg.de;
   Benjamin.Meder@med.uni-heidelberg.de
RI Keller, Andreas/ABB-6412-2021
OI Sedaghat-Hamedani, Farbod/0000-0002-3266-0527; Gi,
   Weng-Tein/0000-0001-8914-8420
FU Deutsches Zentrum fur Herz-Kreislauf-Forschung (German Center for
   Cardiovascular Research, DZHK); German Ministry of Education and
   Research (CaRNAtion) [FKZ 031L0075B]; Informatics for Life (Klaus
   Tschira Foundation); Faculty of Medicine of the Leipzig University;
   European Union (Detectin-HF); Deutsche Forschungsgemeinschaft (DFG);
   Else Kroner Fresenius Foundation
FX This work was supported by grants from the Deutsches Zentrum fur
   Herz-Kreislauf-Forschung (German Center for Cardiovascular Research,
   DZHK), the German Ministry of Education and Research (CaRNAtion, FKZ
   031L0075B), Informatics for Life (Klaus Tschira Foundation), the Faculty
   of Medicine of the Leipzig University (to M.M-W.), the European Union
   (Detectin-HF), and the Deutsche Forschungsgemeinschaft (DFG). B.M. was
   supported by an excellence fellowship of the Else Kroner Fresenius
   Foundation.
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NR 63
TC 10
Z9 10
U1 0
U2 6
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2077-0383
J9 J CLIN MED
JI J. Clin. Med.
PD MAY
PY 2020
VL 9
IS 5
AR 1499
DI 10.3390/jcm9051499
PG 18
WC Medicine, General & Internal
WE Science Citation Index Expanded (SCI-EXPANDED)
SC General & Internal Medicine
GA LY0OO
UT WOS:000540223800256
PM 32429430
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Khoo, B
   Krainer, AR
AF Khoo, Bernard
   Krainer, Adrian R.
TI Splicing therapeutics in SMN2 and APOB
SO CURRENT OPINION IN MOLECULAR THERAPEUTICS
LA English
DT Review
DE Antisense oligonucleotide; APOB; apolipoprotein B; cholesterol; RNA
   splicing; SMN2; spinal muscular atrophy
ID SPINAL MUSCULAR-ATROPHY; SURVIVAL-MOTOR-NEURON; MESSENGER-RNA; ANTISENSE
   OLIGONUCLEOTIDES; GENE-EXPRESSION; PREMESSENGER RNA; CRITICAL EXON;
   IN-VITRO; PROTEIN; ENHANCER
AB Splicing therapeutics are defined as the deliberate modification of RNA splicing to achieve therapeutic goals. Various techniques for splicing therapeutics have been described, and most of these involve the use of antisense oligonucleotide-based compounds that target key elements in the pre-mRNA to control splicing in the nucleus. In this review, recent developments in splicing therapeutics for the treatment of two specific diseases are described: correcting the alternative splicing of survival of motor neuron (SMN)2 pre-mRNA to compensate for the defective SMN1 gene in spinal muscular atrophy, and re-engineering the splicing of apolipoprotein B pre-mRNA to lower circulating cholesterol levels.
C1 [Khoo, Bernard] UCL, Sch Med, Dept Endocrinol, London NW3 2PF, England.
   [Krainer, Adrian R.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA.
C3 University of London; University College London; UCL Medical School;
   Cold Spring Harbor Laboratory
RP Khoo, B (corresponding author), UCL, Sch Med, Dept Endocrinol, Hampstead Campus, London NW3 2PF, England.
EM b.khoo@ucl.ac.uk
RI ; Khoo, Bernard/B-1247-2009
OI Krainer, Adrian/0000-0001-9024-9501; Khoo, Bernard/0000-0002-4223-9736
FU NIGMS NIH HHS [R01 GM042699, R01 GM042699-21] Funding Source: Medline
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NR 65
TC 29
Z9 34
U1 0
U2 2
PU THOMSON REUTERS (SCIENTIFIC) LTD
PI LONDON
PA 77 HATTON GARDEN, LONDON, EC1N 8JS, ENGLAND
SN 1464-8431
J9 CURR OPIN MOL THER
JI Curr. Opin. Mol. Ther.
PD APR
PY 2009
VL 11
IS 2
BP 108
EP 115
PG 8
WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Research & Experimental Medicine
GA 450NA
UT WOS:000266406000002
PM 19330716
DA 2025-04-10
ER

PT J
AU Pandi, B
   Brenman, S
   Black, A
   Ng, DCM
   Lau, E
   Lam, MPY
AF Pandi, Boomathi
   Brenman, Stella
   Black, Alexander
   Ng, Dominic C. M.
   Lau, Edward
   Lam, Maggie P. Y.
TI Tissue Usage Preference and Intrinsically Disordered Region Remodeling
   of Alternative Splicing Derived Proteoforms in the Heart
SO JOURNAL OF PROTEOME RESEARCH
LA English
DT Article
DE alternative splicing; heart tissue usage; proteinisoforms; intrinsically
   disordered regions; IDR; RBP; protein/RNA binding; proteoform
ID PROTEIN; PROTEOMICS; LANDSCAPE; ULTRAFAST; ISOFORMS; GENE
AB A computational analysis of mass spectrometry data was performed to uncover alternative splicing derived protein variants across chambers of the human heart. Evidence for 216 non-canonical isoforms was apparent in the atrium and the ventricle, including 52 isoforms not documented on SwissProt and recovered using an RNA sequencing derived database. Among non-canonical isoforms, 29 show signs of regulation based on statistically significant preferences in tissue usage, including a ventricular enriched protein isoform of tensin-1 (TNS1) and an atrium-enriched PDZ and LIM Domain 3 (PDLIM3) isoform 2 (PDLIM3-2/ALP-H). Examined variant regions that differ between alternative and canonical isoforms are highly enriched with intrinsically disordered regions. Moreover, over two-thirds of such regions are predicted to function in protein binding and RNA binding. The analysis here lends further credence to the notion that alternative splicing diversifies the proteome by rewiring intrinsically disordered regions, which are increasingly recognized to play important roles in the generation of biological function from protein sequences.
C1 [Pandi, Boomathi; Brenman, Stella; Black, Alexander; Ng, Dominic C. M.; Lau, Edward] Univ Colorado, Dept Med, Div Cardiol, Sch Med, Aurora, CO 80045 USA.
   [Lau, Edward; Lam, Maggie P. Y.] Univ Colorado, Consortium Fibrosis Res & Translat CFReT, Sch Med, Aurora, CO 80045 USA.
   [Lam, Maggie P. Y.] Univ Colorado, Dept Biochem & Mol Genet, Sch Med, Aurora, CO 80045 USA.
C3 University of Colorado System; University of Colorado Anschutz Medical
   Campus; University of Colorado System; University of Colorado Anschutz
   Medical Campus; University of Colorado System; University of Colorado
   Anschutz Medical Campus
RP Lam, MPY (corresponding author), Univ Colorado, Consortium Fibrosis Res & Translat CFReT, Sch Med, Aurora, CO 80045 USA.; Lam, MPY (corresponding author), Univ Colorado, Dept Biochem & Mol Genet, Sch Med, Aurora, CO 80045 USA.
EM maggie.lam@cuanschutz.edu
RI Ng, Dominic/C-7291-2015
OI Black, Alex/0009-0003-0306-4720
FU Medicine Translational Research Scholars Program , University of
   Colorado [R21-HL150456, R01-GM144456, R01-HL141278]; NIH; University of
   Colorado School of Medicine Translational Research Scholars Program
FX This work was funded in part by NIH award R35-GM146815 and the
   University of Colorado School of Medicine Translational Research
   Scholars Program to E.L. and NIH awards R21-HL150456, R01-GM144456, and
   R01-HL141278 funding to M.P.Y.L.
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NR 56
TC 1
Z9 1
U1 1
U2 1
PU AMER CHEMICAL SOC
PI WASHINGTON
PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
SN 1535-3893
EI 1535-3907
J9 J PROTEOME RES
JI J. Proteome Res.
PD MAR 8
PY 2024
VL 23
IS 8
BP 3161
EP 3173
DI 10.1021/acs.jproteome.3c00789
EA MAR 2024
PG 13
WC Biochemical Research Methods
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA A6C9B
UT WOS:001181870000001
PM 38456420
OA hybrid, Green Published, Green Submitted
DA 2025-04-10
ER

PT J
AU Xiao, N
   Laha, S
   Das, SP
   Morlock, K
   Jesneck, JL
   Raffel, GD
AF Xiao, Nan
   Laha, Suparna
   Das, Shankar P.
   Morlock, Kayla
   Jesneck, Jonathan L.
   Raffel, Glen D.
TI Ott1 (Rbm15) regulates thrombopoietin response in hematopoietic stem
   cells through alternative splicing of c-Mpl
SO BLOOD
LA English
DT Article
ID RECEPTOR; VARIANT; TRANSCRIPTION; QUIESCENCE; MECHANISMS; INDUCTION;
   FUSION; TARGET; GENE; MKL1
AB Thrombopoietin (Thpo) signaling through the c-Mpl receptor promotes either quiescence or proliferation of hematopoietic stem cells (HSCs) in a concentration-dependent manner; however, in vivo Thpo serum levels are responsive to platelet mass rather than HSC demands, suggesting additional regulation exists. Ott1 (Rbm15), a spliceosomal component originally identified as a fusion partner in t(1;22)-associated acute megakaryocytic leukemia, is also essential for maintaining HSC quiescence under stress. Ott1 controls the alternative splicing of a dominant negative isoform, Mpl-TR, capable of inhibiting HSC engraftment and attenuating Thpo signaling. Ott1, which associates with Hdac3 and the histone methyltransferase, Setd1b, binds to both c-Mpl RNA and chromatin and regulates H4 acetylation and H3K4me3 marks. Histone deacetylase or histone methyltransferase inhibition also increases Mpl-TR levels, suggesting that Ott1 uses an underlying epigenetic mechanism to control alternative splicing of c-Mpl. Manipulation of Ott1-dependent alternative splicing may therefore provide a novel pharmacologic avenue for regulating HSC quiescence and proliferation in response to Thpo.
C1 [Xiao, Nan; Laha, Suparna; Das, Shankar P.; Morlock, Kayla; Raffel, Glen D.] Univ Massachusetts, Sch Med, Div Hematol Oncol, Worcester, MA 01605 USA.
   [Jesneck, Jonathan L.] Essess Inc, Boston, MA USA.
C3 University of Massachusetts System; University of Massachusetts
   Worcester
RP Raffel, GD (corresponding author), Univ Massachusetts, Sch Med, Div Hematol Oncol, 364 Plantat St LRB 319, Worcester, MA 01605 USA.
EM glen.raffel@umassmed.edu
RI Laha, Suparna/GON-7462-2022
OI Das, Dr. Shankar Prasad/0000-0003-2060-7574
FU National Institutes of Health, National Heart, Lung and Blood Institute
   [R01 HL116392]
FX This work was supported in part by a grant from the National Institutes
   of Health, National Heart, Lung and Blood Institute (R01 HL116392).
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NR 43
TC 38
Z9 44
U1 0
U2 4
PU AMER SOC HEMATOLOGY
PI WASHINGTON
PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA
SN 0006-4971
EI 1528-0020
J9 BLOOD
JI Blood
PD FEB 5
PY 2015
VL 125
IS 6
BP 941
EP 948
DI 10.1182/blood-2014-08-593392
PG 8
WC Hematology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Hematology
GA CD1ES
UT WOS:000350817700012
PM 25468569
OA Green Published, Bronze
DA 2025-04-10
ER

PT J
AU Cao, Y
   Yang, YY
   Guo, C
   Zong, JB
   Li, M
   Li, XL
   Yu, T
AF Cao, Ying
   Yang, Yanyan
   Guo, Chuan
   Zong, Jinbao
   Li, Min
   Li, Xiaolu
   Yu, Tao
TI Role of RNA-binding Proteins in Regulating Cell Adhesion and Progression
   of the Atherosclerotic Plaque and Plaque Erosion
SO CURRENT ATHEROSCLEROSIS REPORTS
LA English
DT Review
DE RNA-binding proteins; Atherosclerosis; Alternative splicing; Adhesion;
   Inflammation
ID VASCULAR SMOOTH-MUSCLE; HUMAN-ANTIGEN-R; MESSENGER-RNA; HUR; EXPRESSION;
   RECEPTOR; QUAKING; STABILIZATION; PROLIFERATION; INFLAMMATION
AB Purpose of ReviewRNA-binding proteins (RBPs) have emerged as crucial regulators of post-transcriptional processes, influencing the fate of RNA. This review delves into the biological functions of RBPs and their role in alternative splicing concerning atherosclerosis (AS), highlighting their participation in essential cellular processes. Our goal is to offer new insights for cardiovascular disease research and treatment.Recent FindingDysregulation of RBPs is associated with various human diseases, including autoimmune and neurological disorders. The role of RBPs in the pathogenesis of AS is progressively being elucidated, as they influence plaque formation and disease progression by regulating cell function and gene expression.SummaryRBPs play intricate biological roles in regulating pre-mRNA, including editing, splicing, stability and translation. Alternative splicing has been demonstrated to enhance biological complexity and diversity. Our findings indicate that alternative splicing is extensively involved in the pathogenesis of AS. The dysregulated expression of specific RBPs in AS is linked to the production of adhesion molecules and vascular endothelium damage. Further research on RBPs could pave the way for the development of novel therapeutic targets.
C1 [Cao, Ying; Zong, Jinbao; Li, Min; Yu, Tao] Qingdao Univ, Qingdao Tradit Chinese Med Hosp, Cent Lab, Qingdao Hiser Hosp,Clin Lab, Qingdao 266000, Peoples R China.
   [Yang, Yanyan] Qingdao Univ, Sch Basic Med, Dept Immunol, 308 Ningxia Rd, Qingdao 266000, Peoples R China.
   [Guo, Chuan] Linyi Vocat Univ Sci & Technol, Ind Synergy Innovat Ctr, Linyi 276000, Peoples R China.
   [Li, Xiaolu; Yu, Tao] Qingdao Univ, Dept Cardiac Ultrasound, Affiliated Hosp, Qingdao 266000, Peoples R China.
   [Yu, Tao] Qingdao Univ, Inst Translat Med, Affiliated Hosp, 38 Dengzhou Rd, Qingdao 266021, Peoples R China.
C3 Qingdao University; Qingdao University; Qingdao University; Qingdao
   University
RP Yu, T (corresponding author), Qingdao Univ, Qingdao Tradit Chinese Med Hosp, Cent Lab, Qingdao Hiser Hosp,Clin Lab, Qingdao 266000, Peoples R China.; Yu, T (corresponding author), Qingdao Univ, Dept Cardiac Ultrasound, Affiliated Hosp, Qingdao 266000, Peoples R China.; Yu, T (corresponding author), Qingdao Univ, Inst Translat Med, Affiliated Hosp, 38 Dengzhou Rd, Qingdao 266021, Peoples R China.
EM yutao0112@qdu.edu.cn
RI Zong, Jinbao/AAW-1405-2021
FU National Natural Science Foundation of China [82270442, 82370425];
   Natural science foundation of Shandong Province [ZR2022MH027]
FX This work was supported by National Natural Science Foundation of China
   (No. 82270442, 82370425) and The Natural science foundation of Shandong
   Province (grant no. ZR2022MH027).
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NR 138
TC 0
Z9 0
U1 3
U2 3
PU CURRENT MEDICINE GROUP
PI PHILADELPHIA
PA 400 MARKET STREET, STE 700, PHILADELPHIA, PA 19106 USA
SN 1523-3804
EI 1534-6242
J9 CURR ATHEROSCLER REP
JI Curr. Atheroscleros. Rep.
PD DEC
PY 2024
VL 27
IS 1
AR 8
DI 10.1007/s11883-024-01250-2
PG 16
WC Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA N0H5G
UT WOS:001361245000002
PM 39576410
DA 2025-04-10
ER

PT J
AU Milasin, J
   Muntoni, F
   Severini, GM
   Bartoloni, L
   Vatta, M
   Krajinovic, M
   Mateddu, A
   Angelini, C
   Camerini, F
   Falaschi, A
   Mestroni, L
   Giacca, M
   Pinamonti, B
   Sinagra, G
   DiLenarda, A
   Silvestri, F
   Bussani, R
   Davanzo, M
AF Milasin, J
   Muntoni, F
   Severini, GM
   Bartoloni, L
   Vatta, M
   Krajinovic, M
   Mateddu, A
   Angelini, C
   Camerini, F
   Falaschi, A
   Mestroni, L
   Giacca, M
   Pinamonti, B
   Sinagra, G
   DiLenarda, A
   Silvestri, F
   Bussani, R
   Davanzo, M
TI A point mutation in the 5' splice site of the dystrophin gene first
   intron responsible for X-linked dilated cardiomyopathy
SO HUMAN MOLECULAR GENETICS
LA English
DT Article
ID BECKER MUSCULAR-DYSTROPHY; PROMOTER REGION; MOLECULAR-BASIS; DUCHENNE;
   MUSCLE; PROTEIN; TRANSCRIPTION; POLYMORPHISMS; DELETIONS; TISSUES
AB X-linked dilated cardiomyopathy (XLDC) is a familial heart disease presenting in young males as a rapidly progressive congestive heart failure, without clinical signs of skeletal myopathy. This condition has recently been linked to the dystrophin gene in some families and deletions encompassing the genomic region coding for the first muscle exon have been detected. In order to identify the defect responsible for this disease at the molecular level and to understand the reasons for the selective heart involvement, a family with a severe form of XLDC was studied. In the affected members, no deletions of the dystrophin gene were observed. Analysis of the muscle promoter, first exon and intron regions revealed the presence of a single point mutation at the first exon-intron boundary, inactivating the universally conserved 5' splice site consensus sequence of the first intron. This mutation introduced a new restriction site for Msel, which cosegregates with the disease in the analyzed family. Expression of the major dystrophin mRNA isoforms (from the muscle-, brain- and Purkinje cell-promoters) was completely abolished in the myocardium, while the brain- and Purkinje cell- (but not the muscle-) isoforms were detectable in the skeletal muscle. Immunocytochemical studies with anti-dystrophin antibodies showed that the protein was reduced in quantity but normally distributed in the skeletal muscle, while it was undetectable in the cardiac muscle. These findings indicate that expression of the muscle dystrophin isoform is critical for myocardial function and suggest that selective heart involvement in dystrophin-linked dilated cardiomyopathy is related to the absence, in the heart, of a compensatory expression of dystrophin from alternative promoters.
C1 INT CTR GENET ENGN & BIOTECHNOL,I-34012 TRIESTE,ITALY.
   HAMMERSMITH HOSP,ROYAL POSTGRAD MED SCH,DEPT PEDIAT & NEONATAL MED,LONDON W12 0NN,ENGLAND.
   UNIV PADUA,DEPT BIOL & NEUROL,I-35121 PADUA,ITALY.
   OSPED MAGGIORE TRIESTE,DEPT CARDIOL,I-34100 TRIESTE,ITALY.
   OSPED MAGGIORE TRIESTE,DEPT MORBID ANAT,I-34100 TRIESTE,ITALY.
   UNIV TRIESTE,I-34100 TRIESTE,ITALY.
   UNIV CAGLIARI,DEPT NEUROSCI,I-09100 CAGLIARI,ITALY.
C3 International Center for Genetic Engineering & Biotechnology (ICGEB);
   Imperial College London; University of Padua; University of Trieste;
   University of Cagliari
RI Sinagra, Gianfranco/AAE-3943-2020; Angelini, Corrado/J-3655-2019;
   Bartoloni, Lucia/I-2504-2013; Di Lenarda, Andrea/AAC-2377-2022; Milasin,
   Jelena/J-1247-2019; GIACCA, MAURO/J-9287-2016
OI Angelini, Corrado/0000-0002-9554-8794; Mestroni,
   Luisa/0000-0003-1116-2286; GIACCA, MAURO/0000-0003-2927-7225; Milasin,
   Jelena/0000-0002-6225-7210; SINAGRA, GIANFRANCO/0000-0003-2700-8478;
   Bussani, Rossana/0000-0001-8241-9726
FU Telethon [552] Funding Source: Medline
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U1 0
U2 7
PU OXFORD UNIV PRESS UNITED KINGDOM
PI OXFORD
PA WALTON ST JOURNALS DEPT, OXFORD, ENGLAND OX2 6DP
SN 0964-6906
J9 HUM MOL GENET
JI Hum. Mol. Genet.
PD JAN
PY 1996
VL 5
IS 1
BP 73
EP 79
DI 10.1093/hmg/5.1.73
PG 7
WC Biochemistry & Molecular Biology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Genetics & Heredity
GA TQ475
UT WOS:A1996TQ47500009
PM 8789442
OA Green Published
DA 2025-04-10
ER

PT J
AU Ma, N
   Xu, H
   Zhang, WH
   Sun, XK
   Guo, RM
   Liu, DH
   Zhang, L
   Liu, Y
   Zhang, J
   Qiao, CH
   Chen, D
   Luo, AL
   Bai, JY
AF Ma, Ning
   Xu, Hao
   Zhang, Weihua
   Sun, Xiaoke
   Guo, Ruiming
   Liu, Donghai
   Zhang, Liang
   Liu, Yang
   Zhang, Jian
   Qiao, Chenhui
   Chen, Dong
   Luo, Ailing
   Bai, Jingyun
TI Genome-wide analysis revealed the dysregulation of RNA binding
   protein-correlated alternative splicing events in myocardial ischemia
   reperfusion injury
SO BMC MEDICAL GENOMICS
LA English
DT Article
DE MIRI; RNA-seq; Alternative splicing; RNA binding protein; Correlation
   network
ID EXPRESSION; WORLD
AB BackgroundMyocardial ischemia reperfusion injury (MIRI), the tissue damage which is caused by the returning of blood supply to tissue after a period of ischemia, greatly reduces the therapeutic effect of treatment of myocardial infarction. But the underlying functional mechanisms of MIRI are still unclear.MethodsWe constructed mouse models of MIRI, extracted injured and healthy myocardial tissues, and performed transcriptome sequencing experiments (RNA-seq) to systematically investigate the dysregulated transcriptome of MIRI, especially the alternative splicing (AS) regulation and RNA binding proteins (RBPs). Selected RBPs and MIRI-associated AS events were then validated by RT-qPCR experiments.ResultsThe differentially expressed gene (DEG) analyses indicated that transcriptome profiles were changed by MIRI and that DEGs' enriched functions were consistent with MIRI's dysregulated pathways. Furthermore, the AS profile was synergistically regulated and showed clear differences between the mouse model and the healthy samples. The exon skipping events significantly increased in MIRI model samples, while the opposite cassette exon events significantly decreased. According to the functional analysis, regulated alternative splicing genes (RASGs) were enriched in protein transport, cell division /cell cycle, RNA splicing, and endocytosis pathways, which were associated with the development of MIRI. Meanwhile, 493 differentially expressed RBPs (DE RBPs) were detected, most of which were correlated with the changed ratios of AS events. In addition, nine DE RBP genes were validated, including Eif5, Pdia6, Tagln2, Vasp, Zfp36l2, Grsf1, Idh2, Ndrg2, and Uqcrc1. These nine DE RBPs were correlated with RASGs enriched in translation process, cell growth and division, and endocytosis pathways, highly consistent with the functions of all RASGs. Finally, we validated the AS ratio changes of five regulated alternative splicing events (RASEs) derived from important regulatory genes, including Mtmr3, Cdc42, Cd47, Fbln2, Vegfa, and Fhl2.ConclusionOur study emphasized the critical roles of the dysregulated AS profiles in MIRI development, investigated the potential functions of MIRI-associated RASGs, and identified regulatory RBPs involved in AS regulation. We propose that the identified RASEs and RBPs could serve as important regulators and potential therapeutic targets in MIRI treatment in the future.
C1 [Ma, Ning; Xu, Hao; Zhang, Weihua; Sun, Xiaoke; Guo, Ruiming; Liu, Donghai; Zhang, Liang; Liu, Yang; Zhang, Jian; Qiao, Chenhui] Zhengzhou Univ, Dept Cardiovasc Surg, Affiliated Hosp 1, Zhengzhou 450052, Henan, Peoples R China.
   [Chen, Dong; Luo, Ailing] Wuhan Ruixing Biotechnol Co Ltd, Wuhan 430206, Hubei, Peoples R China.
   [Bai, Jingyun] Zhengzhou Univ, Dept Nephrol, Affiliated Hosp 1, Zhengzhou 450052, Henan, Peoples R China.
C3 Zhengzhou University; Zhengzhou University
RP Bai, JY (corresponding author), Zhengzhou Univ, Dept Nephrol, Affiliated Hosp 1, Zhengzhou 450052, Henan, Peoples R China.
EM jingybai@163.com
RI Guo, Ruiming/AAY-8654-2021; yang, xiao/KHT-9445-2024; zhang,
   weihua/GXV-1334-2022
FU Not applicable.
FX Not applicable.
CR Baeza-Centurion P, 2019, Cell
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NR 41
TC 2
Z9 2
U1 1
U2 6
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1755-8794
J9 BMC MED GENOMICS
JI BMC Med. Genomics
PD OCT 19
PY 2023
VL 16
IS 1
AR 251
DI 10.1186/s12920-023-01706-5
PG 11
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA X0TI0
UT WOS:001095657600001
PM 37858115
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Daguenet, E
   Dujardin, G
   Valcárcel, J
AF Daguenet, Elisabeth
   Dujardin, Gwendal
   Valcarcel, Juan
TI The pathogenicity of splicing defects: mechanistic insights into
   pre-mRNA processing inform novel therapeutic approaches
SO EMBO REPORTS
LA English
DT Review
DE alternative splicing; disease; mutation; RNA; spliceosome
ID SPINAL MUSCULAR-ATROPHY; AMYOTROPHIC-LATERAL-SCLEROSIS; SISTER-CHROMATID
   COHESION; CLERICUZIO-TYPE POIKILODERMA; CHRONIC LYMPHOCYTIC-LEUKEMIA;
   INHERITED DEMENTIA FTDP-17; MOTOR CIRCUIT FUNCTION; SMALL NUCLEAR-RNA;
   MYOTONIC-DYSTROPHY; FAMILIAL DYSAUTONOMIA
AB Removal of introns from pre-mRNA precursors (pre-mRNA splicing) is a necessary step for the expression of most genes in multicellular organisms, and alternative patterns of intron removal diversify and regulate the output of genomic information. Mutation or natural variation in pre-mRNA sequences, as well as in spliceosomal components and regulatory factors, has been implicated in the etiology and progression of numerous pathologies. These range from monogenic to multifactorial genetic diseases, including metabolic syndromes, muscular dystrophies, neurodegenerative and cardiovascular diseases, and cancer. Understanding the molecular mechanisms associated with splicing-related pathologies can provide key insights into the normal function and physiological context of the complex splicing machinery and establish sound basis for novel therapeutic approaches.
C1 [Daguenet, Elisabeth; Dujardin, Gwendal; Valcarcel, Juan] Barcelona Inst Sci & Technol, Ctr Regulacio Genom, Barcelona, Spain.
   [Daguenet, Elisabeth; Dujardin, Gwendal; Valcarcel, Juan] Univ Pompeu Fabra, Barcelona, Spain.
   [Valcarcel, Juan] Inst Catalana Recerca & Estudis Avancats, Barcelona, Spain.
C3 Barcelona Institute of Science & Technology; Pompeu Fabra University;
   Centre de Regulacio Genomica (CRG); Pompeu Fabra University; ICREA
RP Valcárcel, J (corresponding author), Barcelona Inst Sci & Technol, Ctr Regulacio Genom, Barcelona, Spain.
EM juan.valcarcel@crg.eu
RI Daguenet, Elisabeth/N-4122-2019; Valcarcel, Juan/O-9814-2014; Dujardin,
   Gwendal/K-7464-2015; Daguenet, Elisabeth/K-5507-2015
OI Dujardin, Gwendal/0000-0003-4320-6351; Daguenet,
   Elisabeth/0000-0002-6101-1016
FU Fundacion Botin, Banco de Santander through its Santander Universities
   Global Division; Consolider RNAREG; Ministerio de Economia y
   Competitividad; AGAUR; Marie Sklodowska Curie Fellowship Program; ICREA
   Funding Source: Custom
FX We apologize to many colleagues whose work could not be directly
   referenced because of space constraints. We thank members of our
   laboratory for comments on the manuscript. Work in JV laboratory is
   supported by Fundacion Botin, Banco de Santander through its Santander
   Universities Global Division, Consolider RNAREG, Ministerio de Economia
   y Competitividad, and AGAUR. GD is supported by the Marie Sklodowska
   Curie Fellowship Program.
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NR 168
TC 106
Z9 127
U1 0
U2 27
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1469-221X
EI 1469-3178
J9 EMBO REP
JI EMBO Rep.
PD DEC
PY 2015
VL 16
IS 12
BP 1640
EP 1655
DI 10.15252/embr.201541116
PG 16
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA DB0ZH
UT WOS:000368237100010
PM 26566663
OA Green Published
DA 2025-04-10
ER

PT J
AU Lorenzini, PA
   Chew, RSE
   Tan, CWQ
   Yong, JY
   Zhang, F
   Zheng, J
   Roca, X
AF Lorenzini, Paolo Alberto
   Chew, Resilind Su Ern
   Tan, Cheryl Weiqi
   Yong, Jing Yen
   Zhang, Fan
   Zheng, Jie
   Roca, Xavier
TI Human PRPF40B regulates hundreds of alternative splicing targets and
   represses a hypoxia expression signature
SO RNA
LA English
DT Article
DE alternative splicing; PRPF40B; hypoxia; myelodysplastic syndromes; acute
   myeloid leukemia
ID RNA-POLYMERASE-II; SET ENRICHMENT ANALYSIS; GENE-EXPRESSION;
   HEMATOPOIETIC STEM; SR PROTEIN; WEB SERVER; MUTATIONS; DOMAIN; PATHWAY;
   PRP40
AB Altered splicing contributes to the pathogenesis of human blood disorders including myelodysplastic syndromes (MDS) and leukemias. Here we characterize the transcriptomic regulation of PRPF40B, which is a splicing factor mutated in a small fraction of MDS patients. We generated a full PRPF40B knockout (KO) in the K562 cell line by CRISPR/Cas9 technology and rescued its levels by transient overexpression of wild-type (WT), P383L or P540S MDS alleles. Using RNA sequencing, we identified hundreds of differentially expressed genes and alternative splicing (AS) events in the KOthat are rescued by WT PRPF40B, with a majority also rescued by MDS alleles, pointing to mild effects of these mutations. Among the PRPF40B-regulated AS events, we found a net increase in exon inclusion in the KO, suggesting that this splicing factor primarily acts as a repressor. PRPF40B-regulated splicing events are likely cotranscriptional, affecting exons with A-rich downstream intronic motifs and weak splice sites especially for 5' splice sites, consistent with its PRP40 yeast ortholog being part of the U1 small nuclear ribonucleoprotein. Loss of PRPF40B in K562 induces a KLF1 transcriptional signature, with genes involved in iron metabolism and mainly hypoxia, including related pathways like cholesterol biosynthesis and Akt/MAPK signaling. A cancer database analysis revealed that PRPF40B is lowly expressed in acute myeloid leukemia, whereas its paralog PRPF40A expression is high as opposed to solid tumors. Furthermore, these factors negatively or positively correlated with hypoxia regulator HIF1A, respectively. Our data suggest a PRPF40B role in repressing hypoxia in myeloid cells, and that its low expression might contribute to leukemogenesis.
C1 [Lorenzini, Paolo Alberto; Chew, Resilind Su Ern; Tan, Cheryl Weiqi; Yong, Jing Yen; Roca, Xavier] Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore.
   [Lorenzini, Paolo Alberto] Nanyang Technol Univ, IGS, Nanyang Inst Technol Hlth & Med, Singapore 637551, Singapore.
   [Zhang, Fan; Zheng, Jie] Nanyang Technol Univ, Sch Comp Sci & Engn, Singapore 637551, Singapore.
   [Zheng, Jie] ShanghaiTech Univ, Sch Informat Sci & Technol, Shanghai 201210, Peoples R China.
C3 Nanyang Technological University; Nanyang Technological University;
   Nanyang Technological University; ShanghaiTech University
RP Roca, X (corresponding author), Nanyang Technol Univ, Sch Biol Sci, Singapore 637551, Singapore.
EM xroca@ntu.edu.sg
RI Zheng, Jie/AAX-1454-2021; Roca Castella, Francesc Xavier/C-5838-2011
OI Zhang, Fan/0000-0001-8377-0235; Lorenzini, Paolo
   Alberto/0009-0006-4417-4848; Roca Castella, Francesc
   Xavier/0000-0003-3853-5273
FU Singapore's Ministry of Education [MOE2013-T2-1-101 ARC 45/13,
   MOE2016-T2-2-104 (S)]
FX We thank all members of the Roca laboratory for advice. We are grateful
   to Daniela Moses for RNA library preparation and for running the
   Illumina HiSeq machine. We also thank Fursham Hamid for advice. This
   work was supported by Academic Research Fund Tier 2 [MOE2013-T2-1-101
   ARC 45/13 and MOE2016-T2-2-104 (S)], both from Singapore's Ministry of
   Education (https://www.olga.moe.gov.sg/T2/default.aspx). The funders
   played no role in study design, data collection and analysis, decision
   to publish, or preparation of the manuscript.
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NR 88
TC 15
Z9 16
U1 0
U2 10
PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
PI COLD SPRING HARBOR
PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA
SN 1355-8382
EI 1469-9001
J9 RNA
JI RNA
PD AUG
PY 2019
VL 25
IS 8
BP 905
EP 920
DI 10.1261/rna.069534.118
PG 16
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA IJ1VL
UT WOS:000475686900002
PM 31088860
OA Bronze, Green Published
DA 2025-04-10
ER

PT J
AU Upadhyay, SK
   Mackereth, CD
AF Upadhyay, Santosh Kumar
   Mackereth, Cameron D.
TI <SUP>1</SUP>H, <SUP>15</SUP>N and <SUP>13</SUP>C backbone and side chain
   resonance assignments of the RRM domain from human RBM24
SO BIOMOLECULAR NMR ASSIGNMENTS
LA English
DT Article
DE Alternative splicing; Development; Muscle; Heart; mRNA
ID RNA-BINDING PROTEIN; EXPRESSION; RECOGNITION; STABILITY
AB Tissue development requires the expression of a regulated subset of genes, and it is becoming clear that the process of alternative splicing also plays an important role in the production of necessary tissue-specific isoforms. However, only a few of these tissue-specific splicing factors in mammals have so far been discovered. One of these factors is the RNA-binding protein RBM24 which has been recently identified as a major regulator of alternative splicing in cardiac and skeletal muscle development. The RBM24 protein contains an RNA recognition motif (RRM) domain that presumably mediates the binding to target pre-mRNA required for regulation of the splicing patterns. Here we report H-1, N-15 and C-13 chemical shift assignments of the backbone and sidechain atoms for the RRM domain from human RBM24. Secondary chemical shift analysis and relaxation measurement confirm the canonical architecture of the RRM domain. The data will allow for atomic level studies aimed at understanding splicing regulation of target genes in heart and muscle development and investigation into a separate role of RBM24 in modulating mRNA stability of genes involved in the p53 tumor suppressor pathway.
C1 [Upadhyay, Santosh Kumar] CSIR Inst Genom & Integrat Biol, New Delhi 110020, India.
   [Mackereth, Cameron D.] Univ Bordeaux, IECB, 2 Rue Robert Escarpit, F-33607 Pessac, France.
   [Mackereth, Cameron D.] Univ Bordeaux, ARNA Lab, INSERM, U869, F-33076 Bordeaux, France.
C3 Council of Scientific & Industrial Research (CSIR) - India; CSIR -
   Institute of Genomics & Integrative Biology (IGIB); Universite de
   Bordeaux; Universite de Bordeaux; Institut National de la Sante et de la
   Recherche Medicale (Inserm)
RP Upadhyay, SK (corresponding author), CSIR Inst Genom & Integrat Biol, New Delhi 110020, India.
EM skupadhyay@msn.com
RI Upadhyay, Santosh/B-9967-2009; Upadhyay, Dr. Santosh
   Kumar/KDO-8969-2024; Mackereth, Cameron/F-7946-2013
OI Upadhyay, Santosh Kumar/0000-0001-5999-4351; Upadhyay, Dr. Santosh
   Kumar/0009-0003-3434-707X; Mackereth, Cameron/0000-0002-0776-7947
FU Department of Science and Technology (DST), Government of India; DST
   INSPIRE Faculty award [IFA-13 CH-102]
FX This work was supported by grants from the Department of Science and
   Technology (DST), Government of India. SKU is a recipient of the DST
   INSPIRE Faculty award [IFA-13 CH-102].
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NR 17
TC 1
Z9 1
U1 0
U2 3
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 1874-2718
EI 1874-270X
J9 BIOMOL NMR ASSIGN
JI Biomol. NMR Assign.
PD OCT
PY 2016
VL 10
IS 2
BP 237
EP 240
DI 10.1007/s12104-016-9674-y
PG 4
WC Biophysics; Spectroscopy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biophysics; Spectroscopy
GA EC7AI
UT WOS:000388287400001
PM 27002326
DA 2025-04-10
ER

PT J
AU Zühlke, RD
   Bouron, A
   Soldatov, NM
   Reuter, H
AF Zühlke, RD
   Bouron, A
   Soldatov, NM
   Reuter, H
TI Ca<SUP>2+</SUP> channel sensitivity towards the blocker isradipine is
   affected by alternative splicing of the human α1C subunit
   gene
SO FEBS LETTERS
LA English
DT Article
DE Ca2+ channel; splice variant; channel blocker; dihydropyridine; Xenopus
   oocyte
ID HIGH-AFFINITY BINDING; CALCIUM-CHANNEL; FUNCTIONAL EXPRESSION;
   1,4-DIHYDROPYRIDINE SENSITIVITY; DIHYDROPYRIDINE BINDING;
   MOLECULAR-BASIS; BETA-SUBUNIT; LOCALIZATION; MODULATION; DIVERSITY
AB L-type Ca2+ channels are important targets for drugs, such as dihydropyridines (DHPs), in the treatment of cardiovascular diseases. Channel expression is regulated by alternative splicing, It has been suggested that in the cardiovascular system tissue-specific expression of different L-type Ca2+ channel splice variants may underlie the observed differences in sensitivities to channel block by DHPs. We investigated the sensitivity of Ca2+ channel splice variants derived from the hunlan alpha(1C) gene to the DHP isradipine, Among seven alpha(1C) channels we observed up to IO-fold differences in IC50 values for isradipine, as well as changes in the voltage dependence of DHP action. (C) 1998 Federation of European Biochemical Societies.
C1 Univ Bern, Dept Pharmacol, CH-3010 Bern, Switzerland.
C3 University of Bern
RP Zühlke, RD (corresponding author), Univ Bern, Dept Pharmacol, Friedbuhlstr 49, CH-3010 Bern, Switzerland.
OI Bouron, Alexandre/0000-0003-4471-7727
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NR 36
TC 60
Z9 68
U1 0
U2 1
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0014-5793
J9 FEBS LETT
JI FEBS Lett.
PD MAY 8
PY 1998
VL 427
IS 2
BP 220
EP 224
DI 10.1016/S0014-5793(98)00425-6
PG 5
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA ZP199
UT WOS:000073727700014
PM 9607315
DA 2025-04-10
ER

PT J
AU Yang, WW
   Zhou, XR
   Li, QJ
   Yin, MY
   Wang, N
AF Yang, Wenwen
   Zhou, Xinrong
   Li, Qiuju
   Yin, Mingyue
   Wang, Ning
TI The effect of overexpression of CyPA on gene expression in human
   umbilical vein endothelial cells
SO MEDICINE
LA English
DT Article
DE CyPA; diabetes; endothelial dysfunction; HUVEC; PPIA; vascular disease
ID CARDIOVASCULAR-DISEASE; PLASMA CYCLOPHILIN; SERUM; SGK1; INHIBITION;
   APOPTOSIS; ISCHEMIA; STRESS; INJURY
AB The aim of this study is to screen the differentially expressed genes and genes with alternative splicing in PPIA overexpressing cells by transcriptome sequencing. Transcriptome sequencing was performed to identify differentially expressed genes and genes with altered alternative splicing in PPIA overexpressing cells and results were validated by real-time quantitative polymerase chain reaction. The biological function and pathways of those genes were further explored through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes analyses. A total of 157 significantly upregulated genes and 171 significantly downregulated genes were identified in PPIA overexpressing cells, and the splicing pattern of LHPP, APH1A, BRD1, and ORAI3 was found to be altered. GO analyses showed that the most enriched GO terms of the 157 upregulated genes included extracellular region, protein binding, and metal ion, and the most enriched GO terms of the 171 downregulated genes included binding neuron projection, protein binding, and endoplasmic reticulum unfolded protein response. Kyoto Encyclopedia of Genes and Genomes analyses showed that the 157 upregulated genes were mainly enriched in gastric acid secretion, Mitogen-activated protein kinase signaling pathway, etc, and the 171 downregulated genes were mainly enriched in transcriptional misregulation in cancer, Tumor necrosis factor signaling pathway, etc. The overexpression of PPIA in human umbilical vein endothelial cells causes changes in the expression of downstream genes and induces alternative splicing in multiple genes. PPIA alters the expression or the alternative splicing pattern of downstream genes, leading to pathogenesis of vascular endothelial injury by high glucose mediated through CyPA.
C1 [Yang, Wenwen; Li, Qiuju; Yin, Mingyue; Wang, Ning] Xinjiang Med Univ, Affiliated Hosp 1, Dept Gen Internal Med 1, 137 Liyushan South Rd, Urumqi 830000, Peoples R China.
   [Zhou, Xinrong] Xinjiang Med Univ, Affiliated Hosp 1, Coronary Heart Dis Care Unit, CCU, Urumqi, Peoples R China.
   [Wang, Ning] State Key Lab Pathogenesis, Prevent & Treatment High Incidence Dis Cent Asia, Urumqi, Peoples R China.
C3 Xinjiang Medical University; Xinjiang Medical University
RP Wang, N (corresponding author), Xinjiang Med Univ, Affiliated Hosp 1, Dept Gen Internal Med 1, 137 Liyushan South Rd, Urumqi 830000, Peoples R China.
EM yww81873073@163.com; 1051675381@qq.com; 2858724904@qq.com;
   wjk961102921@163.com; 13999994126@163.com
FU State Key Laboratory of Pathogenesis, Prevention and Treatment of High
   Incidence Diseases in Central Asia [SKL-HIDCH-2020-19]
FX This study was supported by the State Key Laboratory of Pathogenesis,
   Prevention and Treatment of High Incidence Diseases in Central Asia
   (SKL-HIDCH-2020-19)
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NR 53
TC 0
Z9 0
U1 4
U2 4
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0025-7974
EI 1536-5964
J9 MEDICINE
JI Medicine (Baltimore)
PD JUL 19
PY 2024
VL 103
IS 29
AR e38886
DI 10.1097/MD.0000000000038886
PG 10
WC Medicine, General & Internal
WE Science Citation Index Expanded (SCI-EXPANDED)
SC General & Internal Medicine
GA ZB5V3
UT WOS:001272852400017
PM 39029007
OA gold
DA 2025-04-10
ER

PT J
AU Gong, QM
   Stump, MR
   Zhou, ZF
AF Gong, Qiuming
   Stump, Matthew R.
   Zhou, Zhengfeng
TI Upregulation of functional Kv11.1a isoform expression by modified U1
   small nuclear RNA
SO GENE
LA English
DT Article
DE hERG; U1 snRNA; Splicing; Alternative polyadenylation; Arrhythmia; Long
   QT syndrome
ID LONG-QT SYNDROME; POTASSIUM CHANNEL; MESSENGER-RNA; K+ CHANNEL;
   CARDIAC-ARRHYTHMIA; SPLICE; HERG; MUTATION; IDENTIFICATION; RECTIFIER
AB The KCNH2 or human ether-a go-go-related gene (hERG) encodes the Kv11.1 potassium channel that conducts the rapidly activating delayed rectifier potassium current in the heart. The expression of Kv11.1 C-terminal isoforms is directed by the alternative splicing and polyadenylation of intron 9. Splicing of intron 9 leads to the formation of a functional, full-length Kv11.1a isoform and polyadenylation of intron 9 results in the production of a non-functional, C-terminally truncated Kv11.1a-USO isoform. The relative expression of Kv11.1a and Kv11.1a-USO plays an important role in regulating Kv11.1 channel function. In the heart, only one-third of KCNH2 pre-mRNA is processed to Kv11.1a due to the weak 5' splice site of intron 9. We previously showed that the weak 5' splice site is caused by sequence deviation from the consensus, and that mutations toward the consensus sequence increased the efficiency of intron 9 splicing. It is well established that 5' splice sites are recognized by complementary base-paring with U1 small nuclear RNA (U1 snRNA). In this study, we modified the sequence of U1 snRNA to increase its complementarity to the 5' splice site of KCNH2 intron 9 and observed a significant increase in the efficiency of intron 9 splicing. RNase protection assay and western blot analysis showed that modified U1 snRNA increased the expression of the functional Kv11.1a isoform and concomitantly decreased the expression of the non-functional Kv11.1a-USO isoform. In patch-clamp experiments, modified U1 snRNA significantly increased Kv11.1 current. Our findings suggest that relative expression of Kv11.1 C-terminal isoforms can be regulated by modified U1 snRNA.
C1 [Gong, Qiuming; Zhou, Zhengfeng] Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA.
   [Stump, Matthew R.] George Fox Univ, Dept Biol, Newberg, OR USA.
C3 Oregon Health & Science University; George Fox University
RP Zhou, ZF (corresponding author), Oregon Hlth & Sci Univ, Knight Cardiovasc Inst, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA.
EM zhouzh@ohsu.edu
FU NIH [HL068854]; American Heart Association [15GRNT23020018]; American
   Heart Association (AHA) [15GRNT23020018] Funding Source: American Heart
   Association (AHA)
FX This work was supported in part by grants from the NIH HL068854 (ZZ) and
   American Heart Association 15GRNT23020018 (ZZ).
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NR 24
TC 4
Z9 4
U1 0
U2 4
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0378-1119
EI 1879-0038
J9 GENE
JI Gene
PD JAN 30
PY 2018
VL 641
BP 220
EP 225
DI 10.1016/j.gene.2017.10.063
PG 6
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA FO2NP
UT WOS:000416616300030
PM 29066300
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Weigand, JE
   Boeckel, JN
   Gellert, P
   Dimmeler, S
AF Weigand, Julia E.
   Boeckel, Jes-Niels
   Gellert, Pascal
   Dimmeler, Stefanie
TI Hypoxia-Induced Alternative Splicing in Endothelial Cells
SO PLOS ONE
LA English
DT Article
ID GENE-EXPRESSION; DOWN-REGULATION; ROBO3 ISOFORMS; PROTEIN; RNA;
   TRANSCRIPTION; ANGIOGENESIS; SYNDECAN-2; PROMOTER; CUGBP1
AB Background: Adaptation to low oxygen by changing gene expression is vitally important for cell survival and tissue development. The sprouting of new blood vessels, initiated from endothelial cells, restores the oxygen supply of ischemic tissues. In contrast to the transcriptional response induced by hypoxia, which is mainly mediated by members of the HIF family, there are only few studies investigating alternative splicing events. Therefore, we performed an exon array for the genome-wide analysis of hypoxia-related changes of alternative splicing in endothelial cells.
   Methodology/Principal findings: Human umbilical vein endothelial cells (HUVECs) were incubated under hypoxic conditions (1% O-2) for 48 h. Genome-wide transcript and exon expression levels were assessed using the Affymetrix GeneChip Human Exon 1.0 ST Array. We found altered expression of 294 genes after hypoxia treatment. Upregulated genes are highly enriched in glucose metabolism and angiogenesis related processes, whereas downregulated genes are mainly connected to cell cycle and DNA repair. Thus, gene expression patterns recapitulate known adaptations to low oxygen supply. Alternative splicing events, until now not related to hypoxia, are shown for nine genes: six which are implicated in angiogenesis-mediated cytoskeleton remodeling (cask, itsn1, larp6, sptan1, tpm1 and robo1); one, which is involved in the synthesis of membrane-anchors (pign) and two universal regulators of gene expression (cugbp1 and max).
   Conclusions/Significance: For the first time, this study investigates changes in splicing in the physiological response to hypoxia on a genome-wide scale. Nine alternative splicing events, until now not related to hypoxia, are reported, considerably expanding the information on splicing changes due to low oxygen supply. Therefore, this study provides further knowledge on hypoxia induced gene expression changes and presents new starting points to study the hypoxia adaptation of endothelial cells.
C1 [Weigand, Julia E.; Boeckel, Jes-Niels; Dimmeler, Stefanie] Goethe Univ Frankfurt, Inst Cardiovasc Regenerat, Ctr Mol Med, Frankfurt, Germany.
   [Gellert, Pascal] Max Planck Inst Heart & Lung Res, Bad Nauheim, Germany.
C3 Goethe University Frankfurt; Max Planck Society
RP Weigand, JE (corresponding author), Goethe Univ Frankfurt, Inst Cardiovasc Regenerat, Ctr Mol Med, Frankfurt, Germany.
EM weigand@bio.tu-darmstadt.de
RI Weigand, Julia/JHT-1680-2023; Dimmeler, Stefanie/D-3108-2011
OI Dimmeler, Stefanie/0000-0002-1045-2436; Weigand,
   Julia/0000-0003-4247-1348; Gellert, Pascal/0000-0001-9325-025X
FU DFG [Exc 147-1]
FX The study was supported by the DFG (Exc 147-1). The funders had no role
   in study design, data collection and analysis, decision to publish, or
   preparation of the manuscript.
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NR 79
TC 67
Z9 76
U1 0
U2 22
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD AUG 2
PY 2012
VL 7
IS 8
AR e42697
DI 10.1371/journal.pone.0042697
PG 11
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 984JA
UT WOS:000307184700058
PM 22876330
OA Green Published, gold, Green Submitted
DA 2025-04-10
ER

PT J
AU Liao, P
   Li, G
   Yu, DJ
   Yong, TF
   Wang, JJ
   Wang, J
   Soong, TW
AF Liao, Ping
   Li, Guang
   Yu, De Jie
   Yong, Tan Fong
   Wang, Jue Jin
   Wang, Jing
   Soong, Tuck Wah
TI Molecular alteration of Cav1.2 calcium channel in chronic
   myocardial infarction
SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
LA English
DT Article
DE Alternative splicing; Ca(v)1.2 channel; Myocardial infarction
ID CA2+ CHANNEL; SPLICE VARIANTS; DEPENDENT INHIBITION; SUBUNIT GENE;
   DIHYDROPYRIDINES; IDENTIFICATION; SENSITIVITY; ARRHYTHMIA; HEART
AB Ca(v)1.2 channels are important for excitation-contraction coupling of cardiac muscles. Alternative splicing of Ca(v)1.2 channels could produce extensive phenotypic variations of channel properties. In a rat model of chronic myocardial infarction, we investigated whether Ca(v)1.2 channels may alter the use of alternatively spliced exons to generate functional variants. A myocardial infarction model on rat was generated by ligating the left anterior descending artery. Eight weeks after ligation, we found that in the scar region, the expression of a number of alternatively spliced exons were changed. The proportions of exon 9* inclusion and exon 33 deletion were detected to increase and localize at the surviving cardiac muscle cells with reverse transcriptase polymerase chain reaction, laser capture microdissection, and immunostaining. The wild-type Delta 9*/33 (deletion of exon 9* and inclusion of exon 33) channel was reduced greatly in the scar region and several other isoforms increased. Importantly, a novel 9*/Delta 33 (inclusion of exon 9* and deletion of exon 33) channel was generated in the scar region. Electrophysiological studies showed that the channels found in scar region exhibited hyperpolarized shifts in both the activation and inactivation potentials when expressed in HEK293 cells. The changes of Ca(v)1.2 channels may play a role either in maintenance of muscle excitability and contractility or contribute to arrhythmogenesis.
C1 [Liao, Ping; Li, Guang; Yu, De Jie; Yong, Tan Fong; Wang, Jue Jin; Soong, Tuck Wah] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore.
   [Wang, Jing; Soong, Tuck Wah] Natl Inst Neurosci, Singapore 308433, Singapore.
C3 National University of Singapore; National Neuroscience Institute (NNI)
RP Soong, TW (corresponding author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117597, Singapore.
EM phsstw@nus.edu.sg
RI Liao, Ping/LBI-1504-2024; Yu, Dejie/AAT-3293-2021; Wang,
   Jue/GVU-0480-2022
OI Liao, Ping/0000-0002-6205-4042
FU Biomedical Research Council of Singapore
FX This work was supported by a grant from the Biomedical Research Council
   of Singapore to Soong T. W.
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U1 0
U2 5
PU SPRINGER HEIDELBERG
PI HEIDELBERG
PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY
SN 0031-6768
EI 1432-2013
J9 PFLUG ARCH EUR J PHY
JI Pflugers Arch.
PD AUG
PY 2009
VL 458
IS 4
BP 701
EP 711
DI 10.1007/s00424-009-0652-4
PG 11
WC Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Physiology
GA 465NA
UT WOS:000267592900007
PM 19263075
DA 2025-04-10
ER

PT J
AU Ladd, AN
   Charlet-B, N
   Cooper, TA
AF Ladd, AN
   Charlet-B, N
   Cooper, TA
TI The CELF family of RNA binding proteins is implicated in cell-specific
   and developmentally regulated alternative splicing
SO MOLECULAR AND CELLULAR BIOLOGY
LA English
DT Article
ID CARDIAC TROPONIN-T; PRE-MESSENGER-RNA; MYOTONIC-DYSTROPHY; TRIPLET
   REPEAT; SR PROTEINS; 3'-UNTRANSLATED REGION; SKELETAL-MUSCLE; ADULT
   ISOFORMS; CTG REPEAT; IN-VITRO
AB Alternative splicing of cardiac troponin T (cTNT) exon 5 undergoes a developmentally regulated snitch such that exon inclusion predominates in embryonic, but not adult, striated muscle. We previously described four muscle-specific splicing enhancers (MSEs) within introns flanking exon 5 in chicken cTNT that are both necessary and sufficient for exon inclusion in embryonic muscle. We also demonstrated that CUG-binding protein (CUG-BP) binds a conserved CUG motif within a human cTNT MSE and positively regulates MSE-dependent exon inclusion. Here we report that CUG-BP is one of a novel family of developmentally regulated RNA binding proteins that includes embryonically lethal abnormal vision-type RNA binding protein 3 (ETR-3). This family, which we call CELF proteins for CUG-BP- and ETR-3-like factors, specifically bound MSE-containing RNAs in vitro and activated MSE-dependent exon inclusion of cTNT minigenes in vivo. The expression of two CELF proteins Is highly restricted to brain. CUG-BP, ETR-3, and CELF4 are more broadly expressed, and expression is developmentally regulated in striated muscle and brain. Changes in the level of expression and isoforms of ETR-3 in two different developmental systems correlated with regulated changes in cTNT splicing. A switch from cTNT exon skipping to inclusion tightly correlated with induction of ETR-3 protein expression during differentiation of C2C12 myoblasts. During heart development, the switch in cTNT splicing correlated with a transition in ETR-3 protein isoforms, We propose that ETR-3 is a major regulator of cTNT alternative splicing and that the CELF family plays an important regulatory role in cell-specific alternative splicing during normal development and disease.
C1 Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA.
C3 Baylor College of Medicine
RP Cooper, TA (corresponding author), Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA.
RI Charlet-Berguerand, Nicolas/GZM-6636-2022; Charlet-Berguerand,
   Nicolas/I-6727-2016
OI Charlet-Berguerand, Nicolas/0000-0002-4423-4920
FU NIAMS NIH HHS [R01 AR045653, AR45653] Funding Source: Medline
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NR 68
TC 354
Z9 414
U1 1
U2 19
PU AMER SOC MICROBIOLOGY
PI WASHINGTON
PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA
SN 0270-7306
J9 MOL CELL BIOL
JI Mol. Cell. Biol.
PD FEB
PY 2001
VL 21
IS 4
BP 1285
EP 1296
DI 10.1128/MCB.21.4.1285-1296.2001
PG 12
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 396TC
UT WOS:000166651800029
PM 11158314
OA Green Published
DA 2025-04-10
ER

PT J
AU Cejas, RB
   Tamaño-Blanco, M
   Fontecha, JE
   Blanco, JG
AF Cejas, Romina Beatriz
   Tamano-Blanco, Miriam
   Fontecha, John Edgar
   Blanco, Javier Guillermo
TI Impact of DYRK1A Expression on TNNT2 Splicing and
   Daunorubicin Toxicity in Human iPSC-Derived Cardiomyocytes
SO CARDIOVASCULAR TOXICOLOGY
LA English
DT Article
DE Human cardiomyocytes; Anthracyclines; Alternative splicing; Troponin;
   Hear; Cardiotoxicity
ID ANTHRACYCLINE-RELATED CARDIOTOXICITY; TROPONIN-T ISOFORMS;
   DOWN-SYNDROME; CA2+ SENSITIVITY; HEART; CARDIOMYOPATHY; INSIGHTS; ADULT;
   EXON
AB Cardiac troponin T (encoded by TNNT2) is involved in the contraction of cardiomyocytes during beating. The alternative splicing of TNNT2 results in four transcript variants with differential Ca2+ sensitivity. The splicing of TNNT2 involves phosphorylation of the splicing factor SRSF6 by DYRK1A. Altered TNNT2 splicing patterns have been identified in failing human hearts. There is a paucity of studies describing DYRK1A-SRSF6-TNNT2 interplays in human cardiomyocytes. Also, it is not known whether the sensitivity of cardiomyocytes to cardiotoxic anthracyclines is modified in the context of variable DYRK1A-TNNT2 expression. In this study, we investigated the impact of DYRK1A on the endogenous expression of TNNT2 splicing variants in iPSC-derived cardiomyocytes. We also examined whether DYRK1A expression modifies the sensitivity of cardiomyocytes to the cardiotoxic drug daunorubicin (DAU). DYRK1A over-expression increased the abundance of TNNT2 fetal variants by similar to 58% whereas the abundance of the adult cTnT3 variant decreased by similar to 27%. High DYRK1A expression increased the phosphorylation of SRSF6 by - similar to 25-65%. DAU cytotoxicity was similar between cardiomyocytes with variable levels of DYRK1A expression. DYRK1A over-expression ameliorated the impact of DAU on beating frequency. This study lays the foundation to further investigate the contribution of variable DYRK1A-TNNT2 expression to Ca2+ handling and beating in human cardiomyocytes.
C1 [Cejas, Romina Beatriz; Tamano-Blanco, Miriam; Blanco, Javier Guillermo] SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Buffalo, NY 14214 USA.
   [Fontecha, John Edgar] SUNY Buffalo, Grp Appl Math Modeling & Analyt GAMMA, Ind & Syst Engn, Buffalo, NY 14214 USA.
C3 State University of New York (SUNY) System; University at Buffalo, SUNY;
   State University of New York (SUNY) System; University at Buffalo, SUNY
RP Blanco, JG (corresponding author), SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Buffalo, NY 14214 USA.
EM jgblanco@buffalo.edu
OI Cejas, Romina/0000-0002-5484-4722
FU Eunice Kennedy Shriver National Institute of Child Health and Human
   Development [R21 HD089053]; National Cancer Institute [R21 CA245067];
   National Institute of General Medical Sciences [R01 GM073646]
FX This study was supported by the Eunice Kennedy Shriver National
   Institute of Child Health and Human Development (Award R21 HD089053),
   the National Cancer Institute (Award R21 CA245067), and the National
   Institute of General Medical Sciences (Award R01 GM073646).
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NR 36
TC 3
Z9 3
U1 0
U2 1
PU HUMANA PRESS INC
PI TOTOWA
PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA
SN 1530-7905
EI 1559-0259
J9 CARDIOVASC TOXICOL
JI Cardiovasc. Toxicol.
PD AUG
PY 2022
VL 22
IS 8
BP 701
EP 712
DI 10.1007/s12012-022-09746-6
EA MAY 2022
PG 12
WC Cardiac & Cardiovascular Systems; Toxicology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Toxicology
GA 2L9AQ
UT WOS:000798472400001
PM 35596909
OA hybrid, Green Published
DA 2025-04-10
ER

PT J
AU Cogan, J
   Austin, E
   Hedges, L
   Womack, B
   West, J
   Loyd, J
   Hamid, R
AF Cogan, Joy
   Austin, Eric
   Hedges, Lora
   Womack, Bethany
   West, James
   Loyd, James
   Hamid, Rizwan
TI Role of BMPR2 Alternative Splicing in Heritable Pulmonary
   Arterial Hypertension Penetrance
SO CIRCULATION
LA English
DT Article
DE alternative splicing; bone morphogenetic protein receptors, type II;
   hypertension, pulmonary; penetrance; SRSF2 protein, human
ID II RECEPTOR; SEROTONIN TRANSPORTER; GENE-EXPRESSION; CELL-LINES;
   MUTATIONS; ASSOCIATION; ENHANCERS; FREQUENCY; DISEASE; HEMODYNAMICS
AB Background-Bone morphogenic protein receptor 2 (BMPR2) gene mutations are the most common cause of heritable pulmonary arterial hypertension. However, only 20% of mutation carriers get clinical disease. Here, we explored the hypothesis that this reduced penetrance is due in part to an alteration in BMPR2 alternative splicing.
   Methods and Results-Our data showed that BMPR2 has multiple alternative spliced variants. Two of these, isoform-A (full length) and isoform-B (missing exon 12), were expressed in all tissues analyzed. Analysis of cultured lymphocytes of 47 BMPR2 mutation-positive heritable pulmonary arterial hypertension patients and 35 BMPR2 mutation-positive unaffected carriers showed that patients had higher levels of isoform-B compared with isoform-A (B/A ratio) than carriers (P=0.002). Furthermore, compared with cells with a low B/A ratio, cells with a high B/A ratio had lower levels of unphosphorylated cofilin after BMP stimulation. Analysis of exon 12 sequences identified an exonic splice enhancer that binds serine arginine splicing factor 2 (SRSF2). Because SRSF2 promotes exon inclusion, reduced SRSF2 expression would mean that exon 12 would not be included in final BMPR2 mRNA (thus promoting increased isoform-B formation). Western blot analysis showed that SRSF2 expression was lower in cells from patients compared with cells from carriers and that siRNA-mediated knockdown of SRSF2 in pulmonary microvascular endothelial cells resulted in elevated levels of isoform-B compared with isoform-A, ie, an elevated B/A ratio.
   Conclusions-Alterations in BMPR2 isoform ratios may provide an explanation of the reduced penetrance among BMPR2 mutation carriers. This ratio is controlled by an exonic splice enhancer in exon 12 and its associated splicing factor, SRSF2. (Circulation. 2012;126:1907-1916.)
C1 [Hamid, Rizwan] Vanderbilt Univ, Med Ctr, Div Med Genet, MCN,Dept Pediat, Nashville, TN 37232 USA.
   [West, James; Loyd, James] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA.
   [Hamid, Rizwan] Vanderbilt Univ, Med Ctr, Dept Canc Biol, Nashville, TN 37232 USA.
C3 Vanderbilt University; Vanderbilt University; Vanderbilt University
RP Hamid, R (corresponding author), Vanderbilt Univ, Med Ctr, Div Med Genet, MCN,Dept Pediat, Room DD2205, Nashville, TN 37232 USA.
EM rizwan.hamid@vanderbilt.edu
RI Austin, Eric/A-6070-2013; West, James/E-2960-2010
OI Cogan, Joy/0000-0001-8106-1216; West, James/0000-0002-6004-0202; Loyd,
   James/0000-0002-5042-7390
FU National Heart, Lung, and Blood Institute [1R01HL102020]
FX The research presented here was supported by National Heart, Lung, and
   Blood Institute grant 1R01HL102020 to Dr Hamid.
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NR 44
TC 49
Z9 54
U1 0
U2 11
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA
SN 0009-7322
J9 CIRCULATION
JI Circulation
PD OCT 9
PY 2012
VL 126
IS 15
BP 1907
EP U307
DI 10.1161/CIRCULATIONAHA.112.106245
PG 12
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 019ZZ
UT WOS:000309779400018
PM 22923426
OA Green Accepted, Bronze
DA 2025-04-10
ER

PT J
AU Carboni, N
   Floris, M
   Mateddu, A
   Porcu, M
   Marrosu, G
   Solla, E
   Cocco, E
   Mura, M
   Marini, S
   Maioli, MA
   Piras, R
   Aste, R
   Marrosu, MG
AF Carboni, Nicola
   Floris, Matteo
   Mateddu, Anna
   Porcu, Maurizio
   Marrosu, Giovanni
   Solla, Elisabetta
   Cocco, Eleonora
   Mura, Marco
   Marini, Stefano
   Maioli, Maria A.
   Piras, Rachele
   Aste, Rinaldo
   Marrosu, Maria G.
TI ABERRANT SPLICING IN THE LMNA GENE CAUSED BY A NOVEL MUTATION ON
   THE POLYPYRIMIDINE TRACT OF INTRON 5
SO MUSCLE & NERVE
LA English
DT Article
DE alternative splicing; canonical site; dilated cardiomyopathy with
   conduction defects; LMNA gene; novel intronic mutation; polypyrimidine
   tract
ID LAMIN A/C MUTATIONS; DILATED CARDIOMYOPATHY; MUSCULAR-DYSTROPHY;
   AUTOSOMAL-DOMINANT; INVOLVEMENT; DISEASE; SITE
AB Introduction: Familial dilated cardiomyopathy with conduction system defects variably associated with skeletal muscle abnormalities is frequently caused by LMNA gene mutations. Methods: A family affected by cardiac abnormalities, either isolated or variably associated with skeletal muscle compromise, was identified. LMNA gene analysis was applied to all family members. Results: A novel intron 5 (c.937-11 C > G) mutation was identified. mRNA transcription analysis was subsequently performed, and cDNA was obtained from mutated patients. It displayed an aberrant splice product featuring the insertion of 40 nucleotides from intron 5, leading to a frameshift. Computational predictions identified a cryptic splice site 40 bp upstream from the canonical site; this alternative splicing event was elicited by intronic mutation, which seems to interfere with the polypyrimidine tract of the canonical site. Conclusions: We have described the first mutation on the LMNA gene interfering with the polypyrimidine tract. Our findings underline the importance of including introns in the search for mutations. Muscle Nerve 43: 688-693, 2011
C1 [Carboni, Nicola; Mateddu, Anna; Marrosu, Giovanni; Solla, Elisabetta; Cocco, Eleonora; Maioli, Maria A.; Piras, Rachele; Marrosu, Maria G.] Univ Cagliari, Multiple Sclerosis Ctr, Neuromuscular Unit, I-09124 Cagliari, Sardinia, Italy.
   [Floris, Matteo] CRS4, Cagliari, Sardinia, Italy.
   [Porcu, Maurizio] Brotzu Hosp, Div Cardiol, Cagliari, Sardinia, Italy.
   [Mura, Marco; Marini, Stefano] Univ Cagliari, Dept Radiol, I-09124 Cagliari, Sardinia, Italy.
   [Aste, Rinaldo] Monte Sirai Hosp, Dept Cardiol, Carbonia, Sardinia, Italy.
C3 University of Cagliari; University of Cagliari
RP Carboni, N (corresponding author), Univ Cagliari, Multiple Sclerosis Ctr, Neuromuscular Unit, Via Is Guaddazonis 2, I-09124 Cagliari, Sardinia, Italy.
EM nikola.carboni@tiscali.it
RI Floris, Matteo/ABH-1274-2020; Porcu, Maurizio/AAO-6175-2020; PIRAS,
   RACHELE/JWP-8152-2024; Mura, Marco/F-8780-2018; Cocco,
   Eleonora/G-5064-2012
OI Marrosu, Maria Giovanna/0000-0003-2334-2081; Piras,
   Rachele/0009-0000-8095-1014; Floris, Matteo/0000-0003-4385-9336; Cocco,
   Eleonora/0000-0002-3878-8820
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   LAMIN A C LMNA SEQUE
NR 32
TC 10
Z9 12
U1 0
U2 2
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0148-639X
EI 1097-4598
J9 MUSCLE NERVE
JI Muscle Nerve
PD MAY
PY 2011
VL 43
IS 5
BP 688
EP 693
DI 10.1002/mus.21937
PG 6
WC Clinical Neurology; Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 748VI
UT WOS:000289420500011
PM 21462202
DA 2025-04-10
ER

PT J
AU Shomron, N
   Hamasaki-Katagiri, N
   Hunt, R
   Hershko, K
   Pommier, E
   Geetha, S
   Blaisdell, A
   Marple, A
   Roma, I
   Newell, J
   Allen, C
   Friedman, S
   Kimchi-Sarfaty, C
AF Shomron, Noam
   Hamasaki-Katagiri, Nobuko
   Hunt, Ryan
   Hershko, Klilah
   Pommier, Elie
   Geetha, S.
   Blaisdell, Adam
   Marple, Andrew
   Roma, Isabella
   Newell, Jordan
   Allen, Courtni
   Friedman, Scott
   Kimchi-Sarfaty, Chava
TI A splice variant of ADAMTS13 is expressed in human hepatic stellate
   cells and cancerous tissues
SO THROMBOSIS AND HAEMOSTASIS
LA English
DT Article
DE ADAMTS13; alternative splicing; intron retention; TTP; CUB domain
ID THROMBOTIC THROMBOCYTOPENIC PURPURA; VON-WILLEBRAND-FACTOR;
   FACTOR-CLEAVING PROTEASE; MESSENGER-RNA; METALLOPROTEASE; ASSOCIATION;
   MUTATION; COMPLEX
AB Although ADAMTS13, the von Willebrand factor (VWF)-cleaving protease, is expressed in a range of tissues, the physiological significance of tissue-specific ADAMTS13 alternative splicing isoforms have yet to be clarified. Screening a panel of human tissues and cell lines revealed a spliced ADAMTS13 transcript in hepatic stellate cells and a hepatoma cell line that retains the 25(th) intron.A nonsense codon within the intron truncates the protease, which gains 64 novel amino acids in lieu of both CUB domains. This isoform, while retaining VWF-cleaving capability, accumulates intracellularly and its biological inaccessibility may prevent its participation in regulating haemostasis and other physiologic functions.
C1 [Shomron, Noam] Tel Aviv Univ, Sackler Fac Med, Dept Cell & Dev Biol, IL-69978 Tel Aviv, Israel.
   [Hamasaki-Katagiri, Nobuko; Hunt, Ryan; Hershko, Klilah; Pommier, Elie; Geetha, S.; Blaisdell, Adam; Newell, Jordan; Allen, Courtni; Kimchi-Sarfaty, Chava] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA.
   [Marple, Andrew; Roma, Isabella] Natl Canc Inst, Cell Biol Lab, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD USA.
   [Friedman, Scott] Mt Sinai Sch Med, Div Liver Dis, New York, NY USA.
C3 Tel Aviv University; Sackler Faculty of Medicine; US Food & Drug
   Administration (FDA); Center for Biologics Evaluation & Research (CBER);
   National Institutes of Health (NIH) - USA; NIH National Cancer Institute
   (NCI); Icahn School of Medicine at Mount Sinai
RP Kimchi-Sarfaty, C (corresponding author), 29 Lincoln Dr, Bethesda, MD 20982 USA.
EM Chava.kimchi-sarfaty@fda.hhs.gov
RI Friedman, Scott/AFV-6304-2022
OI Kimchi-Sarfaty, Chava/0000-0002-9355-8585
FU Intramural NIH HHS [Z01 BC005598-18] Funding Source: Medline
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NR 18
TC 12
Z9 12
U1 0
U2 3
PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN
PI STUTTGART
PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY
SN 0340-6245
J9 THROMB HAEMOSTASIS
JI Thromb. Haemost.
PD SEP
PY 2010
VL 104
IS 3
BP 531
EP 535
DI 10.1160/TH09-12-0860
PG 5
WC Hematology; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Hematology; Cardiovascular System & Cardiology
GA 651ZV
UT WOS:000281969900014
PM 20664912
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Li, SJ
   Guo, W
   Dewey, CN
   Greaser, ML
AF Li, Shijun
   Guo, Wei
   Dewey, Colin N.
   Greaser, Marion L.
TI Rbm20 regulates titin alternative splicing as a splicing repressor
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID ISOFORM EXPRESSION; CARDIAC TITIN; ALPHA-ACTININ; Z-DISC; Z-LINE;
   MUSCLE; BINDING; STIFFNESS; FILAMENTS; GENE
AB Titin, a sarcomeric protein expressed primarily in striated muscles, is responsible for maintaining the structure and biomechanical properties of muscle cells. Cardiac titin undergoes developmental size reduction from 3.7 megadaltons in neonates to primarily 2.97 megadaltons in the adult. This size reduction results from gradually increased exon skipping between exons 50 and 219 of titin mRNA. Our previous study reported that Rbm20 is the splicing factor responsible for this process. In this work, we investigated its molecular mechanism. We demonstrate that Rbm20 mediates exon skipping by binding to titin pre-mRNA to repress the splicing of some regions; the exons/introns in these Rbm20-repressed regions are ultimately skipped. Rbm20 was also found to mediate intron retention and exon shuffling. The two Rbm20 speckles found in nuclei from muscle tissues were identified as aggregates of Rbm20 protein on the partially processed titin pre-mRNAs. Cooperative repression and alternative 30 splice site selection were found to be used by Rbm20 to skip different subsets of titin exons, and the splicing pathway selected depended on the ratio of Rbm20 to other splicing factors that vary with tissue type and developmental age.
C1 [Li, Shijun; Guo, Wei; Greaser, Marion L.] Univ Wisconsin, Muscle Biol Lab, Dept Anim Sci, Madison, WI 53706 USA.
   [Dewey, Colin N.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53706 USA.
C3 University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison
RP Greaser, ML (corresponding author), Univ Wisconsin, Muscle Biol Lab, Dept Anim Sci, Madison, WI 53706 USA.
EM mgreaser@ansci.wisc.edu
RI guo, wei/E-8906-2012; Greaser, Marion/C-6147-2012
OI guo, wei/0000-0002-9158-8107
FU National Institutes of Health (NIH) [HL77196, R01HG005232]; College of
   Agricultural and Life Sciences, University of Wisconsin-Madison;
   National Institute of Food and Agriculture, United States Department of
   Agriculture [WIS01556]
FX National Institutes of Health (NIH) [HL77196 to M.L.G., and R01HG005232
   to C.N.D.]; College of Agricultural and Life Sciences, University of
   Wisconsin-Madison with support from the National Institute of Food and
   Agriculture, United States Department of Agriculture [ID number WIS01556
   to M.L.G.]. Funding for open access charge: University funds.
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NR 39
TC 109
Z9 127
U1 0
U2 12
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0305-1048
EI 1362-4962
J9 NUCLEIC ACIDS RES
JI Nucleic Acids Res.
PD FEB
PY 2013
VL 41
IS 4
BP 2659
EP 2672
DI 10.1093/nar/gks1362
PG 14
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 132IV
UT WOS:000318062000053
PM 23307558
OA Green Published, Green Submitted, gold
DA 2025-04-10
ER

PT J
AU Leduc, V
   Bourque, L
   Poirier, J
   Dufour, R
AF Leduc, Valerie
   Bourque, Lucienne
   Poirier, Judes
   Dufour, Robert
TI Role of rs3846662 and HMGCR alternative splicing in statin
   efficacy and baseline lipid levels in familial hypercholesterolemia
SO PHARMACOGENETICS AND GENOMICS
LA English
DT Article
ID APOLIPOPROTEIN-E POLYMORPHISM; DENSITY-LIPOPROTEIN-CHOLESTEROL;
   LDL-RECEPTOR GENE; CORONARY-HEART-DISEASE; COENZYME-A REDUCTASE;
   ENVIRONMENTAL-INFLUENCES; COA REDUCTASE; CARDIOVASCULAR-DISEASE;
   SIMVASTATIN TREATMENT; ALZHEIMERS-DISEASE
C1 [Poirier, Judes] McGill Univ, Ctr Studies Alzheimers Dis Prevent, Montreal, PQ, Canada.
   [Leduc, Valerie; Poirier, Judes] McGill Univ, Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada.
   [Leduc, Valerie; Bourque, Lucienne; Dufour, Robert] Univ Montreal, Dept Nutr, Clin Res Inst Montreal IRCM, Montreal, PQ H3C 3J7, Canada.
C3 McGill University; McGill University; Institut de Recherche Clinique de
   Montreal (IRCM); Universite de Montreal
RP Dufour, R (corresponding author), 120 Ave Pins Ouest, Montreal, PQ H2W 1R7, Canada.
EM robert.dufour@ircm.qc.ca
OI Leduc, Valerie/0000-0002-7512-8821
FU Canadian Institute of Health Research; Natural Sciences and Engineering
   Research Council of Canada; Fondation Levesque; Canadian Stroke Network;
   Fondation Leducq Transatlantic Networks of Excellence
FX This study was supported by the Canadian Institute of Health Research
   (V.L., J.P.), the Natural Sciences and Engineering Research Council of
   Canada (J.P.), the Fondation Levesque (J.P.), the Canadian Stroke
   Network (V.L.), and the Fondation Leducq Transatlantic Networks of
   Excellence (L.B., R.D.).
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NR 57
TC 26
Z9 28
U1 0
U2 9
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 1744-6872
EI 1744-6880
J9 PHARMACOGENET GENOM
JI Pharmacogenet. Genomics
PD JAN
PY 2016
VL 26
IS 1
BP 1
EP 11
PG 11
WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology
   & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology
   & Pharmacy
GA CY8XD
UT WOS:000366691100001
PM 26466344
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Lin, JHH
   Novakovic, D
   Rizzo, CM
   Zagorac, B
   Garand, M
   Filipieva, A
   Koschinsky, ML
   Boffa, MB
AF Lin, Joellen H. H.
   Novakovic, Dragana
   Rizzo, Christina M.
   Zagorac, Branislava
   Garand, Mathieu
   Filipieva, Anastassia
   Koschinsky, Marlys L.
   Boffa, Michael B.
TI The mRNA encoding TAFI is alternatively spliced in different cell types
   and produces intracellular forms of the protein lacking TAFla activity
SO THROMBOSIS AND HAEMOSTASIS
LA English
DT Article
DE Thrombin-activatable fibrinolysis inhibitor (TAFI); alternative
   splicing; liver; brain; monocytes/macrophages; megakaryocytes
ID ACTIVATABLE FIBRINOLYSIS INHIBITOR; PLASMA PROCARBOXYPEPTIDASE B;
   AMYLOID PRECURSOR PROTEIN; BRAIN CARBOXYPEPTIDASE-B; HUMAN PLATELETS;
   IN-VITRO; GENE; IDENTIFICATION; POLYMORPHISMS; COAGULATION
AB TAFI (thrombin-activatable fibrinolysis inhibitor) is a pro-carboxypeptidase, encoded by the CPB2 gene in humans that links the coagulation cascade to fibrinolysis and inflammation. The liver is the main source for plasma TAFI, and TAFI expression has been documented in platelets and monocyte-derived macrophages. A recent study reported an alternatively spliced CPB2 mRNA variant lacking exon 7 (Delta 7) in HepG2 cells and liver. Another study identified a CPB2 mRNA variant lacking exon 7 and a 52 bp deletion in exon 11 (Delta 7+11) in human hippocampus. We have examined alternative splicing of CPB2 mRNA in various cell types by RT-PCR and have assessed the functional properties of TAFI variants encoded by these transcripts by recombinant expression in mammalian cells. We identified the Delta 7 exon skipping event in liver, Dami megakaryoblasts, THP-1-derived macrophages, peripheral blood mononuclear cells, platelets, testis, cerebellum, and SH-SY5Y neuroblastoma cells. The All alternative splicing event was notably absent in liver cells. We also detected a novel exon Delta 7+8 skipping event in liver and megakaryocytes. Of note, we detected non-alternatively spliced CPB2 transcripts in brain tissues, suggesting the expression of full-length TAFI in brain. Experiments using cultured mammalian cells transfected with wild-type CPB2-, Delta 7-, Delta 7+11-, and Delta 11-cDNA revealed that alternatively spliced TAFI is stored inside the cells, cannot be activated by thrombin-thrombo-modulin, and does not have TAFla activity. The alternative splicing events clearly do not give rise to a secreted protein with basic carboxypeptidase activity, but the intracellular forms may possess novel functions related to intracellular proteolysis.
C1 [Lin, Joellen H. H.] Queens Univ, Dept Biomed & Mol Sci, Kingston, ON, Canada.
   [Novakovic, Dragana; Rizzo, Christina M.; Zagorac, Branislava; Garand, Mathieu; Filipieva, Anastassia; Koschinsky, Marlys L.; Boffa, Michael B.] Univ Windsor, Dept Chem & Biochem, Windsor, ON N9B 3P4, Canada.
C3 Queens University - Canada; University of Windsor
RP Boffa, MB (corresponding author), Univ Windsor, Dept Chem & Biochem, Room 275-3 Essex Hall, Windsor, ON N9B 3P4, Canada.
EM mboffa@uwindsor.ca
RI Tekić, Dragana/GYR-3921-2022; Garand, Mathieu/AAV-3190-2020; Boffa,
   Michael/N-6539-2019
OI Koschinsky, Marlys/0000-0002-2643-2288; Boffa,
   Michael/0000-0003-1211-3064; Komnenov, Dragana/0000-0001-8855-4291
FU Natural Sciences and Engineering Research Council of Canada; Heart and
   Stroke Foundation of Ontario; Canada Foundation for Innovation and the
   Ministry of Research and Innovation (Ontario)
FX This work was supported by grants from the Natural Sciences and
   Engineering Research Council of Canada to M. B. Boffa and from the Heart
   and Stroke Foundation of Ontario to M.L. Koschinsky and M.B. Boffa, as
   well as infrastructure grants from the Canada Foundation for Innovation
   and the Ministry of Research and Innovation (Ontario).
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NR 32
TC 7
Z9 12
U1 0
U2 8
PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN
PI STUTTGART
PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY
SN 0340-6245
J9 THROMB HAEMOSTASIS
JI Thromb. Haemost.
PD JUN
PY 2013
VL 109
IS 6
BP 1033
EP 1044
DI 10.1160/TH12-09-0668
PG 12
WC Hematology; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Hematology; Cardiovascular System & Cardiology
GA 163RY
UT WOS:000320355800008
PM 23595589
DA 2025-04-10
ER

PT J
AU Han, Y
   Wood, SD
   Wright, JM
   Dostal, V
   Lau, E
   Lam, MPY
AF Han, Yu
   Wood, Silas D.
   Wright, Julianna M.
   Dostal, Vishantie
   Lau, Edward
   Lam, Maggie P. Y.
TI Computation-assisted targeted proteomics of alternative splicing protein
   isoforms in the human heart
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Article
DE Targeted proteomics; Mass spectrometry; Parallel reaction monitoring;
   Alternative splicing; Protein isoforms; Proteoforms; Machine learning;
   Heart
AB Alternative splicing is prevalent in the heart and implicated in many cardiovascular diseases, but not every alternative transcript is translated and detecting non-canonical isoforms at the protein level remains challenging. Here we show the use of a computation-assisted targeted proteomics workflow to detect protein alternative isoforms in the human heart. We build on a recent strategy to integrate deep RNA-seq and large-scale mass spectrometry data to identify candidate translated isoform peptides. A machine learning approach is then applied to predict their fragmentation patterns and design protein isoform-specific parallel reaction monitoring detection (PRM) assays. As proof-of-principle, we built PRM assays for 29 non-canonical isoform peptides and detected 22 peptides in a human heart lysate. The predictions-aided PRM assays closely mirrored synthetic peptide standards for non-canonical sequences. This approach may be useful for validating non-canonical protein identification and discovering functionally relevant isoforms in the heart.
C1 [Han, Yu; Wood, Silas D.; Wright, Julianna M.; Dostal, Vishantie; Lau, Edward; Lam, Maggie P. Y.] Univ Colorado, Dept Med Cardiol, Anschutz Med Campus, Aurora, CO 80045 USA.
   [Lam, Maggie P. Y.] Univ Colorado, Dept Biochem & Mol Genet, Anschutz Med Campus, Aurora, CO 80045 USA.
   [Han, Yu; Dostal, Vishantie; Lau, Edward; Lam, Maggie P. Y.] Univ Colorado, Sch Med, Dept Consortium Fibrosis Res & Translat, Anschutz Med Campus, Aurora, CO 80045 USA.
C3 University of Colorado System; University of Colorado Anschutz Medical
   Campus; University of Colorado System; University of Colorado Anschutz
   Medical Campus; University of Colorado System; University of Colorado
   Anschutz Medical Campus
RP Lam, MPY (corresponding author), 12700 E 19th Ave,RC2-8400A, Aurora, CO 80045 USA.
EM maggie.lam@cuanschutz.edu
FU NIH NHLBI [R00HL127302, R01HL141278, R21-HL150456, R00-HL144829]; NIH
   NRSA Postdoctoral Fellowship [F32-HL149191]; University of Colorado
   Postdoctoral Fellowship in Cardiovascular Research [T32-HL007822];
   University of Colorado Consortium for Fibrosis Research and Translation
   Pilot Grant; Univeristy of Colorado Undergraduate Research Opportunity
   Program award; National Heart Lung and Blood Institute [R21HL150456,
   F32HL149191] Funding Source: NIH RePORTER
FX This study was supported in part by the NIH NHLBI awards R00HL127302,
   R01HL141278, R21-HL150456 to M.L. and R00-HL144829 to E.L.; the NIH NRSA
   Postdoctoral Fellowship F32-HL149191 to Y.H.; the University of Colorado
   Postdoctoral Fellowship in Cardiovascular Research T32-HL007822 to V.D.
   and Y.H.; the University of Colorado Consortium for Fibrosis Research
   and Translation Pilot Grant to M.L.; and the Univeristy of Colorado
   Undergraduate Research Opportunity?Program award to J.M.W.
CR Bradbury A, 2015, NATURE, V518, P27, DOI 10.1038/518027a
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NR 15
TC 10
Z9 11
U1 0
U2 13
PU ELSEVIER SCI LTD
PI London
PA 125 London Wall, London, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD MAY
PY 2021
VL 154
BP 92
EP 96
DI 10.1016/j.yjmcc.2021.01.007
EA FEB 2021
PG 5
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA RQ3BA
UT WOS:000642295900001
PM 33549679
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Ames, EG
   Lawson, MJ
   Mackey, AJ
   Holmes, JW
AF Ames, E. G.
   Lawson, M. J.
   Mackey, A. J.
   Holmes, J. W.
TI Sequencing of mRNA identifies re-expression of fetal splice variants in
   cardiac hypertrophy
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Article
DE Heart development; Cardiac hypertrophy; Alternative splicing; RNAseq
ID PRESSURE-OVERLOAD; GENE-EXPRESSION; TRANSCRIPTION FACTORS; ACTIN
   CYTOSKELETON; HEART-DISEASE; MYOSIN-I; MUSCLE; PROTEINS; PROGRAM;
   CARDIOMYOPATHY
AB Cardiac hypertrophy has been well-characterized at the level of transcription. During cardiac hypertrophy, genes normally expressed primarily during fetal heart development are re-expressed, and this fetal gene program is believed to be a critical component of the hypertrophic process. Recently, alternative splicing of mRNA transcripts has been shown to be temporally regulated during heart development, leading us to consider whether fetal patterns of splicing also reappear during hypertrophy. We hypothesized that patterns of alternative splicing occurring during heart development are recapitulated during cardiac hypertrophy. Here we present a study of isoform expression during pressure-overload cardiac hypertrophy induced by 10 days of transverse aortic constriction (TAC) in rats and in developing fetal rat hearts compared to sham-operated adult rat hearts, using high-throughput sequencing of poly(A) tail mRNA. We find a striking degree of overlap between the isoforms expressed differentially in fetal and pressure-overloaded hearts compared to control: forty-four percent of the isoforms with significantly altered expression in TAC hearts are also expressed at significantly different levels in fetal hearts compared to control (P < 0.001). The isoforms that are shared between hypertrophy and fetal heart development are significantly enriched for genes involved in cytoskeletal organization, RNA processing, developmental processes, and metabolic enzymes. Our data strongly support the concept that mRNA splicing patterns normally associated with heart development recur as part of the hypertrophic response to pressure overload. These findings suggest that cardiac hypertrophy shares post-transcriptional as well as transcriptional regulatory mechanisms with fetal heart development. (C) 2013 Elsevier Ltd. All rights reserved.
C1 [Ames, E. G.; Holmes, J. W.] Univ Virginia, Dept Biomed Engn, Charlottesville, VA 22908 USA.
   [Holmes, J. W.] Univ Virginia, Robert M Berne Cardiovasc Res Ctr, Charlottesville, VA 22908 USA.
   [Ames, E. G.] Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA.
   [Lawson, M. J.; Mackey, A. J.] Univ Virginia, Ctr Publ Hlth Genom, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA.
   [Holmes, J. W.] Univ Virginia, Dept Med, Charlottesville, VA 22908 USA.
C3 University of Virginia; University of Virginia; University of Virginia;
   University of Virginia; University of Virginia
RP Holmes, JW (corresponding author), Univ Virginia, Dept Biomed Engn, Hlth Syst Box 800759, Charlottesville, VA 22908 USA.
EM ega2d@virginia.edu; mlawsonvt09@gmail.com; amackey@virginia.edu;
   holmes@virginia.edu
OI Holmes, Jeffrey/0000-0001-9125-7220
FU NIH [R01 HL-075639, T32 GM-007267, T32 GM-008136]
FX This work was funded by NIH R01 HL-075639 (JWH), NIH T32 GM-007267
   (EGA), and NIH T32 GM-008136 (EGA).
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NR 62
TC 31
Z9 36
U1 0
U2 9
PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
PI LONDON
PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD SEP
PY 2013
VL 62
BP 99
EP 107
DI 10.1016/j.yjmcc.2013.05.004
PG 9
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA 198RV
UT WOS:000322940900013
PM 23688780
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Kirwin, SM
   Manolakos, A
   Barnett, SS
   Gonzalez, IL
AF Kirwin, Susan M.
   Manolakos, Athena
   Barnett, Sarah Swain
   Gonzalez, Iris L.
TI Tafazzin splice variants and mutations in Barth syndrome
SO MOLECULAR GENETICS AND METABOLISM
LA English
DT Article
DE Barth syndrome; Tafazzin; TAZ; Alternative splicing; Dilated
   cardiomyopathy; Cardiolipin
ID MESSENGER-RNA EXPRESSION; MASS-SPECTROMETRY; GENE-MUTATIONS;
   CARDIOLIPIN; BLOOD; STABILIZATION; PROTEIN
AB Barth syndrome is caused by mutations in the TAZ (tafazzin) gene on human chromosome Xq28. The human tafazzin gene produces four major mRNA splice variants; two of which have been shown to be functional (TAZ lacking exon 5 and full-length) in complementation studies with yeast and Drosophila. This study characterizes the multiple alternative splice variants of TAZ mRNA and their proportions in blood samples from a cohort of individuals with Barth syndrome (BTHS). Because it has been reported that collection and processing methods can affect the expression of various genes, we tested and chose a stabilizing medium for collecting, shipping and processing of the blood samples of these individuals. In both healthy controls and in BTHS individuals, we found a greater variety of alternatively spliced forms than previously described, with a sizeable proportion of minor splice variants besides the four dominant isoforms. Individuals with certain exonic and intronic splice mutations produce additional mutant mRNAs that could be translated into two or more proteins with different amino acid substitutions in a single individual. A fraction of the minor splice variants is predicted to be non-productive. (C) 2013 Elsevier Inc All rights reserved.
C1 [Kirwin, Susan M.; Manolakos, Athena; Barnett, Sarah Swain; Gonzalez, Iris L.] Nemours Alfred I duPont Hosp Children, Mol Diagnost Lab, Wilmington, DE 19899 USA.
C3 Nemours Alfred I. duPont Hospital for Children
RP Kirwin, SM (corresponding author), Nemours Alfred I duPont Hosp Children, Dept Biomed Res, POB 269, Wilmington, DE 19899 USA.
EM susan.kirwin@nemours.org
OI Kirwin, Susan/0000-0003-2008-4654; Barnett, Sarah/0000-0001-6483-4272
FU Barth Syndrome Foundation; Nemours Foundation
FX This work was funded by a Barth Syndrome Foundation grant award to Susan
   Kirwin and by The Nemours Foundation.
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NR 37
TC 20
Z9 28
U1 0
U2 6
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 1096-7192
EI 1096-7206
J9 MOL GENET METAB
JI Mol. Genet. Metab.
PD JAN
PY 2014
VL 111
IS 1
BP 26
EP 32
DI 10.1016/j.ymgme.2013.11.006
PG 7
WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research &
   Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental
   Medicine
GA 296AS
UT WOS:000330158100004
PM 24342716
DA 2025-04-10
ER

PT J
AU Yamankurt, G
   Wu, HC
   McCarthy, M
   Cunha, SR
AF Yamankurt, Gokay
   Wu, Henry C.
   McCarthy, Michael
   Cunha, Shane R.
TI Exon Organization and Novel Alternative Splicing of Ank3 in Mouse
   Heart
SO PLOS ONE
LA English
DT Article
ID BRONCHIAL EPITHELIAL-CELLS; ANKYRIN-G; LATERAL MEMBRANE; INTERCALATED
   DISC; SKELETAL-MUSCLE; BETA-SPECTRIN; REQUIRES; IDENTIFICATION; DOMAINS;
   BINDING
AB Ankyrin-G is an adaptor protein that links membrane proteins to the underlying cytoskeletal network. Alternative splicing of the Ank3 gene gives rise to multiple ankyrin-G isoforms in numerous tissues. To date, only one ankyrin-G isoform has been characterized in heart and transcriptional regulation of the Ank3 gene is completely unknown. In this study, we describe the first comprehensive analysis of Ank3 expression in heart. Using a PCR-based screen of cardiac mRNA transcripts, we identify two new exons and 28 alternative splice variants of the Ank3 gene. We measure the relative expression of each splice variant using quantitative real-time PCR and exon-exon boundary spanning primers that specifically amplify individual Ank3 variants. Six variants are rarely expressed (< 1%), while the remaining variants display similar expression patterns in three hearts. Of the five first exons in the Ank3 gene, exon 1d is only expressed in heart and skeletal muscle as it was not detected in brain, kidney, cerebellum, and lung. Immunoblot analysis reveals multiple ankyrin-G isoforms in heart, and two ankyrin-G subpopulations are detected in adult cardiomyocytes by immunofluorescence. One population co-localizes with the voltage-gated sodium channel NaV1.5 at the intercalated disc, while the other population expresses at the Z-line. Two of the rare splice variants excise a portion of the ZU5 motif, which encodes the minimal spectrin- binding domain, and these variants lack beta-spectrin binding. Together, these data demonstrate that Ank3 is subject to complex splicing regulation resulting in a diverse population of ankyrin-G isoforms in heart.
C1 [Yamankurt, Gokay] Northwestern Univ, Dept Chem, Evanston, IL USA.
   [Wu, Henry C.; McCarthy, Michael; Cunha, Shane R.] UT Hlth, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA.
C3 Northwestern University
RP Cunha, SR (corresponding author), UT Hlth, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA.
EM shane.r.cunha@uth.tmc.edu
OI McCarthy, Michael/0000-0001-6534-2237
FU NIH NHLBI [092232]
FX This work was supported by the NIH NHLBI 092232 to GY and SRC. The
   funder had no role in study design, data collection and analysis,
   decision to publish, or preparation of the manuscript.
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NR 33
TC 8
Z9 10
U1 0
U2 8
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD MAY 29
PY 2015
VL 10
IS 5
AR e0128177
DI 10.1371/journal.pone.0128177
PG 19
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA CJ2MQ
UT WOS:000355319400074
PM 26024478
OA Green Published, Green Submitted, gold
DA 2025-04-10
ER

PT J
AU Yamazaki, T
   Wälchli, S
   Fujita, T
   Ryser, S
   Hoshijima, M
   Schlegel, W
   Kuroda, S
   Maturana, AD
AF Yamazaki, Tomoko
   Walchli, Sebastien
   Fujita, Toshitsugu
   Ryser, Stephan
   Hoshijima, Masahiko
   Schlegel, Werner
   Kuroda, Shun'ichi
   Maturana, Andres D.
TI Splice variants of Enigma homolog, differentially expressed during heart
   development, promote or prevent hypertrophy
SO CARDIOVASCULAR RESEARCH
LA English
DT Article
DE Hypertrophy; PDZ-LIM protein; Alternative splicing
ID PROTEIN-KINASE-D; LIM-DOMAIN; PDZ; MUSCLE; SYSTEM; CYPHER; ENH;
   CARDIOMYOPATHY; CYTOSKELETON; PATHWAY
AB Proteins with a PDZ (for PSD-95, DLG, ZO-1) and one to three LIM (for Lin11, Isl-1, Mec-3) domains are scaffolding sarcomeric and cytoskeletal elements that form structured muscle fibres and provide for the link to intracellular signalling by selectively associating protein kinases, ion channels, and transcription factors with the mechanical stress-strain sensors. Enigma homolog (ENH) is a PDZ-LIM protein with four splice variants: ENH1 with an N-terminal PDZ domain and three C-terminal LIM domains and ENH2, ENH3, and ENH4 without LIM domains. We addressed the functional role of ENH alternative splicing.
   We studied the expression of the four ENH isoforms in the heart during development and in a mouse model of heart hypertrophy. All four isoforms are expressed in the heart but the pattern of expression is clearly different between embryonic, neonatal, and adult stages. ENH1 appears as the embryonic isoform, whereas ENH2, ENH3, and ENH4 are predominant in adult heart. Moreover, alternative splicing of ENH was changed following induction of heart hypertrophy, producing an ENH isoform pattern similar to that of neonatal heart. Next, we tested a possible causal role of ENH1 and ENH4 in the development of cardiac hypertrophy. When overexpressed in rat neonatal cardiomyocytes, ENH1 promoted the expression of hypertrophy markers and increased cell volume, whereas, on the contrary, ENH4 overexpression prevented these changes.
   Antagonistic splice variants of ENH may play a central role in the adaptive changes of the link between mechanical stress-sensing and signalling occurring during embryonic development and/or heart hypertrophy.
C1 [Kuroda, Shun'ichi] Nagoya Univ, Grad Sch Bioagr Sci, Lab Ind Biosci, Chikusa Ku, Nagoya, Aichi 4648601, Japan.
   [Yamazaki, Tomoko; Fujita, Toshitsugu; Ryser, Stephan; Schlegel, Werner] Univ Geneva, Fac Med, Fdn Rech Med, CH-1211 Geneva, Switzerland.
   [Yamazaki, Tomoko; Maturana, Andres D.] Tokyo Inst Technol, Global Edge Inst, Tokyo 1528550, Japan.
   [Walchli, Sebastien] Natl Hosp Norway, Radiumhosp Med Ctr, Dept Immunol, N-0310 Oslo, Norway.
   [Hoshijima, Masahiko] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA.
   [Maturana, Andres D.] Nagaoka Univ Technol, Dept Bioengn, Nagoya, Aichi 9402188, Japan.
C3 Nagoya University; University of Geneva; Institute of Science Tokyo;
   Tokyo Institute of Technology; University of Oslo; National Hospital
   Norway; University of California System; University of California San
   Diego; Nagaoka University of Technology
RP Kuroda, S (corresponding author), Nagoya Univ, Grad Sch Bioagr Sci, Lab Ind Biosci, Chikusa Ku, Furo Cho, Nagoya, Aichi 4648601, Japan.
EM skuroda@agr.nagoya-u.ac.jp; maturana@vos.nagaokaut.ac.jp
RI Fujita, Toshitsugu/AAB-4964-2022; Kuroda, Shun'Ichi/KVY-1906-2024
OI FUJITA, Toshitsugu/0000-0002-9536-9999; Walchli,
   Sebastien/0000-0001-5869-1746
FU Promotion of Environmental Improvement for Independence of Young
   Researchers; Special Coordination Funds for Promoting Science and
   Technology; Ministry of Education, Culture, Sports, Science, and
   Technology of Japan; Takeda Science Foundation; Fondation pour
   Recherches Medicales, Geneva; Swiss National Science Foundation; Helse
   Sor-Ost; NIH [HL0811401]
FX This work was supported by the Promotion of Environmental Improvement
   for Independence of Young Researchers, Special Coordination Funds for
   Promoting Science and Technology. Ministry of Education, Culture,
   Sports, Science, and Technology of Japan (to A. D. M.). The Takeda
   Science Foundation (to A. D. M.). The Fondation pour Recherches
   Medicales, Geneva and the Swiss National Science Foundation support T.
   Y. and W. S. S. W. was supported by a grant of Helse Sor-Ost. M. H. is
   supported by NIH grant (HL0811401).
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NR 29
TC 46
Z9 50
U1 0
U2 7
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0008-6363
EI 1755-3245
J9 CARDIOVASC RES
JI Cardiovasc. Res.
PD JUN 1
PY 2010
VL 86
IS 3
BP 374
EP 382
DI 10.1093/cvr/cvq023
PG 9
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 597BY
UT WOS:000277732000006
PM 20097676
OA Green Published
DA 2025-04-10
ER

PT J
AU Martí-Gómez, C
   Larrasa-Alonso, J
   López-Olañeta, M
   Villalba-Orero, M
   García-Pavía, P
   Sánchez-Cabo, F
   Lara-Pezzi, E
AF Marti-Gomez, Carlos
   Larrasa-Alonso, Javier
   Lopez-Olaneta, Marina
   Villalba-Orero, Maria
   Garcia-Pavia, Pablo
   Sanchez-Cabo, Fatima
   Lara-Pezzi, Enrique
TI Functional Impact and Regulation of Alternative Splicing in Mouse Heart
   Development and Disease
SO JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
LA English
DT Article
DE Alternative splicing; Heart disease; PTBP1; Splicing regulation
ID LIMB DEVELOPMENT; RECEPTOR; GENE; LRP4; EXPRESSION; MUTATIONS; COMPLEX;
   ERBB2; AGRIN; PTB
AB Alternative splicing (AS) plays a major role in the generation of transcript diversity. In the heart, roles have been described for some AS variants, but the global impact and regulation of AS patterns are poorly understood. Here, we studied the AS profiles in heart disease, their relationship with heart development, and the regulatory mechanisms controlling AS dynamics in the mouse heart. We found that AS profiles characterized the different groups and that AS and gene expression changes affected independent genes and biological functions. Moreover, AS changes, specifically in heart disease, were associated with potential protein-protein interaction changes. While developmental transitions were mainly driven by the upregulation of MBNL1, AS changes in disease were driven by a complex regulatory network, where PTBP1 played a central role. Indeed, PTBP1 over-expression was sufficient to induce cardiac hypertrophy and diastolic dysfunction, potentially by perturbing AS patterns.
C1 [Marti-Gomez, Carlos; Larrasa-Alonso, Javier; Lopez-Olaneta, Marina; Villalba-Orero, Maria; Garcia-Pavia, Pablo; Sanchez-Cabo, Fatima; Lara-Pezzi, Enrique] Ctr Nacl Invest Cardiovasc CNIC, Madrid, Spain.
   [Villalba-Orero, Maria; Garcia-Pavia, Pablo; Lara-Pezzi, Enrique] Ctr Invest Biomed Red Cardiovasc CIBERCV, Madrid, Spain.
   [Villalba-Orero, Maria] Univ Complutense Madrid, Fac Vet, Madrid, Spain.
   [Garcia-Pavia, Pablo] Hosp Univ Puerta Hierro Majadahonda, Dept Cardiol, Heart Failure & Inherited Cardiac Dis Unit, Madrid, Spain.
   [Garcia-Pavia, Pablo] Univ Francisco Vitoria, Fac Ciencias Salud, UFV, Madrid, Spain.
   [Sanchez-Cabo, Fatima] Ctr Nacl Invest Cardiovasc CNIC, Bioinformat Unit, Melchor Fernandez Almagro 3, Madrid 28029, Spain.
C3 Centro Nacional de Investigaciones Cardiovasculares (CNIC); CIBER -
   Centro de Investigacion Biomedica en Red; CIBERCV; Complutense
   University of Madrid; Hospital Puerta de Hierro-Majadahonda; Universidad
   Francisco de Vitoria; Centro Nacional de Investigaciones
   Cardiovasculares (CNIC)
RP Sánchez-Cabo, F; Lara-Pezzi, E (corresponding author), Ctr Nacl Invest Cardiovasc CNIC, Madrid, Spain.; Lara-Pezzi, E (corresponding author), Ctr Invest Biomed Red Cardiovasc CIBERCV, Madrid, Spain.; Sánchez-Cabo, F (corresponding author), Ctr Nacl Invest Cardiovasc CNIC, Bioinformat Unit, Melchor Fernandez Almagro 3, Madrid 28029, Spain.
EM elara@cnic.es
RI Sanchez-Cabo, Fatima/IZD-8966-2023; Garcia-Pavia, Pablo/T-9100-2019;
   Villalba-Orero, María/P-1331-2019; Sanchez-Cabo, Fatima/N-5030-2014;
   Marti Gomez-Aldaravi, Carlos/W-4936-2018; Villalba Orero,
   Maria/B-6765-2016; Lara-Pezzi, Enrique/E-2350-2015
OI Sanchez-Cabo, Fatima/0000-0003-1881-1664; Marti Gomez-Aldaravi,
   Carlos/0000-0002-2042-843X; Garcia-Pavia, Pablo/0000-0002-5470-2257;
   Villalba Orero, Maria/0000-0002-7680-3980; Lara-Pezzi,
   Enrique/0000-0002-2743-1033
FU European Union [289600, 608027]; Spanish Ministry of Economy and
   Competitiveness [SAF2015-65722-R, SAF2012-31451]; Science, Innovation
   and Universities (MCIU) [RTI2018-102084-B-I00]; Carlos III Institute of
   Health [CPII14/00027, RD012/0042/0066]; Madrid Regional Government
   [2010-BMD-2321]; Plan Estatal de I + D + I-European Regional Development
   Fund (ERDF) "A way of making Europe," Spain; Instituto de Salud Carlos
   III (ISCIII); Ministerio de Ciencia e Innovacion (MCIN); Pro CNIC
   Foundation
FX This study was supported by grants from the European Union
   [CardioNeT-ITN-289600 and CardioNext-608027 to E.L-P.], the Spanish
   Ministry of Economy and Competitiveness [SAF2015-65722-R and
   SAF2012-31451 to E.L-P.], the Science, Innovation and Universities
   (MCIU) [RTI2018-102084-B-I00 to F.S.C], the Carlos III Institute of
   Health [CPII14/00027 to E. L-P. and RD012/0042/0066 to P.G-P. and
   E.L-P.], and the Madrid Regional Government [2010-BMD-2321 "Fibroteam"
   to E.L-P.]. The study also received support from the Plan Estatal de I +
   D + I 2013-2016 -European Regional Development Fund (ERDF) "A way of
   making Europe," Spain. The CNIC is supported by the Instituto de Salud
   Carlos III (ISCIII), the Ministerio de Ciencia e Innovacion (MCIN), and
   the Pro CNIC Foundation.
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NR 46
TC 8
Z9 8
U1 0
U2 11
PU SPRINGER
PI NEW YORK
PA ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES
SN 1937-5387
EI 1937-5395
J9 J CARDIOVASC TRANSL
JI J. Cardiovasc. Transl. Res.
PD DEC
PY 2022
VL 15
IS 6
BP 1239
EP 1255
DI 10.1007/s12265-022-10244-x
EA MAR 2022
PG 17
WC Cardiac & Cardiovascular Systems; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Research & Experimental Medicine
GA 6U5HZ
UT WOS:000775982300001
PM 35355220
DA 2025-04-10
ER

PT J
AU Li, PP
   Qin, DX
   Chen, TE
   Hou, W
   Song, XY
   Yin, SM
   Song, MM
   Fernando, WCHA
   Chen, XJ
   Sun, Y
   Wang, JJ
AF Li, Pengpeng
   Qin, Dongxia
   Chen, Tiange
   Hou, Wei
   Song, Xinyu
   Yin, Shumin
   Song, Miaomiao
   Fernando, W. C. Hewith A.
   Chen, Xiaojie
   Sun, Yu
   Wang, Juejin
TI Dysregulated Rbfox2 produces aberrant splicing of CaV1.2
   calcium channel in diabetes-induced cardiac hypertrophy
SO CARDIOVASCULAR DIABETOLOGY
LA English
DT Article
DE Alternative splicing; Ca(V)1; 2 calcium channel; Diabetes; Cardiomyocyte
   hypertrophy
ID VARIANT SPECIFIC MODULATION; VASCULAR MYOGENIC TONE; GLYCATION
   END-PRODUCTS; HEART; EXPRESSION; CAV1.2; CARDIOMYOPATHY; BENIDIPINE;
   BLOCKER
AB BackgroundL-type Ca2+ channel Ca(V)1.2 is essential for cardiomyocyte excitation, contraction and gene transcription in the heart, and abnormal functions of cardiac Ca(V)1.2 channels are presented in diabetic cardiomyopathy. However, the underlying mechanisms are largely unclear. The functions of Ca(V)1.2 channels are subtly modulated by splicing factor-mediated alternative splicing (AS), but whether and how Ca(V)1.2 channels are alternatively spliced in diabetic heart remains unknown.MethodsDiabetic rat models were established by using high-fat diet in combination with low dose streptozotocin. Cardiac function and morphology were assessed by echocardiography and HE staining, respectively. Isolated neonatal rat ventricular myocytes (NRVMs) were used as a cell-based model. Cardiac Ca(V)1.2 channel functions were measured by whole-cell patch clamp, and intracellular Ca2+ concentration was monitored by using Fluo-4 AM.ResultsWe find that diabetic rats develop diastolic dysfunction and cardiac hypertrophy accompanied by an increased Ca(V)1.2 channel with alternative exon 9* (Ca(V)1.2(E9*)), but unchanged that with alternative exon 8/8a or exon 33. The splicing factor Rbfox2 expression is also increased in diabetic heart, presumably because of dominate-negative (DN) isoform. Unexpectedly, high glucose cannot induce the aberrant expressions of Ca(V)1.2 exon 9* and Rbfox2. But glycated serum (GS), the mimic of advanced glycation end-products (AGEs), upregulates Ca(V)1.2(E9*) channels proportion and downregulates Rbfox2 expression in NRVMs. By whole-cell patch clamp, we find GS application hyperpolarizes the current-voltage curve and window currents of cardiac Ca(V)1.2 channels. Moreover, GS treatment raises K+-triggered intracellular Ca2+ concentration ([Ca2+](i)), enlarges cell surface area of NRVMs and induces hypertrophic genes transcription. Consistently, siRNA-mediated knockdown of Rbfox2 in NRVMs upregulates Ca(V)1.2(E9*) channel, shifts Ca(V)1.2 window currents to hyperpolarization, increases [Ca2+](i) and induces cardiomyocyte hypertrophy.ConclusionsAGEs, not glucose, dysregulates Rbfox2 which thereby increases Ca(V)1.2(E9*) channels and hyperpolarizes channel window currents. These make the channels open at greater negative potentials and lead to increased [Ca2+](i) in cardiomyocytes, and finally induce cardiomyocyte hypertrophy in diabetes. Our work elucidates the underlying mechanisms for Ca(V)1.2 channel regulation in diabetic heart, and targeting Rbfox2 to reset the aberrantly spliced Ca(V)1.2 channel might be a promising therapeutic approach in diabetes-induced cardiac hypertrophy.
C1 [Li, Pengpeng; Qin, Dongxia; Chen, Tiange; Hou, Wei; Song, Xinyu; Yin, Shumin; Song, Miaomiao; Fernando, W. C. Hewith A.; Chen, Xiaojie; Sun, Yu; Wang, Juejin] Nanjing Med Univ, Collaborat Innovat Ctr Cardiovasc Dis Translat Med, Key Lab Targeted Intervent Cardiovasc Dis, Nanjing 211166, Jiangsu, Peoples R China.
   [Li, Pengpeng; Qin, Dongxia; Chen, Tiange; Hou, Wei; Song, Xinyu; Yin, Shumin; Song, Miaomiao; Fernando, W. C. Hewith A.; Chen, Xiaojie; Sun, Yu; Wang, Juejin] Nanjing Med Univ, Dept Physiol, Nanjing 211166, Jiangsu, Peoples R China.
C3 Nanjing Medical University; Nanjing Medical University
RP Sun, Y; Wang, JJ (corresponding author), Nanjing Med Univ, Collaborat Innovat Ctr Cardiovasc Dis Translat Med, Key Lab Targeted Intervent Cardiovasc Dis, Nanjing 211166, Jiangsu, Peoples R China.; Sun, Y; Wang, JJ (corresponding author), Nanjing Med Univ, Dept Physiol, Nanjing 211166, Jiangsu, Peoples R China.
EM sunyu716@njmu.edu.cn; juejinwang@njmu.edu.cn
RI Juejin, Wang/JAX-4081-2023; chen, yundai/I-4353-2019
OI Fernando, W.C. Hewith A./0000-0002-5533-5890
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NR 52
TC 4
Z9 4
U1 18
U2 27
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1475-2840
J9 CARDIOVASC DIABETOL
JI Cardiovasc. Diabetol.
PD JUL 6
PY 2023
VL 22
IS 1
AR 168
DI 10.1186/s12933-023-01894-5
PG 16
WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Endocrinology & Metabolism
GA L3QF1
UT WOS:001022431400001
PM 37415128
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Schmieg, N
   Thomas, C
   Yabe, A
   Lynch, DS
   Iglesias, T
   Chakravarty, P
   Schiavo, G
AF Schmieg, Nathalie
   Thomas, Claire
   Yabe, Arisa
   Lynch, David S.
   Iglesias, Teresa
   Chakravarty, Probir
   Schiavo, Giampietro
TI Novel Kidins220/ARMS Splice Isoforms: Potential Specific Regulators of
   Neuronal and Cardiovascular Development
SO PLOS ONE
LA English
DT Article
ID MEMBRANE-SPANNING PROTEIN; NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; SIGNALING
   PATHWAYS; MESSENGER-RNA; BDNF; NEUROTROPHIN; EXPRESSION; VEGF; GENE
AB Kidins220/ARMS is a transmembrane protein playing a crucial role in neuronal and cardiovascular development. Kidins220/ARMS is a downstream target of neurotrophin receptors and interacts with several signalling and trafficking factors. Through computational modelling, we found two potential sites for alternative splicing of Kidins220/ARMS. The first is located between exon 24 and exon 29, while the second site replaces exon 32 by a short alternative terminal exon 33. Here we describe the conserved occurrence of several Kidins220/ARMS splice isoforms at RNA and protein levels. Kidins220/ARMS splice isoforms display spatio-temporal regulation during development with distinct patterns in different neuronal populations. Neurotrophin receptor stimulation in cortical and hippocampal neurons and neuroendocrine cells induces specific Kidins220/ARMS splice isoforms and alters the appearance kinetics of the full-length transcript. Remarkably, alternative terminal exon splicing generates Kidins220/ARMS variants with distinct cellular localisation: Kidins220/ARMS containing exon 32 is targeted to the plasma membrane and neurite tips, whereas Kidins220/ARMS without exon 33 mainly clusters the full-length protein in a perinuclear intracellular compartment in PC12 cells and primary neurons, leading to a change in neurotrophin receptor expression. Overall, this study demonstrates the existence of novel Kidins220/ARMS splice isoforms with unique properties, revealing additional complexity in the functional regulation of neurotrophin receptors, and potentially other signalling pathways involved in neuronal and cardiovascular development.
C1 [Schmieg, Nathalie; Lynch, David S.; Schiavo, Giampietro] UCL, UCL Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, Mol Neuropathobiol Lab, London WC1N 3BG, England.
   [Schmieg, Nathalie; Thomas, Claire; Yabe, Arisa; Chakravarty, Probir] Francis Crick Inst, London WC2A 3LY, England.
   [Lynch, David S.] UCL, Leonard Wolfson Ctr Expt Neurol, London W1G 9LD, England.
   [Iglesias, Teresa] Inst Invest Biomed Alberto Sols CSIC UAM, Madrid 28029, Spain.
   [Iglesias, Teresa] CIBERNED ISCIII, Madrid 28031, Spain.
C3 University of London; University College London; Francis Crick
   Institute; University of London; University College London; Consejo
   Superior de Investigaciones Cientificas (CSIC); CSIC - Instituto de
   Investigaciones Biomedicas Alberto Sols (IIBM); CIBERNED
RP Schiavo, G (corresponding author), UCL, UCL Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, Mol Neuropathobiol Lab, London WC1N 3BG, England.
EM giampietro.schiavo@ucl.ac.uk
RI Vacas, Teresa/ABF-8663-2020; Lynch, David/KGM-0579-2024
OI Iglesias, Teresa/0000-0002-4326-9005; Lynch, David
   S/0000-0003-0615-7159; chakravarty, probir/0000-0003-1146-8824
FU Cancer Research UK [LF4605]; Sobell Department of Motor Neuroscience &
   Movement Disorders [6E8A]; Leonard Wolfson Centre for Experimental
   Neurology, University College London [6HCA]
FX This work was supported by Cancer Research UK (LF4605), NS, CT, AY and
   GS; Sobell Department of Motor Neuroscience & Movement Disorders (6E8A)
   GS; and Leonard Wolfson Centre for Experimental Neurology, University
   College London (6HCA) DSL.
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NR 44
TC 14
Z9 14
U1 0
U2 1
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD JUN 17
PY 2015
VL 10
IS 6
AR e0129944
DI 10.1371/journal.pone.0129944
PG 21
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA CK9NS
UT WOS:000356567400116
PM 26083449
OA Green Published, gold, Green Submitted
DA 2025-04-10
ER

PT J
AU Preussner, M
   Wilhelmi, I
   Schultz, AS
   Finkernagel, F
   Michel, M
   Möröy, T
   Heyd, F
AF Preussner, Marco
   Wilhelmi, Ilka
   Schultz, Astrid-Solveig
   Finkernagel, Florian
   Michel, Monika
   Moeroey, Tarik
   Heyd, Florian
TI Rhythmic U2af26 Alternative Splicing Controls PERIOD1 Stability
   and the Circadian Clock in Mice
SO MOLECULAR CELL
LA English
DT Article
ID DROSOPHILA CLOCK; MESSENGER-RNA; PHASE-SHIFTS; LIGHT; TIMELESS; PROTEIN;
   ENTRAINMENT; EXPRESSION; MECHANISM; TRANSLATION
AB The circadian clock drives daily rhythms in gene expression to control metabolism, behavior, and physiology; while the underlying transcriptional feedback loops are well defined, the impact of alternative splicing on circadian biology remains poorly understood. Here we describe a robust circadian and light-inducible splicing switch that changes the reading frame of the mouse mRNA encoding U2-auxiliary-factor 26 (U2AF26). This results in translation far into the 3' UTR, generating a C terminus with homology to the Drosophila clock regulator TIMELESS. This new U2AF26 variant destabilizes PERIOD1 protein, and U2AF26-deficient mice show nearly arrhythmic PERIOD1 protein levels and broad defects in circadian mRNA expression in peripheral clocks. At the behavioral level, these mice display increased phase advance adaptation following experimental jet lag. These data suggest light-induced U2af26 alternative splicing to be a buffering mechanism that limits PERIOD1 induction, thus stabilizing the circadian clock against abnormal changes in light: dark conditions.
C1 [Preussner, Marco; Wilhelmi, Ilka; Schultz, Astrid-Solveig; Finkernagel, Florian; Michel, Monika; Heyd, Florian] Univ Marburg, Inst Mol Biol & Tumor Res IMT, D-35032 Marburg, Germany.
   [Moeroey, Tarik] Inst Rech Clin Montreal, Montreal, PQ H2W 1R7, Canada.
C3 Philipps University Marburg; Universite de Montreal; Institut de
   Recherche Clinique de Montreal (IRCM)
RP Heyd, F (corresponding author), Free Univ Berlin, Inst Chem & Biochem, Takustr 6, D-14195 Berlin, Germany.
EM florian.heyd@fu-berlin.de
FU Emmy-Noether-Fellowship of the DFG [HE 5398/3-1]; University Hospital
   Giessen-Marburg (UKGM)
FX We thank Achim Kramer and Bert Maier (Humboldt University Berlin) for
   advice and helpful discussions, and Steve McKnight (UTSW, Dallas) for
   constructive comments on the manuscript. We also acknowledge Rolf Muller
   and Matthias Lauth (Philipps University Marburg) for sharing reagents;
   Ursula Koch and Elisabet Garcia-Pino (Free University Berlin) for help
   with SCN preparation; and Marie Hasselluhn for contributing as a
   rotation student. Work in F.H.'s lab is funded by an
   Emmy-Noether-Fellowship of the DFG (HE 5398/3-1); the present work was
   also supported by the University Hospital Giessen-Marburg (UKGM).
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NR 51
TC 55
Z9 61
U1 0
U2 20
PU CELL PRESS
PI CAMBRIDGE
PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA
SN 1097-2765
EI 1097-4164
J9 MOL CELL
JI Mol. Cell
PD MAY 22
PY 2014
VL 54
IS 4
BP 651
EP 662
DI 10.1016/j.molcel.2014.04.015
PG 12
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA AH8IJ
UT WOS:000336380900012
PM 24837677
OA Bronze
DA 2025-04-10
ER

PT J
AU Granzier, HL
   Labeit, S
AF Granzier, HL
   Labeit, S
TI The giant muscle protein titin is an adjustable molecular spring
SO EXERCISE AND SPORT SCIENCES REVIEWS
LA English
DT Review
DE titin; passive force; differential splicing; posttranslational
   modification; muscle mechanics; mechanosensing
ID RAT CARDIAC MYOCYTES; PASSIVE STIFFNESS; DILATED CARDIOMYOPATHY;
   SKELETAL-MUSCLE; EXPRESSION; ISOFORM; TENSION; MYOCARDIUM; MODULATION;
   CALCIUM
AB When muscles are stretched, the giant protein titin develops passive force. Titin's force performs important functions that include maintaining the structural integrity of the sarcomere and triggerng signal transduction pathways. We propose that the mechanical properties of titin can be tuned according to the mechanical demands placed on muscle, using mechanisms that include alternative splicing and posttranslational modifications.
C1 Washington State Univ, Dept Vet & Comparat Anat Pharmacol & Physiol, Pullman, WA 99164 USA.
   Univ Klinikum Mannheim, Inst Anasthesiol & Operat Intens Med, Mannheim, Germany.
C3 Washington State University; Ruprecht Karls University Heidelberg
RP Washington State Univ, Dept Vet & Comparat Anat Pharmacol & Physiol, Wegner Hall 205, Pullman, WA 99164 USA.
EM granzier@wsunix.wsu.edu
FU NHLBI NIH HHS [HL62881, HL61497] Funding Source: Medline
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NR 15
TC 54
Z9 73
U1 1
U2 14
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0091-6331
EI 1538-3008
J9 EXERC SPORT SCI REV
JI Exerc. Sport Sci. Rev.
PD APR
PY 2006
VL 34
IS 2
BP 50
EP 53
DI 10.1249/00003677-200604000-00002
PG 4
WC Physiology; Sport Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Physiology; Sport Sciences
GA 033RM
UT WOS:000236866700002
PM 16672800
OA Bronze
DA 2025-04-10
ER

PT J
AU Ogut, O
   Brozovich, FV
AF Ogut, Ozgur
   Brozovich, Frank V.
TI The potential role of MLC phosphatase and MAPK signalling in the
   pathogenesis of vascular dysfunction in heart failure
SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
LA English
DT Article
DE MYPT1; nitric oxide; smooth muscle; vasoconstriction; vasodilatation;
   angiotensin
ID LIGHT-CHAIN PHOSPHATASE; ACTIVATED PROTEIN-KINASE; ENDOTHELIUM-MEDIATED
   VASODILATION; AT1-TYPE ANGIOTENSIN RECEPTOR; SMOOTH-MUSCLE CONTRACTION;
   RHO-ASSOCIATED KINASE; MYOSIN PHOSPHATASE; NITRIC-OXIDE; OXIDATIVE
   STRESS; INCREASED SENSITIVITY
AB Clinical syndrome of heart failure
   Regulation of smooth muscle contractility
   Ca2+ sensitization
   Ca2+ desensitization
   MYPT1 isoforms and the sensitivity to cGMP
   cGMP and MYPT1 phosphorylation
   Vascular function and cGMP signalling
   Captopril therapy and MYPT1 Expression in HF
   Captopril therapy and gene expression
   Conclusions
   The clinical syndrome of heart failure is associated with both a resting vasoconstriction and reduced sensitivity to nitric oxide mediated vasodilatation, and this review will focus on the role of myosin light chain (MLC) phosphatase in the pathogenesis of the vascular abnormalities of heart failure. Nitric oxide mediates vasodilatation by an activation of guanylate cyclase and an increase in the production of cGMP, which leads to the activation of the type I cGMP-dependent protein kinase (PKGI). PKGI then activates a number of targets that produce smooth muscle relaxation including MLC phosphatase. MLC phosphatase is a holoenzyme consisting of three subunits; a 20 kD subunit of unknown function, an similar to 38-kD catalytic subunit and a myosin targeting subunit (MYPT1). Alternative splicing of a 31 bp 3' exon generates MYPT1 isoforms, which differ by a COOH-terminus leucine zipper (LZ). Further, PKGI-mediated activation of MLC phosphatase requires the expression of a LZ+ MYPT1. Congestive heart failure is associated with a decrease in LZ+ MYPT1 expression, which results in a decrease in the sensitivity to cGMP-mediated smooth muscle relaxation. Beyond their ability to reduce afterload, angiotensin converting enzyme (ACE) inhibitors have a number of beneficial effects that include maintaining the expression of the LZ+ MYPT1 isoform, thereby conserving normal sensitivity to cGMP-mediated vasodilatation, as well as differentially regulating genes associated with mitogen activated protein kinase (MAPK) signalling. ACE inhibition reduces circulating angiotensin II and thus limits the downstream activation of MAPK signalling pathways, possibly preventing the alteration of the vascular phenotype to preserve normal vascular function.
C1 [Ogut, Ozgur; Brozovich, Frank V.] Mayo Clin & Mayo Fdn, Mayo Med Sch, Div Cardiovasc Dis, Rochester, MN 55905 USA.
C3 Mayo Clinic
RP Brozovich, FV (corresponding author), Mayo Clin, 200 1st St SW, Rochester, MN 55905 USA.
EM brozovich.frank@mayo.edu
RI OGUT, OZGE/KHC-3887-2024
FU NIH [HL69894, HL64137, HL78845]
FX This study was supported by NIH grants HL69894 and HL64137 ( to F. V.
   B.) and HL78845 ( to O. O.).
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NR 80
TC 18
Z9 19
U1 0
U2 5
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1582-1838
EI 1582-4934
J9 J CELL MOL MED
JI J. Cell. Mol. Med.
PD DEC
PY 2008
VL 12
IS 6A
BP 2158
EP 2164
DI 10.1111/j.1582-4934.2008.00536.x
PG 7
WC Cell Biology; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Research & Experimental Medicine
GA 378OP
UT WOS:000261334100002
PM 19120700
OA Green Published, Green Accepted
DA 2025-04-10
ER

PT J
AU Jin, JP
   Wang, J
   Ogut, O
AF Jin, JP
   Wang, J
   Ogut, O
TI Developmentally regulated muscle type-specific alternative splicing of
   the COOH-terminal variable region of fast skeletal muscle troponin T and
   an aberrant splicing pathway to encode a mutant COOH-terminus
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
ID COMPLETE NUCLEOTIDE-SEQUENCE; HYPERTROPHIC CARDIOMYOPATHY; THIN
   FILAMENT; ALPHA-TROPOMYOSIN; ADULT ISOFORMS; EXPRESSION; GENE;
   MUTATIONS; BINDING; CONTRACTION
AB Distinct from the cardiac and slow skeletal muscle troponin Ts, an alternative RNA splicing-generated COOH-terminal variable region exists in the fast skeletal muscle troponin T. Mutually exclusive splicing of exon 16 and 17 encoded sequence into the mature mRNA produces the alpha- and beta-isoform, respectively. By cloning and sequence analysis of large numbers of fast troponin T cDNAs, we have quantitatively demonstrated that expression of the exon 16-encoded structure is mature fast muscle-specific (its utilization ranges from null in neonatal mouse muscles to 97% in adult chicken pectoralis), indicating a functional adaptation to the contractile feature of muscle. An aberrant splicing of this variable region to exclude both exons 16 and 17 from the mRNA was found in neonatal mouse skeletal muscle by cloning and sequencing characterization of a full length fTnT cDNA, The unusual splicing of exon 18 and exon 15 in the mRNA sequence results in not only a deletion of the exon 16/17 segment but also a shift of the downstream translation reading frame to produce a troponin T polypeptide with mutant COOH-terminus. Similar to an abnormal splicing of cardiac troponin T caused by cis-mutation and a dominant allele causing human familial hypertrophic cardiomyopathy, this trans-factor-determined aberrant mRNA splicing pathway generates a truncated troponin T molecule lacking the developmentally regulated fast muscle-specific COOH-terminal domain, indicating potential etiopathological significance. (C) 1998 Academic Press.
C1 Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA.
C3 University System of Ohio; Case Western Reserve University
RP Jin, JP (corresponding author), Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, 10900 Euclid Ave, Cleveland, OH 44106 USA.
RI Jin, Jian-Ping/AAD-1149-2020
OI Jin, JP/0000-0001-9932-1063
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NR 24
TC 21
Z9 23
U1 0
U2 1
PU ACADEMIC PRESS INC
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD JAN 26
PY 1998
VL 242
IS 3
BP 540
EP 544
DI 10.1006/bbrc.1997.8006
PG 5
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA YV444
UT WOS:000071824800015
PM 9464252
DA 2025-04-10
ER

PT J
AU Farza, H
   Townsend, PJ
   Carrier, L
   Barton, PJ
   Mesnard, L
   Bährend, E
   Forissier, JF
   Fiszman, M
   Yacoub, MH
   Schwartz, K
AF Farza, H
   Townsend, PJ
   Carrier, L
   Barton, PJ
   Mesnard, L
   Bährend, E
   Forissier, JF
   Fiszman, M
   Yacoub, MH
   Schwartz, K
TI Genomic organisation, alternative splicing and polymorphisms of the
   human cardiac troponin T gene
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Article
DE human cardiac troponin T; gene structure; polymorphisms; sequence;
   alternative splicing
ID FAILING HEART; NUCLEOTIDE-SEQUENCE; ISOFORMS; EXPRESSION; TRANSCRIPTION;
   CLONING; ADULT
AB Troponin T (TnT) is a component of the troponin complex which regulates muscle contraction in response to alterations in intracellular calcium ion concentration. In human heart, multiple isoforms of cardiac TnT have been described on the basis of antibody studies and molecular cloning of corresponding cDNAs, These isoforms are all derived from the transcription of a single gene, TNNT2, located on chromosome 1q32, and generated by alternative splicing, We show here that isoform diversity is achieved by the use of both alternative exons and alternative acceptor sites and present the organisation of the human TN.RITZ gene, which is composed of 17 exons spread over 17 kb. A potential structure of the promoter region is also presented, Several polymorphisms in both the exonic and intronic regions were identified, some of which may act as modulators of the expression of this gene, (C) 1998 Academic Press.
C1 Grp Hosp Pitie Salpetriere, INSERM, Unite Rech 153, F-75634 Paris, France.
   Hop Marie Lannelongue, CNRS, URA 1159, F-92350 Le Plessis Robinson, France.
   Univ London Imperial Coll Sci Technol & Med, Sch Med, NHLI, London, England.
C3 Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire
   Pitie-Salpetriere - APHP; Sorbonne Universite; Institut National de la
   Sante et de la Recherche Medicale (Inserm); Hopital Marie Lannelongue;
   Centre National de la Recherche Scientifique (CNRS); Imperial College
   London
RP Farza, H (corresponding author), Univ Oxford, Inst Mol Med, Dept Cardiovasc Med, Room 266, Oxford OX3 9DS, England.
OI Barton, Paul Jeremy Richard/0000-0002-1165-7767
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NR 18
TC 38
Z9 42
U1 0
U2 5
PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
PI LONDON
PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD JUN
PY 1998
VL 30
IS 6
BP 1247
EP 1253
DI 10.1006/jmcc.1998.0698
PG 7
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA 101GD
UT WOS:000074860500017
PM 9689598
DA 2025-04-10
ER

PT J
AU Jin, JP
   Wang, J
   Zhang, JY
AF Jin, JP
   Wang, J
   Zhang, JY
TI Expression of cDNAs encoding mouse cardiac troponin T isoforms:
   Characterization of a large sample of independent clones
SO GENE
LA English
DT Article
DE nucleotide sequences; gene expression; heart development; mRNA
   alternative splicing
ID COMPLETE NUCLEOTIDE-SEQUENCE; RABBIT SKELETAL-MUSCLE; ADULT ISOFORMS;
   GENE; EXON; TROPOMYOSIN; FRAGMENTS; BINDING; CONTRACTION; HEART
AB We have isolated 52 mouse cardiac troponin-Tr-encoding cDNA clones (TnT) by specific antibody screening of a lambda ZAPII expression library. Sequencing data from the large sample of independent cDNAs demonstrated relationships among the expression of four alternatively-spliced exons of the cardiac TnT gene, producing seven classes of cDNAs encoding four protein isoforms differing in two variable regions. In the N-terminal variable region and next to the embryonic-specific exon 4, an alternatively spliced exon 3a was identified in 20% of the adult isoforms. The alternatively spliced exon 12, corresponding to a central variable, region between the two functional domains of TnT, was found in approx. 79% of the 52 mouse cardiac TnT cDNAs with a single base mutation completely abolishing the splicing at an internal acceptor site. Three novel alternative splicing acceptor sites in the 5'-untranslated portion of exon 2 have been identified with different frequencies.
RP Jin, JP (corresponding author), UNIV CALGARY,FAC MED,DEPT MED BIOCHEM,3330 HOSP DR NW,CALGARY,AB T2N 4N1,CANADA.
RI Jin, Jian-Ping/AAD-1149-2020
OI Jin, JP/0000-0001-9932-1063
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NR 27
TC 47
Z9 54
U1 0
U2 3
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0378-1119
J9 GENE
JI Gene
PD FEB 12
PY 1996
VL 168
IS 2
BP 217
EP 221
DI 10.1016/0378-1119(95)00803-9
PG 5
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA TW664
UT WOS:A1996TW66400016
PM 8654947
DA 2025-04-10
ER

PT J
AU Belanger, K
   Nutter, CA
   Li, J
   Yu, P
   Kuyumcu-Martinez, MN
AF Belanger, KarryAnne
   Nutter, Curtis A.
   Li, Jin
   Yu, Peng
   Kuyumcu-Martinez, Muge N.
TI A developmentally regulated spliced variant of PTBP1 is upregulated in
   type 1 diabetic hearts
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE Diabetic heart; PTBP1; Alternative splicing; RNA binding proteins
ID TRACT BINDING-PROTEIN; PRE-MESSENGER-RNA; ANTAGONISTIC REGULATION;
   CARDIAC-HYPERTROPHY; EXON 6B; CELF; REPRESSION; EXPRESSION; MBNL;
   PATHOGENESIS
AB Alternative splicing (AS) is dysregulated in Type 1 diabetic (T1D) hearts but mechanisms responsible are unclear. Here, we provide evidence that the RNA binding protein (RBP) PIBP1 is modulated in adult T1D hearts contributing to AS changes. We show that a spliced variant of PTBP1 that is highly expressed in normal newborn mouse hearts is aberrantly expressed in adult T1D mouse hearts. Comparing known PTBP1-target datasets to our T1D mouse transcriptome datasets, we discovered a group of genes with PTBP1 binding sites in their pre-mRNAs that are differentially spliced in T1D mouse hearts. We demonstrated that inducible expression of diabetes-induced PTBP1 spliced variant has less repressive splicing function. Notably, PTBP1 regulates AS of some of its targets antagonistically to RBFOX2. In sum, our results indicate that diabetic conditions disrupt developmental regulation of PTBP1 leading to differential AS of PTBP1 target genes. Identification of PTBP1 and PTBP1-regulated RNA networks can provide RNA-based therapies for the treatment of diabetes cardiac complications. (C) 2018 Elsevier Inc. All rights reserved.
C1 [Belanger, KarryAnne; Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA.
   [Nutter, Curtis A.] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Ctr NeuroGenet, Gainesville, FL 32610 USA.
   [Nutter, Curtis A.] Univ Florida, Coll Med, Genet Inst, Gainesville, FL 32610 USA.
   [Li, Jin; Yu, Peng] Texas A&M Univ, Dept Elect & Comp Engn, College Stn, TX 77843 USA.
   [Li, Jin; Yu, Peng] Texas A&M Univ, TEES AgriLife Ctr Bioinformat & Genom Syst Engn, College Stn, TX 77843 USA.
   [Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Dept Neurosci Cell Biol & Anat, Galveston, TX 77555 USA.
   [Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Inst Translat Sci, Galveston, TX 77555 USA.
C3 University of Texas System; University of Texas Medical Branch
   Galveston; State University System of Florida; University of Florida;
   State University System of Florida; University of Florida; Texas A&M
   University System; Texas A&M University College Station; Texas A&M
   University System; Texas A&M University College Station; University of
   Texas System; University of Texas Medical Branch Galveston; University
   of Texas System; University of Texas Medical Branch Galveston
RP Kuyumcu-Martinez, MN (corresponding author), Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA.
EM nmmartin@utmb.edu
RI Li, Jin/GOH-1431-2022
OI Kuyumcu-Martinez, Muge N./0000-0003-3171-5861
FU American Heart Association [15GRNT22830010]; UTMB Department of
   Biochemistry and Molecular Biology Bridging funds; National Institutes
   of Health/National Heart Lung Blood Institute [1R01HL135031]; ECE
   department; Texas A&M Engineering Experiment Station/Dwight Look College
   of Engineering at Texas AM University; TEES-AgriLife Center for
   Bioinformatics and Genomic Systems Engineering (CBGSE) at Texas AM
   University; TEES seed grant; Texas A&M University-CAPES Research Grant
   Program; American Heart Association (AHA) [15GRNT22830010] Funding
   Source: American Heart Association (AHA)
FX We thank Dr. Mariano Garcia-Blanco for providing the PTBP1 antibody and
   Flp-in T-REx 293 cells. We thank Dr. Benjamin J. Blencowe for the Triple
   flag-tagged human PTBP1+ex9 and human PTBP1 Delta ex9 pcDNA5/FRT/TO
   expression vectors. This work was supported, in part, by an American
   Heart Association Grant [15GRNT22830010]; UTMB Department of
   Biochemistry and Molecular Biology Bridging funds; and a grant from the
   National Institutes of Health/National Heart Lung Blood Institute
   [1R01HL135031] to M.N.K-M. The contents of the manuscript are solely the
   responsibility of the authors and do not necessarily represent the
   official views of NHLBI of NIH. This work was also supported by startup
   funding to P.Y. from the ECE department and Texas A&M Engineering
   Experiment Station/Dwight Look College of Engineering at Texas A&M
   University; by funding from TEES-AgriLife Center for Bioinformatics and
   Genomic Systems Engineering (CBGSE) at Texas A&M University, by TEES
   seed grant; and by Texas A&M University-CAPES Research Grant Program.
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NR 43
TC 11
Z9 12
U1 1
U2 10
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD FEB 5
PY 2019
VL 509
IS 2
BP 384
EP 389
DI 10.1016/j.bbrc.2018.12.150
PG 6
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA HK6MM
UT WOS:000458094800010
PM 30594394
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Huang, QQ
   Chen, AH
   Jin, JP
AF Huang, QQ
   Chen, AH
   Jin, JP
TI Genomic sequence and structural organization of mouse slow skeletal
   muscle troponin T gene
SO GENE
LA English
DT Article
DE alternative RNA splicing; DNA cloning; exon evolution; TnT isoforms
ID COMPLETE NUCLEOTIDE-SEQUENCE; RAPID PURIFICATION; CA2+ SENSITIVITY;
   ADULT ISOFORMS; SINGLE-GENE; TROPOMYOSIN; EXPRESSION; EXON; RAT;
   CONTRACTION
AB Three muscle type-specific troponin T (TnT) genes are present in vertebrate to encode a number of protein isoforms via alternative mRNA splicing. While the genomic structures of cardiac and fast skeletal muscle TnT genes have been documented, this study cloned and characterized the slow skeletal muscle TnT (sTnT) gene. Complete nucleotide sequence and genomic organization revealed that the mouse sTnT gene spans 11.1 kb and contains 14 exons, which is smaller and simpler than the fast skeletal muscle and cardiac TnT genes. Potentially representing a prototype of the TnT gene family, the 5'-region of the sTnT gene contains fewer unsplit large exons, among which two alternatively spliced exons are responsible for the NH2-terminal variation of three sTnT isoforms. The sTnT gene structure shows that the alternatively spliced central segment found in human sTnT cDNAs may be a result from splicing using an alternative acceptor site at the intron Il-exon 12 boundary. Together with the well-conserved protein structure, the highly specific expression of sTnT in slow skeletal muscles indicates a differentiated function of this member of the TnT gene family. The determination of genomic structure and alternative splicing pathways of sTnT gene lays a foundation to further understand the TnT structure-function evolution as well as contractile characteristics of different types of muscle fiber. (C) 1999 Elsevier Science B.V. All rights reserved.
C1 Case Western Reserve Univ, Sch Med, Dept Phys & Biophys, Cleveland, OH 44106 USA.
C3 University System of Ohio; Case Western Reserve University
RP Case Western Reserve Univ, Sch Med, Dept Phys & Biophys, 10900 Euclid Ave, Cleveland, OH 44106 USA.
EM jxj12@po.cwru.edu
RI Jin, Jian-Ping/AAD-1149-2020
OI Jin, JP/0000-0001-9932-1063
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NR 30
TC 47
Z9 50
U1 0
U2 0
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0378-1119
EI 1879-0038
J9 GENE
JI Gene
PD MAR 18
PY 1999
VL 229
IS 1-2
BP 1
EP 10
DI 10.1016/S0378-1119(99)00051-7
PG 10
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 179XP
UT WOS:000079355600001
PM 10095098
DA 2025-04-10
ER

PT J
AU Bebee, TW
   Sims-Lucas, S
   Park, JW
   Bushnell, D
   Cieply, B
   Xing, Y
   Bates, CM
   Carstens, RP
AF Bebee, Thomas W.
   Sims-Lucas, Sunder
   Park, Juw Won
   Bushnell, Daniel
   Cieply, Benjamin
   Xing, Yi
   Bates, Carlton M.
   Carstens, Russ P.
TI Ablation of the Epithelial-specific Splicing Factor Esrp1 Results in
   Ureteric Branching Defects and Reduced Nephron Number
SO DEVELOPMENTAL DYNAMICS
LA English
DT Article
DE alternative splicing; kidney development; fibroblast growth factor
   receptors; epithelial splicing regulatory proteins
ID FACTOR RECEPTOR 2; ENTERIC NERVOUS-SYSTEM; MICE LACKING GDNF; KIDNEY
   DEVELOPMENT; MESENCHYMAL TRANSITION; REGULATORY NETWORK;
   GENE-EXPRESSION; GROWTH; BUD; MORPHOGENESIS
AB Background: Abnormalities in ureteric bud (UB) branching morphogenesis lead to congenital anomalies of the kidney and reduced nephron numbers associated with chronic kidney disease (CKD) and hypertension. Previous studies showed that the epithelial fibroblast growth factor receptor 2 (Fgfr2) IIIb splice variant supports ureteric morphogenesis in response to ligands from the metanephric mesenchyme during renal organogenesis. The epithelial-specific splicing regulator Esrp1 is required for expression of Fgfr2-IIIb and other epithelial-specific splice variants. Our objective was to determine whether Esrp1 is required for normal kidney development. Results: Ablation of Esrp1 in mice, alone or together with its paralog Esrp2, was associated with reduced kidney size and increased incidence of renal aplasia. Three-dimensional imaging showed that embryonic Esrp1 knockout (KO) kidneys had fewer ureteric tips and reduced nephron numbers. Analysis of alternative splicing in Esrp-null ureteric epithelial cells by RNA-Seq confirmed a splicing switch in Fgfr2 as well as numerous other transcripts. Conclusions: Our findings reveal that Esrp1-regulated splicing in ureteric epithelial cells plays an important role in renal development. Defects in Esrp1 KO kidneys likely reflect reduced and/or absent ureteric branching, leading to decreased nephron induction secondary to incorrect Fgfr2 splicing and other splicing alterations. (C) 2016 The Authors. Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.
C1 [Bebee, Thomas W.; Cieply, Benjamin; Carstens, Russ P.] Univ Penn, Dept Med, Div Renal, Perelman Sch Med, Philadelphia, PA 19104 USA.
   [Sims-Lucas, Sunder; Bushnell, Daniel; Bates, Carlton M.] Univ Pittsburgh, Sch Med, Dept Pediat, Div Nephrol, Pittsburgh, PA 15261 USA.
   [Park, Juw Won] Univ Louisville, Dept Comp Engn & Comp Sci, KBRIN Bioinformat Core, Louisville, KY 40292 USA.
   [Xing, Yi] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA.
   [Bates, Carlton M.] UPMC, Rangos Res Ctr, Childrens Hosp Pittsburgh, Pittsburgh, PA USA.
   [Carstens, Russ P.] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA.
C3 University of Pennsylvania; Pennsylvania Commonwealth System of Higher
   Education (PCSHE); University of Pittsburgh; University of Louisville;
   University of California System; University of California Los Angeles;
   Pennsylvania Commonwealth System of Higher Education (PCSHE); University
   of Pittsburgh; University of Pennsylvania
RP Carstens, RP (corresponding author), 575 CRB,415 Curie Blvd, Philadelphia, PA 19104 USA.; Bates, CM (corresponding author), 4401 Penn Ave,3rd Floor, Pittsburgh, PA 15224 USA.
EM batescm@upmc.edu; russcars@upenn.edu
RI Xing, yi/E-2884-2010; Sims-Lucas, Sunder/ADM-2975-2022
OI Carstens, Russ/0000-0002-8083-0412
FU Pittsburgh O'Brien Center P30 [DK079307]; RPC [R01-GM088809,
   R56-DK097257];  [T32-DK700638];  [F32-DK098917];  [K01-DK096996]; 
   [R01-DK095748]
FX Grant sponsor: TWB; Grant numbers: T32-DK700638 and F32-DK098917; Grant
   sponsor: SSL; Grant number: K01-DK096996; Grant sponsor: CMB; Grant
   number: R01-DK095748; Grant sponsor: Pittsburgh O'Brien Center P30;
   Grant number: DK079307; Grant sponsor: RPC; Grant numbers: R01-GM088809
   and R56-DK097257.
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NR 49
TC 16
Z9 18
U1 0
U2 2
PU WILEY-BLACKWELL
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1058-8388
EI 1097-0177
J9 DEV DYNAM
JI Dev. Dyn.
PD OCT
PY 2016
VL 245
IS 10
BP 991
EP 1000
DI 10.1002/DVDY.24431
PG 10
WC Anatomy & Morphology; Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Anatomy & Morphology; Developmental Biology
GA DX9YI
UT WOS:000384752700002
PM 27404344
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Lu, SJ
   Borst, DE
   Horowits, R
AF Lu, Shajia
   Borst, Diane E.
   Horowits, Robert
TI Expression and Alternative Splicing of N-RAP During Mouse Skeletal
   Muscle Development
SO CELL MOTILITY AND THE CYTOSKELETON
LA English
DT Article
DE myofibrillogenesis; myotube; sarcomere
ID CULTURED CHICK CARDIOMYOCYTES; NEBULIN-RELATED PROTEIN; TIME
   QUANTITATIVE PCR; STRIATED-MUSCLE; LIM PROTEIN; CARDIAC
   MYOFIBRILLOGENESIS; MYOTONIC-DYSTROPHY; GENE-EXPRESSION; PRECARDIAC
   MESODERM; INTERCALATED DISKS
AB N-RAP alternative splicing and protein localization were studied in developing skeletal Muscle tissue from pre- and postnatal mice and in fusing primary myotubes in Culture. Messages encoding N-RAP-s and N-RAP-c, the predominant isoforms of N-RAP detected in adult skeletal muscle and heart, respectively, were present in a 5:1 ratio in skeletal muscle isolated from E16.5 embryos. N-RAP-s mRNA levels increased three-fold over the first 3 weeks of postnatal development, while N-RAP-c mRNA levels remained low. N-RAP alternative splicing during myotube differentiation in culture was similar to the pattern observed in embryonic and neonatal muscle, with N-RAP-s expression increasing and N-RAP-c mRNA levels remaining low. In both developing skeletal muscle and cultured myotubes, N-RAP protein was primarily associated with developing myofibrillar structures containing alpha-actinin, but was not present in mature myofibrils. The results establish that N-RAP-s is the predominant spliced form of N-RAP present throughout skeletal muscle development. Cell Motil. Cytoskeleton 65: 945-954, 2008. Published 2008 Wiley-Liss, Inc.
C1 [Lu, Shajia; Horowits, Robert] NIAMSD, Muscle Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA.
   [Borst, Diane E.] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Institute of
   Arthritis & Musculoskeletal & Skin Diseases (NIAMS); Uniformed Services
   University of the Health Sciences - USA
RP Horowits, R (corresponding author), NIAMSD, Muscle Biol Lab, NIH, Dept Hlth & Human Serv, Bldg 50,Room 1154,MSC 8024, Bethesda, MD 20892 USA.
EM horowits@helix.nih.gov
FU Uniformed Services University of the Health Sciences [CO70VY]
FX Contracct grant sponsor: Uniformed Services University of the Health
   Sciences; Contract grant number: CO70VY.
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NR 36
TC 18
Z9 22
U1 1
U2 4
PU WILEY-LISS
PI HOBOKEN
PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA
SN 0886-1544
J9 CELL MOTIL CYTOSKEL
JI Cell Motil. Cytoskeleton
PD DEC
PY 2008
VL 65
IS 12
BP 945
EP 954
DI 10.1002/cm.20317
PG 10
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 381UT
UT WOS:000261562100003
PM 18792955
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Shen, JZ
   Shentu, JQ
   Zhong, CM
   Huang, QK
   Duan, SW
AF Shen, Jinze
   Shentu, Jianqiao
   Zhong, Chenming
   Huang, Qiankai
   Duan, Shiwei
TI RNA splicing factor RBFOX2 is a key factor in the progression of cancer
   and cardiomyopathy
SO CLINICAL AND TRANSLATIONAL MEDICINE
LA English
DT Review
DE alternative splicing; pre-mRNA; RBFOX2; therapeutic targeting
ID CA(V)1.2 CALCIUM-CHANNEL; REGULATOR RBFOX2; IN-VITRO; BINDING; ISOFORM;
   EXPRESSION; MUSCLE; ACTIVATION; FOX-1; AUTOREGULATION
AB BackgroundAlternative splicing of pre-mRNA is a fundamental regulatory process in multicellular eukaryotes, significantly contributing to the diversification of the human proteome. RNA-binding fox-1 homologue 2 (RBFOX2), a member of the evolutionarily conserved RBFOX family, has emerged as a critical splicing regulator, playing a pivotal role in the alternative splicing of pre-mRNA. This review provides a comprehensive analysis of RBFOX2, elucidating its splicing activity through direct and indirect binding mechanisms. RBFOX2 exerts substantial influence over the alternative splicing of numerous transcripts, thereby shaping essential cellular processes such as differentiation and development.Main body of the abstractDysregulation of RBFOX2-mediated alternative splicing has been closely linked to a spectrum of cardiovascular diseases and malignant tumours, underscoring its potential as a therapeutic target. Despite significant progress, current research faces notable challenges. The complete structural characterisation of RBFOX2 remains elusive, limiting in-depth exploration beyond its RNA-recognition motif. Furthermore, the scarcity of studies focusing on RBFOX2-targeting drugs poses a hindrance to translating research findings into clinical applications.ConclusionThis review critically assesses the existing body of knowledge on RBFOX2, highlighting research gaps and limitations. By delineating these areas, this analysis not only serves as a foundational reference for future studies but also provides strategic insights for bridging these gaps. Addressing these challenges will be instrumental in unlocking the full therapeutic potential of RBFOX2, paving the way for innovative and effective treatments in various diseases.
   RNA-binding fox-1 homologue 2 (RBFOX2) binds to RNA, influencing splicing and recruiting PRC2 for transcriptional repression. RBFOX2 impacts electromyographic signalling, L-type Ca2+ channels, sliding filaments and mitochondria. RBFOX2 is involved in tumour cell proliferation, invasion, migration and drug resistance. Targeting RBFOX2 with compounds, such as T-1101 tosylate and RNA-PROTACs, shows promise for treating related diseases. CTD, C-terminal domain; PRC2, polycomb repressive complex 2; PROTAC, proteolysis-targeting chimeras; RRM, RNA-recognition motif. Created with BioRender.com. image
C1 [Shen, Jinze; Shentu, Jianqiao; Huang, Qiankai; Duan, Shiwei] Hangzhou City Univ, Sch Med, Key Lab Novel Targets & Drug Study Neural Repair Z, Hangzhou, Peoples R China.
   [Zhong, Chenming] Ningbo Univ, Med Genet Ctr, Sch Med, Ningbo, Peoples R China.
C3 Hangzhou City University; Ningbo University
RP Duan, SW (corresponding author), Hangzhou City Univ, Sch Med, Key Lab Novel Targets & Drug Study Neural Repair Z, Hangzhou, Peoples R China.
EM duansw@hzcu.edu.cn
RI 沈, 锦泽/IQV-5094-2023; Duan, Shiwei/AAA-4782-2022
OI Duan, Shiwei/0000-0001-7682-2877
FU Qiantang Scholars Fund in Hangzhou City University;  [210000-581835]
FX The authors would like to express their sincere gratitude for the
   support provided by the Qiantang Scholars Fund in Hangzhou City
   University (grant no. 210000-581835) for this study.
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NR 127
TC 1
Z9 1
U1 5
U2 6
PU JOHN WILEY & SONS LTD
PI CHICHESTER
PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND
SN 2001-1326
J9 CLIN TRANSL MED
JI Clin. Transl. Med.
PD SEP
PY 2024
VL 14
IS 9
AR e1788
DI 10.1002/ctm2.1788
PG 23
WC Oncology; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Research & Experimental Medicine
GA F0C0J
UT WOS:001306575900001
PM 39243148
OA gold
DA 2025-04-10
ER

PT J
AU Le Sénéchal, R
   Keruzoré, M
   Quillévéré, A
   Loaëc, N
   Dinh, V
   Reznichenko, O
   Guixens-Gallardo, P
   Corcos, L
   Teulade-Fichou, MP
   Granzhan, A
   Blondel, M
AF Le Senechal, Ronan
   Keruzore, Marc
   Quillevere, Alicia
   Loaec, Nadege
   Dinh, Van-Trang
   Reznichenko, Oksana
   Guixens-Gallardo, Pedro
   Corcos, Laurent
   Teulade-Fichou, Marie-Paule
   Granzhan, Anton
   Blondel, Marc
TI Alternative splicing of BCL-x is controlled by RBM25 binding to a
   G-quadruplex in BCL-x pre-mRNA
SO NUCLEIC ACIDS RESEARCH
LA English
DT Article
ID CELL-CYCLE CONTROL; PROTEIN; APOPTOSIS; DNA; IDENTIFICATION; SITE;
   OLIGONUCLEOTIDES; RECOGNITION; COMPOUND; MODULATE
AB BCL-x is a master regulator of apoptosis whose pre-mRNA is alternatively spliced into either a long (canonical) anti-apoptotic Bcl-xL isoform, or a short (alternative) pro-apoptotic Bcl-xS isoform. The balance between these two antagonistic isoforms is tightly regulated and overexpression of Bcl-xL has been linked to resistance to chemotherapy in several cancers, whereas overexpression of Bcl-xS is associated to some forms of diabetes and cardiac disorders. The splicing factor RBM25 controls alternative splicing of BCL-x: its overexpression favours the production of Bcl-xS, whereas its downregulation has the opposite effect. Here we show that RBM25 directly and specifically binds to GQ-2, an RNA G-quadruplex (rG4) of BCL-x pre-mRNA that forms at the vicinity of the alternative 5 ' splice site leading to the alternative Bcl-xS isoform. This RBM25/rG4 interaction is crucial for the production of Bcl-xS and depends on the RE (arginine-glutamate-rich) motif of RBM25, thus defining a new type of rG4-interacting domain. PhenDC3, a benchmark G4 ligand, enhances the binding of RBM25 to the GQ-2 rG4 of BCL-x pre-mRNA, thereby promoting the alternative pro-apoptotic Bcl-xS isoform and triggering apoptosis. Furthermore, the screening of a combinatorial library of 90 putative G4 ligands led to the identification of two original compounds, PhenDH8 and PhenDH9, superior to PhenDC3 in promoting the Bcl-xS isoform and apoptosis. Thus, favouring the interaction between RBM25 and the GQ-2 rG4 of BCL-x pre-mRNA represents a relevant intervention point to re-sensitize cancer cells to chemotherapy.
   Graphical Abstract
C1 [Le Senechal, Ronan; Keruzore, Marc; Quillevere, Alicia; Loaec, Nadege; Dinh, Van-Trang; Corcos, Laurent; Blondel, Marc] Univ Brest, Hop Morvan, Inserm UMR1078, Etab Francais Sang EFS Bretagne,CHRU Brest,Lab Gen, 22 Ave Camille Desmoulins, F-29200 Brest, France.
   [Reznichenko, Oksana; Guixens-Gallardo, Pedro; Teulade-Fichou, Marie-Paule; Granzhan, Anton] Univ Paris Saclay, Inst Curie, Chem & Modelling Biol Canc CMBC, CNRS UMR9187,Inserm U1196, F-91405 Orsay, France.
C3 Universite de Bretagne Occidentale; CHU Brest; Institut National de la
   Sante et de la Recherche Medicale (Inserm); UNICANCER; Universite PSL;
   Institut Curie; Universite Paris Saclay; Institut National de la Sante
   et de la Recherche Medicale (Inserm); Centre National de la Recherche
   Scientifique (CNRS); CNRS - Institute of Chemistry (INC)
RP Blondel, M (corresponding author), Univ Brest, Hop Morvan, Inserm UMR1078, Etab Francais Sang EFS Bretagne,CHRU Brest,Lab Gen, 22 Ave Camille Desmoulins, F-29200 Brest, France.
EM marc.blondel@univ-brest.fr
RI ; Blondel, Marc/AAJ-9049-2020; Corcos, Laurent/K-1859-2015; Granzhan,
   Anton/A-7492-2008
OI Le Senechal, Ronan/0009-0005-5674-4273; Loaec,
   Nadege/0000-0001-5567-0210; Dinh, Van Trang/0000-0002-6010-718X;
   Blondel, Marc/0000-0003-4897-2995; Corcos, Laurent/0000-0001-8019-2505;
   Teulade-Fichou, Marie-Paule/0000-0002-2053-7513; Granzhan,
   Anton/0000-0002-0424-0461; Quillevere, Alicia/0000-0002-4963-1941;
   KERUZORE, Marc/0009-0006-2030-8872
FU We thank Rodrigo Prado Martins (INRAe, Nouzilly) for valuable
   discussions and critical proofreading of the manuscript and Laurent
   Maillet and Philippe Juin (Inserm Nantes) for valuable discussions and
   the kind gift of the Bcl-x null cell line.
FX We thank Rodrigo Prado Martins (INRAe, Nouzilly) for valuable
   discussions and critical proofreading of the manuscript and Laurent
   Maillet and Philippe Juin (Inserm Nantes) for valuable discussions and
   the kind gift of the Bcl-x null cell line.
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NR 81
TC 7
Z9 7
U1 3
U2 12
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0305-1048
EI 1362-4962
J9 NUCLEIC ACIDS RES
JI Nucleic Acids Res.
PD NOV 10
PY 2023
VL 51
IS 20
BP 11239
EP 11257
DI 10.1093/nar/gkad772
EA OCT 2023
PG 19
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA X7ST1
UT WOS:001077593500001
PM 37811881
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Babini, E
   Paukert, M
   Geisler, HS
   Gründer, S
AF Babini, E
   Paukert, M
   Geisler, HS
   Gründer, S
TI Alternative splicing and interaction with di- and polyvalent cations
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SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID EXTRACELLULAR CALCIUM; SODIUM-CHANNEL; POTASSIUM CHANGES; NEURONS;
   RECEPTOR; ISCHEMIA; POTENTIATION; POLYAMINES; SENSATION; RELEASE
AB Homomeric acid-sensing ion channel 1 (ASIC1) can be activated by extracellular H+ in the physiological pH range and may, therefore, contribute to neurotransmission and peripheral pain perception. ASIC1a and ASIC1b are alternative splice products of the ASIC1 gene. Here we show that both splice variants show steady-state inactivation when exposed to slightly decreased pH, limiting their operational range. Compared with ASIC1a, steady-state inactivation and pH activation of ASIC1b are shifted to more acidic values by 0.25 and 0.7 pH units, respectively, extending the dynamic range of ASIC1. Shifts of inactivation and activation are intimately linked; only two amino acids in the ectodomain, which are exchanged by alternative splicing, control both properties. Moreover, we show that extracellular, divalent cations like Ca2+ and Mg2+ as well as the polyvalent cation spermine shift the steady-state inactivation of ASIC1a and ASIC1b to more acidic values. This leads to a potentiation of the channel response and is due to a stabilization of the resting state. Our results indicate that ASIC1b is an effective sensor of transient H+ signals during slight acidosis and that, in addition to alternative splicing, interaction with di- and polyvalent cations extends the dynamic range of ASIC H+ sensors.
C1 Res Grp Sensory Physiol, Dept Otolaryngol, D-72076 Tubingen, Germany.
RP Gründer, S (corresponding author), Res Grp Sensory Physiol, Dept Otolaryngol, D-72076 Tubingen, Germany.
RI Gründer, Stefan/I-2495-2019
OI Grunder, Stefan/0000-0002-7635-9883
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NR 32
TC 189
Z9 212
U1 0
U2 5
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
SN 0021-9258
J9 J BIOL CHEM
JI J. Biol. Chem.
PD NOV 1
PY 2002
VL 277
IS 44
BP 41597
EP 41603
DI 10.1074/jbc.M205877200
PG 7
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 610WR
UT WOS:000178985300039
PM 12198124
OA hybrid
DA 2025-04-10
ER

PT J
AU Shkreta, L
   Delannoy, A
   Salvetti, A
   Chabot, B
AF Shkreta, Lulzim
   Delannoy, Aurelie
   Salvetti, Anna
   Chabot, Benoit
TI SRSF10: an atypical splicing regulator with critical roles in stress
   response, organ development, and viral replication
SO RNA
LA English
DT Review
DE RNA binding proteins; SR proteins; alternative splicing; splicing;
   stress
ID MESSENGER-RNA; SR PROTEINS; REPRESSOR SRP38; BINDING; PHOSPHORYLATION;
   RECOGNITION; PROMOTES; NSSR1; EXON; DIFFERENTIATION
AB Serine/arginine splicing factor 10 (SRSF10) is a member of the family of mammalian splicing regulators known as SR proteins. Like several of its SR siblings, the SRSF10 protein is composed of an RNA binding domain (RRM) and of arginine and serine-rich auxiliary domains (RS) that guide interactions with other proteins. The phosphorylation status of SRSF10 is of paramount importance for its activity and is subjected to changes during mitosis, heat-shock, and DNA damage. SRSF10 overexpression has functional consequences in a growing list of cancers. By controlling the alternative splicing of specific transcripts, SRSF10 has also been implicated in glucose, fat, and cholesterol metabolism, in the development of the embryonic heart, and in neurological processes. SRSF10 is also important for the proper expression and processing of HIV-1 and other viral transcripts. We discuss how SRSF10 could become a potentially appealing therapeutic target to combat cancer and viral infections.
C1 [Shkreta, Lulzim; Delannoy, Aurelie; Chabot, Benoit] Univ Sherbrooke, Fac Med & Hlth Sci, RNA Grp, Dept Microbiol & Infect Dis, Sherbrooke, PQ J1E 4K8, Canada.
   [Salvetti, Anna] CNRS, INSERM, UMR 5308, Ctr Int Rech Infectiol Lyon CIRI,U1111, Lyon, France.
C3 University of Sherbrooke; Institut National de la Sante et de la
   Recherche Medicale (Inserm); Universite Claude Bernard Lyon 1; Centre
   National de la Recherche Scientifique (CNRS); CNRS - National Institute
   for Biology (INSB)
RP Chabot, B (corresponding author), Univ Sherbrooke, Fac Med & Hlth Sci, RNA Grp, Dept Microbiol & Infect Dis, Sherbrooke, PQ J1E 4K8, Canada.
EM Benoit.Chabot@usherbrooke.ca
RI Salvetti, Anna/F-9560-2013; Chabot, Benoit/A-8943-2008
OI Salvetti, Anna/0000-0003-2007-8350; Chabot, Benoit/0000-0003-0994-0042
FU Canadian Institutes of Health Research [PJT-165966]; Institut National
   de la Sante et de la Recherche Medicale (INSERM); Agence Nationale de la
   Recherche sur le Sida et les Hepatites virales (ANRS)
FX Work in the laboratory of B.C. is supported by grant PJT-165966 from the
   Canadian Institutes of Health Research. Work in the laboratory of A.S.
   is supported by funding from the Institut National de la Sante et de la
   Recherche Medicale (INSERM) and grants from the Agence Nationale de la
   Recherche sur le Sida et les Hepatites virales (ANRS).
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NR 122
TC 14
Z9 19
U1 1
U2 15
PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
PI COLD SPRING HARBOR
PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA
SN 1355-8382
EI 1469-9001
J9 RNA
JI RNA
PD NOV
PY 2021
VL 27
IS 11
BP 1302
EP 1317
DI 10.1261/rna.078879.121
PG 16
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA WK0KO
UT WOS:000709424100002
PM 34315816
OA Bronze, Green Submitted, Green Published
DA 2025-04-10
ER

PT J
AU Ho, TH
   Savkur, RS
   Poulos, MG
   Mancini, MA
   Swanson, MS
   Cooper, TA
AF Ho, TH
   Savkur, RS
   Poulos, MG
   Mancini, MA
   Swanson, MS
   Cooper, TA
TI Colocalization of muscleblind with RNA foci is separable from
   mis-regulation of alternative splicing in myotonic dystrophy
SO JOURNAL OF CELL SCIENCE
LA English
DT Article
DE alternative splicing; MBNL; muscleblind; myotonic dystrophy
ID PRE-MESSENGER-RNA; 3 UNTRANSLATED REGION; TRINUCLEOTIDE REPEAT; NUCLEAR
   FOCI; SKELETAL-MUSCLE; CTG REPEAT; IN-VIVO; PROTEINS; TRANSCRIPTS;
   EXPANSION
AB Myotonic dystrophy type I (DM1), which is caused by a non-coding CTG-repeat expansion in the dystrophia myotonica-protein kinase (DMPK) gene, is an RNA-mediated disease. Expanded CUG repeats in transcripts of mutant DMPK form nuclear foci that recruit muscleblind-like (MBNL) proteins, a family of alternative splicing factors. Although transcripts of mutant DMPK and MBNL proteins accumulate in nuclear RNA foci, it is not clear whether foci formation is required for splicing misregulation. Here, we use a co-transfection strategy to show that both CUG and CAG repeats form RNA foci that colocalize with green fluorescent protein (GFP)-MBNL1 and endogenous MBNL1. However, only CUG repeats alter splicing of the two tested pre-mRNAs, cardiac troponin T (cTNT) and insulin receptor (IR). Using FRAP, we demonstrate that GFP-MBNL1 in CUG and CAG foci have similar half-times of recovery and fractions of immobile molecules, suggesting that GFP-MBNL1 is bound by both CUG and CAG repeats. We also find an immobile fraction of GFP-MBNL1 in DM1 fibroblasts and a similar rapid exchange in endogenous CUG RNA foci. Therefore, formation of RNA foci and disruption of MBNL1-regulated splicing are separable events.
C1 Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
   Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA.
   Eli Lilly & Co, Lilly Res Lab, Indianapolis, IN 46285 USA.
   Univ Florida, Coll Med, Powell Gene Therapy Ctr, Dept Mol Genet & Microbiol, Gainesville, FL 32610 USA.
C3 Baylor College of Medicine; Baylor College of Medicine; Eli Lilly; Lilly
   Research Laboratories; State University System of Florida; University of
   Florida
RP Baylor Coll Med, Dept Mol & Cellular Biol, 1 Baylor Plaza, Houston, TX 77030 USA.
EM tcooper@bcm.tmc.edu
OI Ho, Thai/0000-0003-0023-2939; Swanson, Maurice/0000-0001-6245-5367;
   Poulos, Michael/0000-0002-7622-9966
FU NIAMS NIH HHS [AR46799, R01AR45653] Funding Source: Medline; NINDS NIH
   HHS [NS48843] Funding Source: Medline
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NR 39
TC 144
Z9 175
U1 0
U2 2
PU COMPANY BIOLOGISTS LTD
PI CAMBRIDGE
PA BIDDER BUILDING, STATION RD, HISTON, CAMBRIDGE CB24 9LF, ENGLAND
SN 0021-9533
EI 1477-9137
J9 J CELL SCI
JI J. Cell Sci.
PD JUL 1
PY 2005
VL 118
IS 13
BP 2923
EP 2933
DI 10.1242/jcs.02404
PG 11
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA 952WK
UT WOS:000231036200015
PM 15961406
DA 2025-04-10
ER

PT J
AU Xu, R
   Li, SP
   Chien, CJ
   Zhong, YW
   Xiao, HH
   Fang, SY
   Du, SJ
AF Xu, Rui
   Li, Siping
   Chien, Chien-Ju
   Zhong, Yongwang
   Xiao, Huanhuan
   Fang, Shengyun
   Du, Shaojun
TI Expression of Smyd1b_tv1 by Alternative Splicing in Cardiac Muscle is
   Critical for Sarcomere Organization in Cardiomyocytes and Heart Function
SO MOLECULAR AND CELLULAR BIOLOGY
LA English
DT Article
DE Smyd1; sarcomere; cardiomyocyte; alternative splicing
ID PROTEIN ISOFORM; TITIN ISOFORM; RNA; SKELETAL; GENE; METHYLTRANSFERASE;
   SKNAC; BOP; CARDIOMYOPATHY; MITOCHONDRIA
AB Smyd1, a member of the Smyd lysine methyltransferase family, plays an important role in myofibrillogenesis of skeletal and cardiac muscles. Loss of Smyd1b (a Smyd1 ortholog) function in zebrafish results in embryonic death from heart malfunction. smyd1b encodes two isoforms, Smyd1b_tv1 and Smyd1b_tv2, differing by 13 amino acids due to alternative splicing. While smyd1 alternative splicing is evolutionarily conserved, the isoform-specific expression and function of Smyd1b_tv1 and Smyd1b_tv2 remained unknown. Here we analyzed their expression and function in skeletal and cardiac muscles. Our analysis revealed expression of smyd1b_tv1 predominately in cardiac and smyd1b_tv2 in skeletal muscles. Using zebrafish models expressing only one isoform, we demonstrated that Smyd1b_tv1 is essential for cardiomyocyte differentiation and fish viability, whereas Smyd1b_tv2 is dispensable for heart development and fish survival. Cellular and biochemical analyses revealed that Smyd1b_tv1 differs from Smyd1b_tv2 in protein localization and binding with myosin chaperones. While Smyd1b_tv2 diffused in the cytosol of muscle cells, Smyd1b_tv1 was localized to M-lines and essential for sarcomere organization in cardiomyocytes. Co-IP analysis revealed a stronger binding of Smyd1b_tv1 with chaperones and cochaperones compared with Smyd1b_tv2. Collectively, these findings highlight the nonequivalence of Smyd1b isoforms in cardiomyocyte differentiation, emphasizing the critical role of Smyd1b_tv1 in cardiac function.
C1 [Xu, Rui; Li, Siping; Chien, Chien-Ju; Xiao, Huanhuan; Du, Shaojun] Univ Maryland, Sch Med, Inst Marine & Environm Technol, Dept Biochem & Mol Biol, Baltimore, MD 21250 USA.
   [Li, Siping] Chinese Acad Fishery Sci, East China Sea Fisheries Res Inst, Shanghai, Peoples R China.
   [Zhong, Yongwang; Fang, Shengyun] Univ Maryland, Sch Med, Ctr Biomed Engn, Dept Physiol, Baltimore, MD USA.
C3 University System of Maryland; University of Maryland Baltimore;
   University of Maryland Center for Environmental Science; Institute of
   Marine & Environmental Technology; Chinese Academy of Fishery Sciences;
   East China Sea Fisheries Research Institute, CAFS; University System of
   Maryland; University of Maryland Baltimore
RP Du, SJ (corresponding author), Univ Maryland, Sch Med, Inst Marine & Environm Technol, Dept Biochem & Mol Biol, Baltimore, MD 21250 USA.
EM sdu@som.umaryland.edu
RI Li, Siping/IUQ-5400-2023; Rothan, Hussin/AAV-9877-2020; Xiao,
   Huanhuan/JWP-2322-2024
FU National Institutes of Health; University of Maryland Baltimore
FX We thank Dr Charles C. Hong and Dr Young Chun at University of Maryland
   School of Medicine for providing cDNA of iPSC-derived human
   cardiomyocytes. We acknowledge the technical assistance from Electron
   Microscopy Core Imaging Facility of the University of Maryland
   Baltimore.
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NR 76
TC 1
Z9 2
U1 3
U2 3
PU TAYLOR & FRANCIS INC
PI PHILADELPHIA
PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA
SN 0270-7306
EI 1098-5549
J9 MOL CELL BIOL
JI Mol. Cell. Biol.
PD DEC 1
PY 2024
VL 44
IS 12
BP 543
EP 561
DI 10.1080/10985549.2024.2402660
EA SEP 2024
PG 19
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA M9A1U
UT WOS:001319422400001
PM 39320962
DA 2025-04-10
ER

PT J
AU Lin, J
   Hu, Y
   Nunez, S
   Foulkes, AS
   Cieply, B
   Xue, CY
   Gerelus, M
   Li, WJ
   Zhang, HR
   Rader, DJ
   Musunuru, K
   Li, MY
   Reilly, MP
AF Lin, Jennie
   Hu, Yu
   Nunez, Sara
   Foulkes, Andrea S.
   Cieply, Benjamin
   Xue, Chenyi
   Gerelus, Mark
   Li, Wenjun
   Zhang, Hanrui
   Rader, Daniel J.
   Musunuru, Kiran
   Li, Mingyao
   Reilly, Muredach P.
TI Transcriptome-Wide Analysis Reveals Modulation of Human Macrophage
   Inflammatory Phenotype Through Alternative Splicing
SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
LA English
DT Article
DE alternative splicing; genetics; inflammation; macrophages; RNA
ID RNA-SEQ; POLARIZATION; EXPRESSION; MONOCYTE; CELLS; MODEL;
   DIFFERENTIATION; MECHANISMS; SIGNATURES; PROMOTERS
AB Objective-Human macrophages can shift phenotype across the inflammatory M1 and reparative M2 spectrum in response to environmental challenges, but the mechanisms promoting inflammatory and cardiometabolic disease-associated M1 phenotypes remain incompletely understood. Alternative splicing (AS) is emerging as an important regulator of cellular function, yet its role in macrophage activation is largely unknown. We investigated the extent to which AS occurs in M1 activation within the cardiometabolic disease context and validated a functional genomic cell model for studying human macrophage-related AS events.
   Approach and Results-From deep RNA-sequencing of resting, M1, and M2 primary human monocyte-derived macrophages, we found 3860 differentially expressed genes in M1 activation and detected 233 M1-induced AS events; the majority of AS events were cell-and M1-specific with enrichment for pathways relevant to macrophage inflammation. Using genetic variant data for 10 cardiometabolic traits, we identified 28 trait-associated variants within the genomic loci of 21 alternatively spliced genes and 15 variants within 7 differentially expressed regulatory splicing factors in M1 activation. Knockdown of 1 such splicing factor, CELF1, in primary human macrophages led to increased inflammatory response to M1 stimulation, demonstrating CELF1's potential modulation of the M1 phenotype. Finally, we demonstrated that an induced pluripotent stem cell-derived macrophage system recapitulates M1-associated AS events and provides a high-fidelity macrophage AS model.
   Conclusions-AS plays a role in defining macrophage phenotype in a cell-and stimulus-specific fashion. Alternatively spliced genes and splicing factors with trait-associated variants may reveal novel pathways and targets in cardiometabolic diseases.
C1 [Lin, Jennie] Univ Penn, Dept Med, Perelman Sch Med, Renal Electrolyte & Hypertens Div, 1 Founders,3400 Spruce St, Philadelphia, PA 19104 USA.
   [Hu, Yu; Li, Mingyao] Univ Penn, Dept Genet, Perelman Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA.
   [Gerelus, Mark; Li, Wenjun; Musunuru, Kiran] Univ Penn, Dept Med, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA.
   [Reilly, Muredach P.] Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, 622 West 168th St,PH10-305, New York, NY USA.
   [Xue, Chenyi; Zhang, Hanrui; Reilly, Muredach P.] Columbia Univ, Dept Med, Div Cardiol, Med Ctr, New York, NY USA.
   [Nunez, Sara; Foulkes, Andrea S.] Mt Holyoke Coll, Dept Math & Stat, S Hadley, MA 01075 USA.
C3 University of Pennsylvania; University of Pennsylvania; University of
   Pennsylvania; Columbia University; Columbia University; Mount Holyoke
   College
RP Lin, J (corresponding author), Univ Penn, Dept Med, Perelman Sch Med, Renal Electrolyte & Hypertens Div, 1 Founders,3400 Spruce St, Philadelphia, PA 19104 USA.; Reilly, MP (corresponding author), Columbia Univ, Med Ctr, Irving Inst Clin & Translat Res, 622 West 168th St,PH10-305, New York, NY USA.
EM linjenn@mail.med.upenn.edu; mpr2144@cumc.columbia.edu
RI Hu, Yu/I-1761-2019; Musunuru, Kiran/JPL-8412-2023; Rader,
   Daniel/AFQ-9696-2022
OI Zhang, Hanrui/0000-0001-8655-938X; Lin, Jennie/0000-0002-9328-6700;
   Gerelus, Mark/0000-0001-8986-4523; Reilly, Muredach/0000-0002-3035-9386
FU [R01-HL-113147];  [K24-HL-107643];  [R01-GM-108600];  [R01-HL-107196]; 
   [U01-HG-006398];  [KL2-TR-000139]
FX This work was supported by R01-HL-113147 (M.P. Reilly and M.Li),
   K24-HL-107643 (to M.P. Reilly), R01-GM-108600 (to M. Li), R01-HL-107196
   (to A.S. Foulkes), and U01-HG-006398 (to D.J. Rader). J. Lin was
   supported by KL2-TR-000139.
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NR 81
TC 30
Z9 36
U1 0
U2 16
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 1079-5642
EI 1524-4636
J9 ARTERIOSCL THROM VAS
JI Arterioscler. Thromb. Vasc. Biol.
PD JUN
PY 2016
VL 36
IS 7
BP 1434
EP +
DI 10.1161/ATVBAHA.116.307573
PG 23
WC Hematology; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Hematology; Cardiovascular System & Cardiology
GA DP4WF
UT WOS:000378497000018
PM 27230130
OA Green Accepted, Bronze
DA 2025-04-10
ER

PT J
AU Lee, JH
   Horak, CE
   Khanna, C
   Meng, ZJ
   Yu, LR
   Veenstra, TD
   Steeg, PS
AF Lee, Jong Heun
   Horak, Christine E.
   Khanna, Chand
   Meng, Zhaojing
   Yu, Li Rong
   Veenstra, Timothy D.
   Steeg, Patricia S.
TI Alterations in Gemin5 expression contribute to alternative mRNA splicing
   patterns and tumor cell motility
SO CANCER RESEARCH
LA English
DT Article
ID SMN COMPLEX; PROTEIN; ACTIVATION; NM23-H1; RHO
AB The role of Gemin5 in alternative mRNA splicing, tumor cell motility, and proteomic instability was investigated. Isotope Capture Affinity Tag proteomic analysis was conducted on MDA-MB-435 tumor cells transfected with either a control vector (C-100) or the Nm23-H1 metastasis suppressor (H1-177). Ingenuity pathway analysis revealed that RNA posttranscriptional processing was the most prominent class of differentially expressed proteins. Within this category, overexpression of Acinus1, Poly(a) binding protein, HNRPA2B1, Bop1, and Gemin5 was confirmed in less metastatic H1-177 cells. Overexpression of the latter four proteins was also observed in the lower metastatic antisense Ezrin transfectant of a murine osteosarcoma model system, confirming the general relevance of the trends. Gemin5, a component of the spliceosomal complex, was chosen for further study. Analysis of global mRNA splicing by SpliceArray chips revealed that 16 genes were differentially spliced in C-100 compared with H1-177 cells; transient transfection of gemin5 into C-100 cells restored the splice pattern to that of H1-177 cells. Alternative splicing patterns for the engulfment and cell motility 1 and thrombospondin 4 genes were confirmed by semiquantitative reverse transcription-PCR. Gemin5 overexpression coordinately reduced C-100 cell motility by 50%, and siRNA-mediated reduction of Gemin5 expression increased the motility of H1-177 cells by 2-fold (P < 0.004). The data provide the first demonstration that alterations in the expression of a spliceosome protein can effect both specific splicing events and tumor cell motility. The data also show that changes in mRNA splicing patterns accompany metastatic progression, which may contribute to proteome instability.
C1 [Lee, Jong Heun; Horak, Christine E.; Steeg, Patricia S.] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA.
   [Khanna, Chand] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA.
   [Meng, Zhaojing; Yu, Li Rong; Veenstra, Timothy D.] NCI, Sci Applicat Int Corp Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD 21701 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Cancer Institute
   (NCI); National Institutes of Health (NIH) - USA; NIH National Cancer
   Institute (NCI); National Institutes of Health (NIH) - USA; NIH National
   Cancer Institute (NCI); Science Applications International Corporation
   (SAIC)
RP Steeg, PS (corresponding author), Bldg 37,Room 1122, Bethesda, MD 20892 USA.
EM steegp@mail.nih.gov
RI Lee, Jong-Heun/E-3923-2012
FU Intramural NIH HHS [Z01 SC000892-24] Funding Source: Medline
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NR 20
TC 34
Z9 39
U1 1
U2 1
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 0008-5472
J9 CANCER RES
JI Cancer Res.
PD FEB 1
PY 2008
VL 68
IS 3
BP 639
EP 644
DI 10.1158/0008-5472.CAN-07-2632
PG 6
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 259QD
UT WOS:000252952900004
PM 18245461
OA Green Accepted, Green Submitted, Bronze
DA 2025-04-10
ER

PT J
AU Shi, NQ
   Ye, B
   Makielski, JC
AF Shi, NQ
   Ye, B
   Makielski, JC
TI Function and distribution of the SUR isoforms and splice variants
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Article
DE K-ATP channels; SUR isoforms; splice variant; Gene
ID K-ATP CHANNEL; SENSITIVE POTASSIUM CHANNELS; PERSISTENT HYPERINSULINEMIC
   HYPOGLYCEMIA; SULFONYLUREA RECEPTOR; SKELETAL-MUSCLE; MITOCHONDRIAL;
   TRAFFICKING; GENE; CLONING; BINDING
AB Alternative splicing allows multiple mRNAs to be generated from a single gene, which in turn can be translated into a group of diverse proteins with different roles and structures. The outcome of alternative splicing leads to the co-existence of multiple splice variants of a gene at different concentrations in different tissues. The pore-forming subunit of the K-ATP channel (K(IR)6.x) and the regulatory sulfonylurea receptor (SURx) subunits exist in a 4:4 stoichiometry to form hetero-octameric ATP-sensitive potassium channel (K-ATP) channels, which are widely distributed in various types of tissues at either the plasma membrane (cellK(ATP)) or mitochondrial inner membrane (the mitochondrial form of K-ATP channel, mitoK(ATP)). They perform important physiological functions in regulating insulin secretion in pancreatic beta-cells, providing ischemic protection in heart and brain, and regulating vascular tone in smooth muscles. Two separate genes, the regulatory subunit protein I (SUR1) and the regulatory subunit protein II (SUR2) encode the high- and low-affinity SUR, respectively. This review summarizes the current studies on the function and distribution of the SUR isoforms and alternative splice variants, and to a lesser extent the KIR6.x subunits. The different isoforms and splice variants allow for many K-ATP channel combinations, and therefore, increases the channel diversity and the possibility of complexity in function. (c) 2005 Elsevier Ltd. All rights reserved.
C1 Univ Wisconsin, Dept Med, Cardiovasc Med Sect, Madison, WI 53705 USA.
C3 University of Wisconsin System; University of Wisconsin Madison
RP Univ Wisconsin, Dept Med, 600 Highland Ave H6-349, Madison, WI 53792 USA.
EM jcm@medicine.wisc.edu
OI Shi, Nian-Qing/0000-0001-7487-3582
FU NHLBI NIH HHS [R01-HL057414] Funding Source: Medline
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NR 80
TC 83
Z9 111
U1 0
U2 10
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD JUL
PY 2005
VL 39
IS 1
BP 51
EP 60
DI 10.1016/j.yjmcc.2004.11.024
PG 10
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA 944NF
UT WOS:000230435000004
PM 15978902
DA 2025-04-10
ER

PT J
AU Bogdanov, VY
   Kirk, RI
   Miller, C
   Hathcock, JJ
   Vele, S
   Gazdoiu, M
   Nemerson, Y
   Taubman, MB
AF Bogdanov, VY
   Kirk, RI
   Miller, C
   Hathcock, JJ
   Vele, S
   Gazdoiu, M
   Nemerson, Y
   Taubman, MB
TI Identification and characterization of murine alternatively spliced
   tissue factor
SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS
LA English
DT Article
DE alternative splicing; development; thrombosis; tissue factor
ID FACTOR PATHWAY INHIBITOR; HUMAN ATHEROSCLEROTIC PLAQUES; SHED MEMBRANE
   MICROPARTICLES; FACTOR-RESPONSIVE GENE; SMOOTH-MUSCLE-CELLS;
   PROCOAGULANT ACTIVITY; INTIMAL HYPERPLASIA; REPERFUSION INJURY; ARTERIAL
   INJURY; WHOLE-BLOOD
AB Tissue factor (TF) is a transmembrane glycoprotein that initiates coagulation and plays a critical role in regulating hemostasis and thrombosis. We have recently reported a naturally occurring, soluble form of human tissue factor (asTF) generated by alternative splicing. This splice variant has a novel C-terminus with no homology to that of the full-length TF (flTF), lacks a transmembrane domain, and is active in the presence of phospholipids. Mouse models offer unique opportunities to examine the relative importance of flTF and asTF in mediating thrombosis, the response to arterial injury, and ischemic damage. To that end, we have identified and characterized murine asTF (masTF). Like the human splice variant, masTF lacks a transmembrane domain and has a unique C-terminus. We have generated antibodies specific to masTF and murine flTF (mflTF) to examine the expression of both forms of TF. masTF antigen is widely and abundantly expressed, with a pattern similar to that of mflTF, in adult tissues, in experimentally induced thrombi, and during development. These studies demonstrate that masTF contributes to the pool of total TF and may thus play an important role in mediating TF-dependent processes.
C1 Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA.
   Mt Sinai Sch Med, Cardiovasc Inst, New York, NY 10029 USA.
   Univ Rochester, Sch Med & Dent, Ctr Cellular & Mol Cardiol, Rochester, NY USA.
   Univ Rochester, Sch Med & Dent, Dept Med, Rochester, NY USA.
C3 Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at
   Mount Sinai; University of Rochester; University of Rochester
RP Mt Sinai Sch Med, Dept Med, 1 Gustave L Levy Pl,Box 1079, New York, NY 10029 USA.
EM mark_taubman@urmc.rochester.edu
OI Bogdanov, Vladimir/0000-0003-4968-1129
FU NHLBI NIH HHS [P50 HL54469, HL77669] Funding Source: Medline; NIDDK NIH
   HHS [K01 DK65752] Funding Source: Medline
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NR 38
TC 43
Z9 46
U1 0
U2 2
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1538-7933
EI 1538-7836
J9 J THROMB HAEMOST
JI J. Thromb. Haemost.
PD JAN
PY 2006
VL 4
IS 1
BP 158
EP 167
DI 10.1111/j.1538-7836.2005.01680.x
PG 10
WC Hematology; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Hematology; Cardiovascular System & Cardiology
GA 995GX
UT WOS:000234089900028
PM 16409465
OA Bronze
DA 2025-04-10
ER

PT J
AU Karim, SM
   Rhee, AY
   Given, AM
   Faulx, MD
   Hoit, BD
   Brozovich, FV
AF Karim, SM
   Rhee, AY
   Given, AM
   Faulx, MD
   Hoit, BD
   Brozovich, FV
TI Vascular reactivity in heart failure - Role of myosin light chain
   phosphatase
SO CIRCULATION RESEARCH
LA English
DT Article
DE cGMP; vascular function; nitric oxide; congestive heart failure
ID ENDOTHELIUM-MEDIATED VASODILATION; SMOOTH-MUSCLE; NITRIC-OXIDE;
   TARGETING SUBUNIT; CYCLIC-GMP; VENTRICULAR-FUNCTION;
   SIGNAL-TRANSDUCTION; CHICKEN GIZZARD; ANGIOTENSIN-II; L-ARGININE
AB Congestive heart failure (CHF) is a clinical syndrome, which is the result of systolic or diastolic ventricular dysfunction. During CHF, vascular tone is regulated by the interplay of neurohormonal mechanisms and endothelial-dependent factors and is characterized by both central and peripheral vasoconstriction as well as a resistance to nitric oxide ( NO)-mediated vasodilatation. At the molecular level, vascular tone depends on the level of regulatory myosin light chain phosphorylation, which is determined by the relative activities of myosin light chain kinase and myosin light chain phosphatase (MLCP). The MLCP is a trimeric enzyme with a catalytic, a 20-kDa and a myosin targeting (MYPT1) subunit. Alternative splicing of a 3' exon produces leucine zipper positive and negative (LZ(+/-)) MYPT1 isoforms. Expression of a LZ(+) MYPT1 has been suggested to be required for NO-mediated smooth muscle relaxation. Thus, we hypothesized that the resistance to NO-mediated vasodilatation in CHF could be attributable to a change in the relative expression of LZ(+/-) MYPT1 isoforms. To test this hypothesis, left coronary artery ligation was used to induce CHF in rats, and both the dose response relationship of relaxation to 8-Br-cGMP in skinned smooth muscle and the relative expression of LZ(+/-) MYPT1 isoforms were determined. In control animals, the expression of the LZ(+) MYPT1 isoform predominated in both the aorta and iliac artery. In CHF rats, LVEF was reduced to 30 +/- 5% and there was a significant decrease in both the sensitivity to 8-Br-cGMP and expression of the LZ(+) MYPT1 isoform. These results indicate that CHF is associated with a decrease in the relative expression of the LZ(+) MYPT1 isoform and the sensitivity to 8-Br-cGMP -mediated smooth muscle relaxation. The data suggest that the resistance to NO-mediated relaxation observed during CHF lies at least in part at the level of the smooth muscle and is a consequence of the decrease in the expression of the LZ(+) MYPT1 isoform.
C1 Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA.
   Case Western Reserve Univ, Dept Med Cardiol, Cleveland, OH 44106 USA.
C3 University System of Ohio; Case Western Reserve University; University
   System of Ohio; Case Western Reserve University
RP Case Western Reserve Univ, Dept Physiol, 10900 Euclid Ave, Cleveland, OH 44106 USA.
EM Frank.Brozovich@case.edu
FU NHLBI NIH HHS [T32 HL07887, HL69894] Funding Source: Medline
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NR 43
TC 38
Z9 47
U1 0
U2 0
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7330
EI 1524-4571
J9 CIRC RES
JI Circ.Res.
PD SEP 17
PY 2004
VL 95
IS 6
BP 612
EP 618
DI 10.1161/01.RES.0000142736.39359.58
PG 7
WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Hematology
GA 854IM
UT WOS:000223896300011
PM 15321927
OA Bronze
DA 2025-04-10
ER

PT J
AU Feng, Y
   Valley, MT
   Lazar, J
   Yang, AL
   Bronson, RT
   Firestein, S
   Coetzee, WA
   Manley, JL
AF Feng, Ying
   Valley, Matthew T.
   Lazar, Josef
   Yang, Allison L.
   Bronson, Roderick T.
   Firestein, Stuart
   Coetzee, William A.
   Manley, James L.
TI SRp38 Regulates Alternative Splicing and Is Required for Ca<SUP>2+</SUP>
   Handling in the Embryonic Heart
SO DEVELOPMENTAL CELL
LA English
DT Article
ID BETA-ADRENERGIC MODULATION; MESSENGER-RNA; FACTOR ASF/SF2; SR PROTEINS;
   TARGETED DISRUPTION; GENE; MICE; MECHANISMS; REPRESSOR; INSIGHTS
AB SRp38 is an atypical SR protein splicing regulator. To define the functions of SRp38 in vivo, we generated SRp38 null mice. The majority of homozygous mutants survived only until E15.5 and displayed multiple cardiac defects. Evaluation of gene expression profiles in the SRp38(-/-) embryonic heart revealed a defect in processing of the pre-mRNA encoding cardiac triadin, a protein that functions in regulation of Ca2+ release from the sarcoplasmic reticulum during excitation-contraction coupling. This defect resulted in significantly reduced levels of triadin, as well as those of the interacting protein calsequestrin 2. Purified SRp38 was shown to bind specifically to the regulated exon and to modulate triadin splicing in vitro. Extending these results, isolated SRp38(-/-) embryonic cardiomyocytes displayed defects in Ca2+ handling compared with wild-type controls. Taken together, our results demonstrate that SRp38 regulates cardiac-specific alternative splicing of triadin pre-mRNA and, reflecting this, is essential for proper Ca2+ handling during embryonic heart development.
C1 [Feng, Ying; Valley, Matthew T.; Lazar, Josef; Yang, Allison L.; Firestein, Stuart; Manley, James L.] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA.
   [Bronson, Roderick T.] Harvard Univ, Sch Med, Boston, MA 02115 USA.
   [Coetzee, William A.] NYU, Sch Med, New York, NY 10016 USA.
C3 Columbia University; Harvard University; Harvard Medical School; New
   York University
RP Manley, JL (corresponding author), Columbia Univ, Dept Biol Sci, New York, NY 10027 USA.
EM jlm2@columbia.edu
RI , Stuart Firestein/HZK-1465-2023; Lazar, Josef/H-7487-2014; Lazar,
   Josef/D-8523-2012
OI Lazar, Josef/0000-0002-6285-3995; Coetzee, William/0000-0003-1522-8326;
   Lazar, Josef/0000-0002-8579-8589; Valley, Matthew/0000-0002-7204-5457;
   Manley, James/0000-0002-8341-1459
FU NIH [GM48259]
FX We are grateful to A. Beg, L. Yamasaki, and A. Minden for advice and
   assistance with the generation of SRp38<SUP>-/-</SUP> mice. We thank C.
   Yang at the Rockefeller ES cell facility for help with the ES cell
   culture and injection. We thank Microarray core facility at the Columbia
   University Cancer Center for help with microarray analysis. We also
   thank I. Boluk for help preparing the manuscript and members of the
   Manley laboratory for helpful discussions and comments. This work was
   supported by NIH grant NIH GM48259 to J.L.M.
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NR 43
TC 82
Z9 89
U1 0
U2 6
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
SN 1534-5807
EI 1878-1551
J9 DEV CELL
JI Dev. Cell
PD APR 21
PY 2009
VL 16
IS 4
BP 528
EP 538
DI 10.1016/j.devcel.2009.02.009
PG 11
WC Cell Biology; Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Developmental Biology
GA 437EX
UT WOS:000265470400009
PM 19386262
OA Green Accepted, Bronze
DA 2025-04-10
ER

PT J
AU Paterson, HAB
   Yu, SJ
   Artigas, N
   Prado, MA
   Haberman, N
   Wang, YF
   Jobbins, AM
   Pahita, E
   Mokochinski, J
   Hall, Z
   Guerin, M
   Paulo, JA
   Ng, SS
   Villarroya, F
   Rashid, ST
   Le Goff, W
   Lenhard, B
   Cebola, I
   Finley, D
   Gygi, SP
   Sibley, CR
   Vernia, S
AF Paterson, Helen A. B.
   Yu, Sijia
   Artigas, Natalia
   Prado, Miguel A.
   Haberman, Nejc
   Wang, Yi-Fang
   Jobbins, Andrew M.
   Pahita, Elena
   Mokochinski, Joao
   Hall, Zoe
   Guerin, Maryse
   Paulo, Joao A.
   Ng, Soon Seng
   Villarroya, Francesc
   Rashid, Sheikh Tamir
   Le Goff, Wilfried
   Lenhard, Boris
   Cebola, Ines
   Finley, Daniel
   Gygi, Steven P.
   Sibley, Christopher R.
   Vernia, Santiago
TI Liver RBFOX2 regulates cholesterol homeostasis via Scarb1
   alternative splicing in mice
SO NATURE METABOLISM
LA English
DT Article
ID HIGH-DENSITY-LIPOPROTEIN; DIFFERENTIAL EXPRESSION ANALYSIS; SCAVENGER
   RECEPTOR BI; SR-BI; CARDIOVASCULAR RISK; PROTEIN; FOX-1; AUTOREGULATION;
   TRANSCRIPTOME; METABOLISM
AB RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein 2 (RBFOX2) in maintaining cholesterol homeostasis in a lipogenic environment in the liver. Using enhanced individual-nucleotide-resolution ultra-violet cross-linking and immunoprecipitation, we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I (Scarb1). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesity-induced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases.
C1 [Paterson, Helen A. B.; Yu, Sijia; Artigas, Natalia; Haberman, Nejc; Wang, Yi-Fang; Jobbins, Andrew M.; Pahita, Elena; Mokochinski, Joao; Lenhard, Boris; Vernia, Santiago] MRC London Inst Med Sci, London, England.
   [Paterson, Helen A. B.; Yu, Sijia; Artigas, Natalia; Haberman, Nejc; Wang, Yi-Fang; Jobbins, Andrew M.; Pahita, Elena; Mokochinski, Joao; Lenhard, Boris; Vernia, Santiago] Imperial Coll London, Inst Clin Sci, Hammersmith Hosp Campus, London, England.
   [Prado, Miguel A.; Paulo, Joao A.; Finley, Daniel; Gygi, Steven P.] Harvard Med Sch, Dept Cell Biol, Boston, MA USA.
   [Hall, Zoe; Ng, Soon Seng; Rashid, Sheikh Tamir] Imperial Coll London, Dept Metab Digest & Reprod, Div Syst Med, Hammersmith Hosp Campus, London, England.
   [Guerin, Maryse; Le Goff, Wilfried] Sorbonne Univ, Inst Cardiometab & Nutr ICAN, INSERM, UMR S1166, Paris, France.
   [Villarroya, Francesc] Univ Barcelona, Inst Biomed, Biochem & Mol Biomed Dept, Barcelona, Spain.
   [Villarroya, Francesc] Res Inst St Joan de Deu, Barcelona, Spain.
   [Villarroya, Francesc] ISCIII, Ctr Invest Biomed Red Fisiopatol Obes & Nutr CIBER, Madrid, Spain.
   [Cebola, Ines] Imperial Coll London, Dept Metab Digest & Reprod, Sect Genet & Genom, Hammersmith Hosp Campus, London, England.
   [Sibley, Christopher R.] Inst Invest Sanitaria Principado Asturias, Inst Quantitat Biol Biochem & Biotechnol, Sch Biol Sci, Ave Hosp Univ, Oviedo, Spain.
C3 Imperial College London; Harvard University; Harvard Medical School;
   Imperial College London; Sorbonne Universite; Institut National de la
   Sante et de la Recherche Medicale (Inserm); University of Barcelona;
   Instituto de Salud Carlos III; Imperial College London; Instituto de
   Investigacion Sanitaria del Principado de Asturias (ISPA)
RP Vernia, S (corresponding author), MRC London Inst Med Sci, London, England.; Vernia, S (corresponding author), Imperial Coll London, Inst Clin Sci, Hammersmith Hosp Campus, London, England.
EM santiago.vernia@lms.mrc.ac.uk
RI Cebola, Inês/AAG-9652-2020; Guerin, Maryse/N-5794-2017; Paulo,
   Joao/AAO-3981-2020; Villarroya, Francesc/K-4357-2014; Haberman,
   Nejc/AFI-2162-2022; Prado, Miguel/P-3922-2017; Le Goff,
   Wilfried/N-6326-2017; Vernia, Santiago/Q-7038-2017
OI Haberman, Nejc/0000-0001-9247-4139; Prado, Miguel/0000-0002-4914-1619;
   Le Goff, Wilfried/0000-0002-7611-9644; Artigas,
   Natalia/0000-0003-3290-2052; Rashid, Sheikh Tamir/0000-0001-6779-2506;
   Wang, Yi-Fang/0000-0001-7137-2010; Vernia, Santiago/0000-0001-6728-5555;
   Lenhard, Boris/0000-0002-1114-1509; GUERIN, Maryse/0000-0003-0150-1360
FU LMS/NIHR Imperial Biomedical Research Centre Flow Cytometry Facility;
   Goldberg Fund Fellowship; Miguel Servet Program [CP21/00017]; Imperial
   College President's Scholarship; Goldberg Fellowship Award; Rutherford
   Fund fellowship; NIH/NIGMS [R01 GM132129, R01GM043601, GM67945]; MRC
   [MR/W019132/1]; Analytical Chemistry Trust Fund; National Institute for
   Health Research (NIHR) Imperial Biomedical Research Centre; Academy of
   Medical Sciences Springboard Fellowship [SBF005\1050]; British Heart
   Foundation; Diabetes UK; Global Challenges Research Fund; Government
   Department for Business, Energy and Industrial Strategy; Wellcome Trust;
   Sir Henry Dale fellowship; Royal Society [215454/Z/19/Z]; Medical
   Research Council (MRC); MRC [MR/W019132/1] Funding Source: UKRI;
   Wellcome Trust [215454/Z/19/Z] Funding Source: Wellcome Trust
FX We thank I. Miguel-Aliaga and D. Withers for the critical reading of
   this manuscript and T. Vidal-Puig and M. Vacca for helpful discussions.
   We thank C. Amourda and the other members of the Vernia laboratory
   (M.G.R.) for help and useful discussions. We thank G. Riddihough (Life
   Science Editors) for help with editing the manuscript. Some of the
   figures were created with BioRender.com. We also thank K. Morris for
   modelling PLA2G6 structure, H. Kramer for advice in metabolomic
   experiments and S. Khadayate for ingenuity pathway analysis. We thank
   the members of the LMS-MRC genomics, transgenics, whole animal
   physiology imaging facility, proteomics, bioinformatics and the members
   of the LMS-MRC administrative team for their excellent assistance. We
   thank the LMS/NIHR Imperial Biomedical Research Centre Flow Cytometry
   Facility for the support. For the purpose of open access, the author has
   applied a Creative Commons Attribution (CC BY) licence. M.A.P. was
   supported by the Goldberg Fund Fellowship and the Miguel Servet Program
   (grant no. CP21/00017). H.A.B.P. is recipient of the Imperial College
   President's Scholarship. M.A.P. was supported by the Goldberg Fellowship
   Award. N.A. is recipient of the Rutherford Fund fellowship. This work
   was funded in part by NIH/NIGMS grant nos. R01 GM132129 (J.A.P.),
   R01GM043601 (D.F.) and GM67945 (S.P.G.). Z.H. is supported by the MRC
   (grant no. MR/W019132/1) and the Analytical Chemistry Trust Fund
   (CAMS-UK fellowship). I.C. is supported by the National Institute for
   Health Research (NIHR) Imperial Biomedical Research Centre and is
   recipient of an Academy of Medical Sciences Springboard Fellowship
   (grant no. SBF005\1050), which is supported by the British Heart
   Foundation, Diabetes UK, the Global Challenges Research Fund, the
   Government Department for Business, Energy and Industrial Strategy and
   the Wellcome Trust. C.R.S. was supported by a Sir Henry Dale fellowship
   jointly funded by the Wellcome Trust and the Royal Society (grant no.
   215454/Z/19/Z). S.V. was supported by the Medical Research Council
   (MRC).
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NR 90
TC 21
Z9 22
U1 7
U2 21
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
EI 2522-5812
J9 NAT METAB
JI Nat. Metab.
PD DEC
PY 2022
VL 4
IS 12
BP 1812
EP +
DI 10.1038/s42255-022-00681-y
EA DEC 2022
PG 35
WC Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Endocrinology & Metabolism
GA 9A4ZW
UT WOS:000900912800001
PM 36536133
OA hybrid, Green Published
DA 2025-04-10
ER

PT J
AU Park, JY
   Li, WC
   Zheng, DH
   Zhai, PY
   Zhao, Y
   Matsuda, T
   Vatner, SF
   Sadoshima, J
   Tian, B
AF Park, Ji Yeon
   Li, Wencheng
   Zheng, Dinghai
   Zhai, Peiyong
   Zhao, Yun
   Matsuda, Takahisa
   Vatner, Stephen F.
   Sadoshima, Junichi
   Tian, Bin
TI Comparative Analysis of mRNA Isoform Expression in Cardiac Hypertrophy
   and Development Reveals Multiple Post-Transcriptional Regulatory Modules
SO PLOS ONE
LA English
DT Article
ID 3' UNTRANSLATED REGIONS; FETAL GENE PROGRAM; ALTERNATIVE
   POLYADENYLATION; TRANSCRIPTION FACTORS; HEART-FAILURE; END FORMATION;
   STEM-CELLS; MICRORNAS; DISEASE; CARDIOMYOPATHY
AB Cardiac hypertrophy is enlargement of the heart in response to physiological or pathological stimuli, chiefly involving growth of myocytes in size rather than in number. Previous studies have shown that the expression pattern of a group of genes in hypertrophied heart induced by pressure overload resembles that at the embryonic stage of heart development, a phenomenon known as activation of the "fetal gene program". Here, using a genome-wide approach we systematically defined genes and pathways regulated in short-and long-term cardiac hypertrophy conditions using mice with transverse aortic constriction (TAC), and compared them with those regulated at different stages of embryonic and postnatal development. In addition, exon-level analysis revealed widespread mRNA isoform changes during cardiac hypertrophy resulting from alternative usage of terminal or internal exons, some of which are also developmentally regulated and may be attributable to decreased expression of Fox-1 protein in cardiac hypertrophy. Genes with functions in certain pathways, such as cell adhesion and cell morphology, are more likely to be regulated by alternative splicing. Moreover, we found 3'UTRs of mRNAs were generally shortened through alternative cleavage and polyadenylation in hypertrophy, and microRNA target genes were generally de-repressed, suggesting coordinated mechanisms to increase mRNA stability and protein production during hypertrophy. Taken together, our results comprehensively delineated gene and mRNA isoform regulation events in cardiac hypertrophy and revealed their relations to those in development, and suggested that modulation of mRNA isoform expression plays an importance role in heart remodeling under pressure overload.
C1 [Park, Ji Yeon; Zhai, Peiyong; Matsuda, Takahisa; Vatner, Stephen F.; Sadoshima, Junichi] Univ Med & Dent New Jersey, Dept Cell Biol & Mol Med, Newark, NJ 07103 USA.
   [Li, Wencheng; Zheng, Dinghai; Zhao, Yun; Tian, Bin] Univ Med & Dent New Jersey, Dept Biochem & Mol Biol, Newark, NJ 07103 USA.
   [Park, Ji Yeon; Tian, Bin] Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA.
   [Park, Ji Yeon; Tian, Bin] Univ Med & Dent New Jersey, Grad Sch Biomed Sci, Newark, NJ 07103 USA.
C3 Rutgers University System; Rutgers University New Brunswick; Rutgers
   University Biomedical & Health Sciences; Rutgers University System;
   Rutgers University New Brunswick; Rutgers University Biomedical & Health
   Sciences; Rutgers University System; Rutgers University New Brunswick;
   Rutgers University Biomedical & Health Sciences; Rutgers University
   System; Rutgers University New Brunswick; Rutgers University Biomedical
   & Health Sciences
RP Park, JY (corresponding author), Univ Med & Dent New Jersey, Dept Cell Biol & Mol Med, Newark, NJ 07103 USA.
EM btian@umdnj.edu
RI Li, Wencheng/J-7675-2012; Zheng, Dinghai/R-7161-2016
OI Zheng, Dinghai/0000-0002-4500-7666; Sadoshima,
   Junichi/0000-0003-3724-4132; Tian, Bin/0000-0001-8903-8256
FU National Institutes of Health (NIH) [HL59139, HL67724, HL69020, HL91469,
   HL102738, AG27211, HL098802, GM084089]; Foundation of Leducq
   Transatlantic Network of Excellence
FX This work was funded by National Institutes of Health (NIH) grants
   HL59139, HL67724, HL69020, HL91469, HL102738, and AG27211 (to J.S.), and
   the Foundation of Leducq Transatlantic Network of Excellence (to J.S.),
   and NIH grants HL098802 and GM084089 (to B.T.). The funders had no role
   in study design, data collection and analysis, decision to publish, or
   preparation of the manuscript.
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NR 73
TC 60
Z9 72
U1 0
U2 6
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD JUL 22
PY 2011
VL 6
IS 7
AR e22391
DI 10.1371/journal.pone.0022391
PG 13
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 797BJ
UT WOS:000293097300042
PM 21799842
OA Green Published, Green Submitted, gold
DA 2025-04-10
ER

PT J
AU Cote, GJ
   Zhu, W
   Thomas, A
   Martin, E
   Murad, F
   Sharina, IG
AF Cote, Gilbert J.
   Zhu, Wen
   Thomas, Anthony
   Martin, Emil
   Murad, Ferid
   Sharina, Iraida G.
TI Hydrogen Peroxide Alters Splicing of Soluble Guanylyl Cyclase and
   Selectively Modulates Expression of Splicing Regulators in Human Cancer
   Cells
SO PLOS ONE
LA English
DT Article
ID TRACT-BINDING-PROTEIN; IRES-MEDIATED TRANSLATION; MESSENGER-RNA BINDING;
   OXIDATIVE STRESS; NITRIC-OXIDE; CYSTEINE OXIDATION; EXON INCLUSION;
   MECHANISMS; ATHEROSCLEROSIS; PROLIFERATION
AB Background: Soluble guanylyl cyclase (sGC) plays a central role in nitric oxide (NO)-mediated signal transduction in the cardiovascular, nervous and gastrointestinal systems. Alternative RNA splicing has emerged as a potential mechanism to modulate sGC expression and activity. C-alpha 1 sGC is an alternative splice form that is resistant to oxidation-induced protein degradation and demonstrates preferential subcellular distribution to the oxidized environment of endoplasmic reticulum (ER).
   Methodology/Principal Findings: Here we report that splicing of C-alpha 1 sGC can be modulated by H2O2 treatment in BE2 neuroblastoma and MDA-MD-468 adenocarcinoma human cells. In addition, we show that the H2O2 treatment of MDA-MD-468 cells selectively decreases protein levels of PTBP1 and hnRNP A2/B1 splice factors identified as potential alpha 1 gene splicing regulators by in silico analysis. We further demonstrate that down-regulation of PTBP1 by H2O2 occurs at the protein level with variable regulation observed in different breast cancer cells.
   Conclusions/Significance: Our data demonstrate that H2O2 regulates RNA splicing to induce expression of the oxidation-resistant C-alpha 1 sGC subunit. We also report that H2O2 treatment selectively alters the expression of key splicing regulators. This process might play an important role in regulation of cellular adaptation to conditions of oxidative stress.
C1 [Cote, Gilbert J.; Zhu, Wen] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA.
   [Thomas, Anthony; Martin, Emil; Sharina, Iraida G.] Univ Texas Med Sch, UTHealth, Dept Internal Med Cardiol, Houston, TX USA.
   [Murad, Ferid] George Washington Univ, Dept Biochem & Mol Biol, Washington, DC USA.
C3 University of Texas System; UTMD Anderson Cancer Center; University of
   Texas System; University of Texas Health Science Center Houston; George
   Washington University
RP Cote, GJ (corresponding author), Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA.
EM Iraida.G.Sharina@uth.tmc.edu
RI Martin, Emil/HLX-8442-2023; Zhu, Wen/KIA-0726-2024; Sharina,
   Iraida/C-9888-2014
OI Martin, Emil/0000-0002-9094-4165
FU NIH [RO1 HL088128, 3R01HL088128]; AHA South Central Affiliate
   [09GRNT2060182]; American Heart Association (AHA) [09GRNT2060182]
   Funding Source: American Heart Association (AHA)
FX This work was supported by NIH grants RO1 HL088128 and 3R01HL088128 and
   AHA South Central Affiliate Grant-in-Aid 09GRNT2060182 to E. M. and
   departmental start-up funds to I. S. The funders had no role in study
   design, data collection and analysis, decision to publish, or
   preparation of the manuscript.
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   Sharina IG, 2011, NITRIC OXIDE
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NR 51
TC 21
Z9 24
U1 0
U2 3
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD JUL 20
PY 2012
VL 7
IS 7
AR e41099
DI 10.1371/journal.pone.0041099
PG 9
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 977GL
UT WOS:000306644600048
PM 22911749
OA gold, Green Submitted, Green Published
DA 2025-04-10
ER

PT J
AU Rojas, EA
   Corchete, LA
   San-Segundo, L
   Martínez-Blanch, JF
   Codoñer, FM
   Paíno, T
   Puig, N
   García-Sanz, R
   Mateos, MV
   Ocio, EM
   Misiewicz-Krzeminska, I
   Gutiérrez, NC
AF Rojas, Elizabeta A.
   Antonio Corchete, Luis
   San-Segundo, Laura
   Martinez-Blanch, Juan F.
   Codoner, Francisco M.
   Paino, Teresa
   Puig, Noemi
   Garcia-Sanz, Ramon
   Victoria Mateos, Maria
   Ocio, Enrique M.
   Misiewicz-Krzeminska, Irena
   Gutierrez, Norma C.
TI Amiloride, An Old Diuretic Drug, Is a Potential Therapeutic Agent for
   Multiple Myeloma
SO CLINICAL CANCER RESEARCH
LA English
DT Article
ID ZIRCONIUM CYCLOSILICATE ZS-9; KIDNEY-DISEASE; IN-VITRO; CELLS; CANCER;
   INHIBITION; P53; PHOSPHORYLATION; HYPERKALEMIA; COMBINATION
AB Purpose: The search for new drugs that control the continuous relapses of multiple myeloma is still required. Here, we report for the first time the potent antimyeloma activity of amiloride, an old potassium-sparing diuretic approved for the treatment of hypertension and edema due to heart failure.
   Experimental Design: Myeloma cell lines and primary samples were used to evaluate cytotoxicity of amiloride. In vivo studies were carried out in a xenograft mouse model. The mechanisms of action were investigated using RNA-Seq experiments, qRT-PCR, immunoblotting, and immunofluorescence assays.
   Results: Amiloride-induced apoptosis was observed in a broad panel of multiple myeloma cell lines and in a xenograft mouse model. Moreover, amiloride also had a synergistic effect when combined with dexamethasone, melphalan, lenalidomide, and pomalidomide. RNA-Seq experiments showed that amiloride not only significantly altered the level of transcript isoforms and alternative splicing events, but also deregulated the spliceosomal machinery. In addition, disruption of the splicing machinery in immunofluorescence studies was associated with the inhibition of myeloma cell viability after amiloride exposure. Although amiloride was able to induce apoptosis in myeloma cells lacking p53 expression, activation of p53 signaling was observed in wild-type and mutated TP53 cells after amiloride exposure. On the other hand, we did not find a significant systemic toxicity in mice treated with amiloride.
   Conclusions: Overall, our results demonstrate the antimyeloma activity of amiloride and provide a mechanistic rationale for its use as an alternative treatment option for relapsed multiple myeloma patients, especially those with 17p deletion or TP53 mutations that are resistant to current therapies. (C) 2017 AACR.
C1 [Rojas, Elizabeta A.; Antonio Corchete, Luis; San-Segundo, Laura; Paino, Teresa; Puig, Noemi; Garcia-Sanz, Ramon; Victoria Mateos, Maria; Ocio, Enrique M.; Misiewicz-Krzeminska, Irena; Gutierrez, Norma C.] Canc Res Ctr IBMCC USAL CSIC, Salamanca, Spain.
   [Rojas, Elizabeta A.; Antonio Corchete, Luis; San-Segundo, Laura; Paino, Teresa; Puig, Noemi; Garcia-Sanz, Ramon; Victoria Mateos, Maria; Ocio, Enrique M.; Misiewicz-Krzeminska, Irena; Gutierrez, Norma C.] Inst Biomed Res Salamanca IBSAL, Salamanca, Spain.
   [Antonio Corchete, Luis; Puig, Noemi; Garcia-Sanz, Ramon; Victoria Mateos, Maria; Ocio, Enrique M.; Gutierrez, Norma C.] Univ Hosp Salamanca, Hematol Dept, Paseo San Vicente 58-182, Salamanca 37007, Spain.
   [Martinez-Blanch, Juan F.; Codoner, Francisco M.] Lifesequencing SL, Valencia, Spain.
   [Misiewicz-Krzeminska, Irena] Natl Med Inst, Warsaw, Poland.
C3 Consejo Superior de Investigaciones Cientificas (CSIC); CSIC-USAL -
   Instituto de Biologia Molecular y Celular del Cancer de Salamanca
   (IBMCC); University of Salamanca; National Medicines Institute Lekow
   (NIL)
RP Gutiérrez, NC (corresponding author), Univ Hosp Salamanca, Hematol Dept, Paseo San Vicente 58-182, Salamanca 37007, Spain.
EM normagu@usal.es
RI Mateos, Maria/AFP-2658-2022; Rodriguez, Juan/ABB-6650-2020; Rojas
   Ricardo, Elizabeta de los A./J-3243-2016; Garcia-Sanz,
   Ramon/B-7986-2017; MISIEWICZ-KRZEMINSKA, IRENA/M-4629-2015; San Segundo,
   Laura/E-6441-2018; Corchete Sanchez, Luis Antonio/D-1336-2018
OI Martinez-Blanch, Juan F/0000-0002-9340-6207; Rojas Ricardo, Elizabeta de
   los A./0000-0002-2541-7254; Garcia-Sanz, Ramon/0000-0003-4120-2787;
   MISIEWICZ-KRZEMINSKA, IRENA/0000-0002-4206-8586; Gutierrez,
   Norma/0000-0001-5834-9510; San Segundo, Laura/0000-0003-2391-5935;
   Corchete Sanchez, Luis Antonio/0000-0003-4577-8599; Ocio, Enrique
   M./0000-0002-5765-0085
FU Instituto de Salud Carlos III-Cofinanciacion; FEDER [PI13/00111,
   PI16/01074]; Asociacion Espanola Contra el Cancer (AECC) [GCB120981SAN];
   Gerencia Regional de Salud, Junta de Castilla y Leon [BIO/SA57/13,
   BIO/SA22/15]; INNOCAMPUS Program [CEI10-1-0010]; International Myeloma
   Foundation; Fundacion Espanola de Hematologia y Hemoterapia
FX This study was partially supported by the Instituto de Salud Carlos
   III-Cofinanciacion with funding from FEDER (PI13/00111 and PI16/01074),
   Asociacion Espanola Contra el Cancer (AECC, GCB120981SAN), Gerencia
   Regional de Salud, Junta de Castilla y Leon (BIO/SA57/13 and
   BIO/SA22/15), and the INNOCAMPUS Program (CEI10-1-0010). I.
   Misiewicz-Krzeminska was supported by a Black Swan Research Initiative
   (R) grant from the International Myeloma Foundation. L.A. Corchete was
   supported by a grant from the Fundacion Espanola de Hematologia y
   Hemoterapia.
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NR 50
TC 27
Z9 28
U1 1
U2 8
PU AMER ASSOC CANCER RESEARCH
PI PHILADELPHIA
PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA
SN 1078-0432
EI 1557-3265
J9 CLIN CANCER RES
JI Clin. Cancer Res.
PD NOV 1
PY 2017
VL 23
IS 21
BP 6602
EP 6615
DI 10.1158/1078-0432.CCR-17-0678
PG 14
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA FL3ZI
UT WOS:000414165200024
PM 28790111
OA Green Submitted
DA 2025-04-10
ER

PT J
AU Medina, MW
   Gao, F
   Ruan, WM
   Rotter, JI
   Krauss, RM
AF Medina, Marisa Wong
   Gao, Feng
   Ruan, Weiming
   Rotter, Jerome I.
   Krauss, Ronald M.
TI Alternative splicing of 3-hydroxy-3-methylglutaryl coenzyme a reductase
   is associated with plasma low-density lipoprotein cholesterol response
   to simvastatin
SO CIRCULATION
LA English
DT Article
DE cholesterol; genes; genetics; statins
ID GENE; POLYMORPHISM; PRAVASTATIN; VARIANTS; RECEPTOR; THERAPY; PROTEIN;
   EVENTS; SITE
AB Background - HMGCR (3-Hydroxy-3-methylglutaryl coenzyme A reductase), the direct target of statin inhibition, undergoes alternative splicing of exon 13, which encodes part of the statin-binding domain of the enzyme. We hypothesized that HMGCR alternative splicing might be related to the interindividual variation in plasma low-density lipoprotein cholesterol response to statin treatment.
   Methods and Results - We measured mRNA expression of both the full-length and the alternatively spliced HMGCR transcript lacking exon 13 (HMGCRv_1) in 170 simvastatin-incubated immortalized lymphocyte cell lines derived from participants in the Cholesterol and Pharmacogenetics ( CAP) study who were treated with simvastatin 40 mg/d for 6 weeks. Greater upregulation of HMGCRv_1 in vitro was significantly correlated ( P <= 0.0001) with smaller in vivo reductions of plasma total cholesterol, low-density lipoprotein cholesterol, apoprotein B, and triglycerides and explained 6% to 15% of the variation in their response to treatment. In contrast, no significant relationship was found between expression of the full-length HMGCR transcript and in vivo response. By siRNA knockdown of the full-length transcript, we found that HMGCR enzyme activity measured in cells enriched in HMGCRv_1 was relatively resistant to statin inhibition, consistent with the association of increased alternative splicing with reduced statin response in the CAP study. In addition, we found that a common HMGCR single-nucleotide polymorphism (rs3846662) located within intron 13 was associated with variation in the proportion of HMGCR mRNA that is alternatively spliced.
   Conclusions - Variation in the production of an HMGCR isoform with reduced statin sensitivity is a determinant of interindividual differences in low-density lipoprotein cholesterol, apolipoprotein B, and triglyceride response to statin treatment.
C1 [Medina, Marisa Wong; Gao, Feng; Ruan, Weiming; Krauss, Ronald M.] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA.
   [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA.
C3 Children's Hospital Oakland Research Institute; University of California
   System; University of California San Francisco; UCSF Medical Center;
   UCSF Benioff Children's Hospital Oakland; Cedars Sinai Medical Center
RP Krauss, RM (corresponding author), Childrens Hosp Oakland, Res Inst, 5700 Martin Luther King Jr Way, Oakland, CA 94609 USA.
EM rkrauss@chori.org
RI Rotter, Jerome/AAY-6598-2021; Krauss, Ronald M./LTD-4078-2024
FU NHLBI NIH HHS [U01 HL069757, U01 HL069757-06, U01 HL069757-07, U01
   HL69757] Funding Source: Medline
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NR 36
TC 118
Z9 135
U1 1
U2 6
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7322
EI 1524-4539
J9 CIRCULATION
JI Circulation
PD JUL 22
PY 2008
VL 118
IS 4
BP 355
EP 362
DI 10.1161/CIRCULATIONAHA.108.773267
PG 8
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 328KR
UT WOS:000257797800007
PM 18559695
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Hatje, K
   Rahman, RU
   Vidal, RO
   Simm, D
   Hammesfahr, B
   Bansal, V
   Rajput, A
   Mickael, ME
   Sun, T
   Bonn, S
   Kollmar, M
AF Hatje, Klas
   Rahman, Raza-Ur
   Vidal, Ramon O.
   Simm, Dominic
   Hammesfahr, Bjorn
   Bansal, Vikas
   Rajput, Ashish
   Mickael, Michel Edwar
   Sun, Ting
   Bonn, Stefan
   Kollmar, Martin
TI The landscape of human mutually exclusive splicing
SO MOLECULAR SYSTEMS BIOLOGY
LA English
DT Article
DE alternative splicing; differential expression; mutually exclusive
   splicing; splicing mechanisms
ID HUMAN TRANSCRIPTOME; HUMAN GENOME; GENE; DSCAM; INTEGRATION; ISOFORMS;
   CONSERVATION; PREDICTION; ARRHYTHMIA; PROTEOME
AB Mutually exclusive splicing of exons is a mechanism of functional gene and protein diversification with pivotal roles in organismal development and diseases such as Timothy syndrome, cardiomyopathy and cancer in humans. In order to obtain a first genomewide estimate of the extent and biological role of mutually exclusive splicing in humans, we predicted and subsequently validated mutually exclusive exons (MXEs) using 515 publically available RNA-Seq datasets. Here, we provide evidence for the expression of over 855 MXEs, 42% of which represent novel exons, increasing the annotated human mutually exclusive exome more than fivefold. The data provide strong evidence for the existence of large and multi-cluster MXEs in higher vertebrates and offer new insights into MXE evolution. More than 82% of the MXE clusters are conserved in mammals, and five clusters have homologous clusters in Drosophila. Finally, MXEs are significantly enriched in pathogenic mutations and their spatio-temporal expression might predict human disease pathology.
C1 [Hatje, Klas; Simm, Dominic; Hammesfahr, Bjorn; Kollmar, Martin] Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, Grp Syst Biol Motor Proteins, Gottingen, Germany.
   [Hatje, Klas; Rahman, Raza-Ur; Vidal, Ramon O.; Bansal, Vikas; Rajput, Ashish; Mickael, Michel Edwar; Sun, Ting; Bonn, Stefan] German Ctr Neurodegenerat Dis, Grp Computat Syst Biol, Gottingen, Germany.
   [Rahman, Raza-Ur; Bansal, Vikas; Rajput, Ashish; Mickael, Michel Edwar; Sun, Ting; Bonn, Stefan] Univ Clin Hamburg Eppendorf, Inst Med Syst Biol, Ctr Mol Neurobiol, Hamburg, Germany.
   [Simm, Dominic] Georg August Univ, Inst Comp Sci, Theoret Comp Sci & Algorithm Methods, Gottingen, Germany.
   [Bonn, Stefan] German Ctr Neurodegenerat Dis, Tubingen, Germany.
   [Hatje, Klas] Roche Innovat Ctr Basel, Roche Pharmaceut Res & Early Dev, Pharmaceut Sci, Basel, Switzerland.
   [Vidal, Ramon O.] Max Delbruck Ctr Mol Med, Berlin, Germany.
   [Hammesfahr, Bjorn] KWS SAAT SE, RD DM, Einbeck, Germany.
C3 Max Planck Society; Helmholtz Association; German Center for
   Neurodegenerative Diseases (DZNE); University of Hamburg; University
   Medical Center Hamburg-Eppendorf; University of Gottingen; Eberhard
   Karls University of Tubingen; Eberhard Karls University Hospital;
   Helmholtz Association; German Center for Neurodegenerative Diseases
   (DZNE); Roche Holding; Helmholtz Association; Max Delbruck Center for
   Molecular Medicine
RP Kollmar, M (corresponding author), Max Planck Inst Biophys Chem, Dept NMR Based Struct Biol, Grp Syst Biol Motor Proteins, Gottingen, Germany.; Bonn, S (corresponding author), German Ctr Neurodegenerat Dis, Grp Computat Syst Biol, Gottingen, Germany.; Bonn, S (corresponding author), Univ Clin Hamburg Eppendorf, Inst Med Syst Biol, Ctr Mol Neurobiol, Hamburg, Germany.; Bonn, S (corresponding author), German Ctr Neurodegenerat Dis, Tubingen, Germany.
EM sbonn@uke.de; mako@nmr.mpibpc.mpg.de
RI Hatje, Klas/D-1076-2014; Kollmar, Martin/AAF-4966-2020
OI Bonn, Stefan/0000-0003-4366-5662; Mickael, Michel
   Edwar/0000-0002-4186-4900; Bansal, Vikas/0000-0002-0944-7226; Rahman,
   Raza-Ur/0000-0002-7019-5486; Sun, Ting/0000-0002-7104-7215; Simm,
   Dominic/0000-0003-1689-1947; Kollmar, Martin/0000-0002-9768-1855
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NR 90
TC 47
Z9 51
U1 0
U2 17
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1744-4292
J9 MOL SYST BIOL
JI Mol. Syst. Biol.
PD DEC
PY 2017
VL 13
IS 12
AR 959
DI 10.15252/msb.20177728
PG 19
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA FR0KJ
UT WOS:000418750100004
PM 29242366
OA Green Submitted, Green Published, gold
DA 2025-04-10
ER

PT J
AU Warren, CM
   Krzesinski, PR
   Campbell, KS
   Moss, RL
   Greaser, ML
AF Warren, CM
   Krzesinski, PR
   Campbell, KS
   Moss, RL
   Greaser, ML
TI Titin isoform changes in rat myocardium during development
SO MECHANISMS OF DEVELOPMENT
LA English
DT Article
DE titin; cardiac; alternative splicing; rat; passive tension
ID CARDIAC MYOFIBRILLOGENESIS; IMMUNOELECTRON MICROSCOPY; GEL
   ELECTROPHORESIS; STRUCTURAL BASIS; SKELETAL-MUSCLE; ELASTIC PROTEIN;
   Z-LINE; EXPRESSION; MYOSIN; SEQUENCE
AB Developmental changes in the alternative splicing patterns of titin were observed in rat cardiac muscle. Titin from 16-day fetal hearts consisted of a single 3710 kDa band on SDS agarose gels, and it disappeared by 10 days after birth. The major adult N2B isoform (2990 kDa) first appeared in 18-day fetal hearts and its proportion in the ventricle increased to approximately 85% from 20 days of age and older. Changes in three other intermediate-sized N2BA isoform bands also occurred during this same time period. The cDNA sequences of fetal cardiac, adult ventricle, and adult soleus were different in the PEVK and alternatively spliced middle Ig domain. Extensive heterogeneity in splice patterns was found in the N2BA PEVK region. The extra length of the fetal titin isoforms appeared to be due to both a greater number of middle Ig domains expressed plus the inclusion of more PEVK exons. Passive tension measurements on myocyte-sized fragments indicated a significantly lower tension in neonate versus adult ventricles at sarcomere lengths greater than 2.1 mum, consistent with the protein and cDNA sequence results. The time course of the titin isoform switching was similar to that occurring with myosin and troponin I during development. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
C1 Univ Wisconsin, Muscle Biol Lab, Madison, WI 53706 USA.
   Univ Wisconsin, Dept Physiol, Madison, WI 53706 USA.
C3 University of Wisconsin System; University of Wisconsin Madison;
   University of Wisconsin System; University of Wisconsin Madison
RP Univ Wisconsin, Muscle Biol Lab, 1805 Linden Dr W, Madison, WI 53706 USA.
EM mgreaser@ansci.wisc.edu
RI Greaser, Marion/C-6147-2012; Campbell, Kenneth/C-3285-2008
OI Campbell, Kenneth/0000-0001-5615-5958; Krzesinski,
   Pawel/0000-0003-1909-0993
FU NHLBI NIH HHS [HL47053, HL62466] Funding Source: Medline
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NR 53
TC 88
Z9 102
U1 1
U2 7
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0925-4773
EI 1872-6356
J9 MECH DEVELOP
JI Mech. Dev.
PD NOV
PY 2004
VL 121
IS 11
BP 1301
EP 1312
DI 10.1016/j.mod.2004.07.003
PG 12
WC Developmental Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Developmental Biology
GA 861WG
UT WOS:000224448700001
PM 15454261
OA Bronze
DA 2025-04-10
ER

PT J
AU Hua, YL
   Li, XL
   Yin, B
   Lu, SN
   Qian, BL
   Zhou, YZ
   Li, ZY
   Meng, ZZ
   Ma, Y
AF Hua, Yongliang
   Li, Xinglong
   Yin, Bing
   Lu, Shounan
   Qian, Baolin
   Zhou, Yongzhi
   Li, Zhongyu
   Meng, Zhanzhi
   Ma, Yong
TI Genome-wide analysis of alternative splicing differences in hepatic
   ischemia reperfusion injury
SO SCIENTIFIC REPORTS
LA English
DT Article
AB Alternative splicing (AS) contributes to transcript and protein diversity, affecting their structure and function. However, the specific transcriptional regulatory mechanisms underlying AS in the context of hepatic ischemia reperfusion (IR) injury in mice have not been extensively characterized. In this study, we investigated differentially alternatively spliced (DAS) genes and differentially expressed transcripts (DETs) in a mouse model of hepatic IR injury using the high throughput RNA sequencing (RNA-seq) analysis and replicate multivariate analysis of transcript splicing (rMATS) analysis. We further conducted Gene ontology (GO) term enrichment, the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and the protein-protein interaction (PPI) network. A total of 898 DAS genes (p <= 0.05) were screened out in the hepatic IR group compared to the sham group, while functional enrichment analysis revealed that DETs and DAS genes were significantly associated with the ATP-dependent chromain, splicesome and metabolic pathways. The expression level of the DAS genes: Gabpb2, Smg1, Tnrc6c, Mettl17, Smpd4, Kcnt2, D16Ertd472e, Rab3gap2, Echdc2 and Ssx2ip were verified by RT-PCR and qRT-PCR. Our findings provide a comprehensive genome-wide view of AS events in hepatic IR injury in mice, enhancing our understanding of AS dynamics and the molecular mechanisms governing alternative pre-mRNA splicing.
C1 [Hua, Yongliang; Li, Xinglong; Yin, Bing; Lu, Shounan; Qian, Baolin; Zhou, Yongzhi; Li, Zhongyu; Meng, Zhanzhi; Ma, Yong] Harbin Med Univ, Dept Minimally Invas Hepat Surg, Key Lab Hepatosplen Surg, Minist Educ,Affiliated Hosp 1, Harbin, Heilongjiang, Peoples R China.
   [Hua, Yongliang] Harbin Med Univ, Dept Pediat Surg, Key Lab Hepatosplen Surg, Minist Educ,Affiliated Hosp 6, Harbin, Heilongjiang, Peoples R China.
C3 Harbin Medical University; Harbin Medical University
RP Ma, Y (corresponding author), Harbin Med Univ, Dept Minimally Invas Hepat Surg, Key Lab Hepatosplen Surg, Minist Educ,Affiliated Hosp 1, Harbin, Heilongjiang, Peoples R China.
EM mayong@ems.hrbmu.edu.cn
RI Li, Zhongyu/HDO-2794-2022; Ma, Yong/JLM-1543-2023
OI Ma, Yong/0000-0002-6508-508X
FU Scientific Foundation of the First Affiliated Hospital of Harbin Medical
   University [2019L01, HYD2020JQ0007]; Heilongjiang Postdoctoral
   Foundation [LBH-Z11066]; Natural Science Foundation of Heilongjiang
   Province of China [LC2018037]; National Scientific Foundation of China
   [81100305, 81470876, 81270527, 82370643]
FX This work was supported by the Scientific Foundation of the First
   Affiliated Hospital of Harbin Medical University under Grant 2019L01,
   HYD2020JQ0007; Heilongjiang Postdoctoral Foundation under Grant
   LBH-Z11066; Natural Science Foundation of Heilongjiang Province of China
   under Grant LC2018037 and the National Scientific Foundation of China
   under Grant 81100305, 81470876, 81270527 and 82370643.
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   Yang XX, 2022, OXID MED CELL LONGEV, V2022, DOI 10.1155/2022/4942519
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NR 41
TC 0
Z9 0
U1 2
U2 2
PU NATURE PORTFOLIO
PI BERLIN
PA HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY
SN 2045-2322
J9 SCI REP-UK
JI Sci Rep
PD DEC 28
PY 2024
VL 14
IS 1
AR 31349
DI 10.1038/s41598-024-82846-1
PG 10
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA Q6Q5D
UT WOS:001385899200044
PM 39732885
OA gold
DA 2025-04-10
ER

PT J
AU Basnakian, AG
   Singh, AB
   Shah, SV
AF Basnakian, AG
   Singh, AB
   Shah, SV
TI Identification and expression of deoxyribonuclease (DNase) I alternative
   transcripts in the rat
SO GENE
LA English
DT Article
DE deoxyribonuclease I; pre-messenger RNA; alternative splicing; apoptosis;
   kidney; ischemia
ID MESSENGER-RNA LEADER; TRANSLATIONAL INITIATION;
   SACCHAROMYCES-CEREVISIAE; GENOMIC ORGANIZATION; SECONDARY STRUCTURE;
   CELL-DEATH; APOPTOSIS; INHIBITION; PROTEIN; STABILITY
AB Deoxyribonuclease (DNasc) I has been implicated in the induction of DNA fragmentation and cell death, however little is known about its regulation in vivo. In the present study, we describe that DNase I messenger RNA (mRNA) is alternatively spliced in rat kidney, and the activity of the DNase I correlates with the alternative splicing during the course of renal ischemia/reperfusion. Northern blot analysis with mRNA from control rat kidneys and kidneys subjected to ischemia/reperfusion in vivo yielded two bands of approximately 1.3 and 1.5 kb, suggesting the possibility of alternative splicing. However, prolonged reperfusion up to 16 It resulted in the predominant expression of 1.3 kb transcript, The disappearance of the 1.5 kDa band was associated with the increased DNase I activity in the kidney during ischemia/reperfusion. To study the alternative splicing of the DNase I mRNA, rat kidney cortex DNA complementary to RNA library was screened using rat DNasc I probe, Twenty-one positive clones were obtained and were compared with the reported DNase I mRNA transcript cloned from rat parotid gland. All clones showed 100% homology with the reported DNase I coding sequence and part of 5'-untranslated region (5'-UTR), named exon 1 a by us. Twelve out of 21 isolated clones had longer 5'-UTR than previously described, and DNase I pre-mRNA was alternatively spliced in this region. Six out of these 12 clones contained extra up to 153 bp in extreme 5' end, whereas, in six other clones, an internal 132 bp segment (exon 1 b) of this additional sequence was absent, and only the extreme 5'UTR sequence (exon 1c) was found in these clones. The nucleotide analysis showed that alternating exon I b has the possibility of a secondary structure with high internal homology and potential for at least one major stable stein-loop. Both newly identified segments, exons 1 b and 1 c, were also identified in genomic DNA. The long splice variant, containing exon 1 b, is expressed only in the kidney among different tissues tested. Exon 1 b inhibited translational activity of DNasc I mRNA in vitro. Our data suggest that alternative splicing in 5'-UTR in the kidney may provide a prompt DNA-independent regulation of DNase I activity when DNA is damaged during ischemic injury. (C) 2002 Elsevier Science B.V. All rights reserved.
C1 Univ Arkansas Med Sci, Dept Internal Med, Div Nephrol, Little Rock, AR 72205 USA.
   Cent Arkansas Vet Healthcare Syst, Little Rock, AR 72205 USA.
C3 University of Arkansas System; University of Arkansas Medical Sciences;
   US Department of Veterans Affairs; Veterans Health Administration (VHA);
   Central Arkansas Veterans Healthcare System
RP Univ Arkansas Med Sci, Dept Internal Med, Div Nephrol, 4301 W Markham St,Slot 501, Little Rock, AR 72205 USA.
EM basnakianalexeig@uams.edu
RI Shah, Shivam/KXQ-6421-2024
FU NIDDK NIH HHS [P01 DK58324-01A1] Funding Source: Medline
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NR 36
TC 12
Z9 16
U1 0
U2 2
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0378-1119
EI 1879-0038
J9 GENE
JI Gene
PD MAY 1
PY 2002
VL 289
IS 1-2
BP 87
EP 96
AR PII S0378-1119(02)00479-1
DI 10.1016/S0378-1119(02)00479-1
PG 10
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 591EP
UT WOS:000177867000011
PM 12036587
DA 2025-04-10
ER

PT J
AU Shin, J
   Kim, J
AF Shin, Jiheon
   Kim, Jaesang
TI Novel alternative splice variants of chicken NPAS3 are expressed
   in the developing central nervous system
SO GENE
LA English
DT Article
DE NPAS3; Alternative splice variants; Reelin; Sox2; Isl1/2
ID ADULT HIPPOCAMPAL NEUROGENESIS; SCHIZOPHRENIA; GENE; MICE
AB We report isolation of novel splice variants of chicken Neuronal Per-Arnt-Sim domain protein 3 (cNPAS3) gene distinct from the previously predicted cNPAS3 at the 5' end. Newly identified cNPAS3 splice variants feature N-terminus coding sequences with high degrees of homology to human NPAS3 (hNAPS3). We also show that the alternative splicing pattern of NPAS3 is conserved between chicken and human. RNA in situ hybridization indicated that the expression of cNPAS3 in the developing central nervous system (CNS) is limited to the ventricular zone and only partially overlaps with that of chicken Reelin (cReelin), the only known regulatory target gene of NPAS3 in the adult brain. Overexpression of cNPAS3 by in ovo electroporation had little effect on the expression of Sox2, a marker for neural precursors, or of Isl1/2, a marker for early differentiating motor neurons. Taken together with the little effect of cNPAS3 overexpression on cReelin, it is noted that the function of NPAS3 in the developing CNS remains to be determined. Still, identification of proper cDNA sequences for cNPAS3 should represent a solid beginning of the understanding process. (c) 2013 Elsevier B.V. All rights reserved.
C1 [Kim, Jaesang] Ewha Womans Univ, Dept Life Sci, Seoul 120750, South Korea.
   Ewha Womans Univ, Ewha Res Ctr Syst Biol, Seoul 120750, South Korea.
C3 Ewha Womans University; Ewha Womans University
RP Kim, J (corresponding author), Dept Life Sci, Sci Bldg C-516,52 Ewhayeodae Gil, Seoul 120750, South Korea.
EM jkim1964@ewha.ac.kr
RI Kim, Jung Kyu/C-3271-2012
FU Brain Research Center of the 21st Century Frontier Research Program
   [2010K000803]; Ministry of Science, ICT & Future Planning, Republic of
   Korea; Systems Biology Infrastructure Establishment Grant; Gwangju
   Institute of Science and Technology through the Ewha Research Center for
   Systems Biology (ERCSB)
FX This research was supported by a grant (2010K000803) from Brain Research
   Center of the 21st Century Frontier Research Program funded by the
   Ministry of Science, ICT & Future Planning, Republic of Korea and by the
   "Systems Biology Infrastructure Establishment Grant" provided by Gwangju
   Institute of Science and Technology in 2008 through the Ewha Research
   Center for Systems Biology (ERCSB).
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NR 16
TC 4
Z9 5
U1 0
U2 15
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0378-1119
EI 1879-0038
J9 GENE
JI Gene
PD NOV 10
PY 2013
VL 530
IS 2
BP 222
EP 228
DI 10.1016/j.gene.2013.08.024
PG 7
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 235TG
UT WOS:000325743000009
PM 23962688
DA 2025-04-10
ER

PT J
AU Liu, XL
   Ramjiganesh, T
   Chen, YH
   Chung, SW
   Hall, SR
   Schissel, SL
   Padera, RF
   Liao, R
   Ackerman, KG
   Kajstura, J
   Leri, A
   Anversa, P
   Yet, SF
   Layne, MD
   Perrella, MA
AF Liu, Xiaoli
   Ramjiganesh, Tripurasundari
   Chen, Yen-Hsu
   Chung, Su Wol
   Hall, Sean R.
   Schissel, Scott L.
   Padera, Robert F., Jr.
   Liao, Ronglih
   Ackerman, Kate G.
   Kajstura, Jan
   Leri, Annarosa
   Anversa, Piero
   Yet, Shaw-Fang
   Layne, Matthew D.
   Perrella, Mark A.
TI Disruption of Striated Preferentially Expressed Gene Locus Leads to
   Dilated Cardiomyopathy in Mice
SO CIRCULATION
LA English
DT Article
DE cardiomyopathy; hypertrophy; myocytes; genes
ID LIGHT-CHAIN KINASES; SMOOTH-MUSCLE-CELLS; HEART-FAILURE; INTEGRATIVE
   BIOLOGY; ALPHA-TROPOMYOSIN; MYOCARDIAL REGENERATION; PROMOTER ANALYSIS;
   GENOMIC CIRCUITS; TRANSGENIC MICE; STEM-CELLS
AB Background-The striated preferentially expressed gene (Speg) generates 4 different isoforms through alternative promoter use and tissue-specific splicing. Depending on the cell type, Speg isoforms may serve as markers of striated or smooth muscle differentiation.
   Methods and Results-To elucidate function of Speg gene isoforms, we disrupted the Speg gene locus in mice by replacing common exons 8, 9, and 10 with a lacZ gene. beta-Galactosidase activity was detected in cardiomyocytes of the developing heart starting at day 11.5 days post coitum (dpc). beta-Galactosidase activity in other cell types, including vascular smooth muscle cells, did not begin until 18.5 dpc. In the developing heart, protein expression of only Speg alpha and Speg beta isoforms was present in cardiomyocytes. Homozygous Speg mutant hearts began to enlarge by 16.5 dpc, and by 18.5 dpc, they demonstrated dilation of right and left atria and ventricles. These cardiac abnormalities in the absence of Speg were associated with a cellular hypertrophic response, myofibril degeneration, and a marked decrease in cardiac function. Moreover, Speg mutant mice exhibited significant neonatal mortality, with increased death occurring by 2 days after birth.
   Conclusions-These findings demonstrate that mutation of the Speg locus leads to cardiac dysfunction and a phenotype consistent with a dilated cardiomyopathy. (Circulation. 2009;119:261-268.)
C1 [Perrella, Mark A.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA.
   [Padera, Robert F., Jr.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA.
   [Kajstura, Jan; Leri, Annarosa; Anversa, Piero] Brigham & Womens Hosp, Dept Anesthesia, Boston, MA 02115 USA.
   [Liao, Ronglih; Kajstura, Jan; Leri, Annarosa; Anversa, Piero] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA.
   [Liu, Xiaoli; Ramjiganesh, Tripurasundari; Chung, Su Wol; Hall, Sean R.; Schissel, Scott L.; Liao, Ronglih; Kajstura, Jan; Leri, Annarosa; Anversa, Piero; Perrella, Mark A.] Harvard Univ, Sch Med, Boston, MA USA.
   [Padera, Robert F., Jr.] Harvard MIT, Div Hlth Sci & Technol, Boston, MA USA.
   [Chen, Yen-Hsu] Kaohsiung Med Univ, Dept Internal Med, Div Infect Dis, Kaohsiung, Taiwan.
   [Chung, Su Wol] Univ Ulsan, Coll Nat Sci, Sch Biol Sci & Technol, Ulsan 680749, South Korea.
   [Ackerman, Kate G.] Univ Rochester, Dept Pediat, Rochester, NY USA.
   [Yet, Shaw-Fang] Natl Hlth Res Inst, Cardiovasc & Blood Med Res Ctr, Zhunan Town, Taiwan.
   [Layne, Matthew D.] Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA.
C3 Harvard University; Harvard University Medical Affiliates; Brigham &
   Women's Hospital; Harvard University; Harvard University Medical
   Affiliates; Brigham & Women's Hospital; Harvard University; Harvard
   University Medical Affiliates; Brigham & Women's Hospital; Harvard
   University; Harvard University Medical Affiliates; Brigham & Women's
   Hospital; Harvard University; Harvard Medical School; Harvard
   University; Massachusetts Institute of Technology (MIT); Kaohsiung
   Medical University; University of Ulsan; University of Rochester;
   National Health Research Institutes - Taiwan; Boston University
RP Perrella, MA (corresponding author), Brigham & Womens Hosp, Div Pulm & Crit Care Med, 75 Francis St, Boston, MA 02115 USA.
EM mperrella@rics.bwh.harvard.edu
RI Liu, Xiaoli/ADL-6153-2022; Chen, Yen-Hsu/D-5484-2009; Yet,
   Shaw-Fang/B-1067-2010
OI Padera, Robert/0000-0002-4571-5494; Yet, Shaw-Fang/0000-0001-9097-3962;
   Liao, Ronglih/0000-0002-9598-9020; Chen, Yen-hsu/0000-0002-8667-4844;
   Layne, Matthew/0000-0003-0007-4870; Liu, Xiaoli/0000-0003-2904-4413
FU National Institutes of Health [HL65639, HL60788, GM53249]; Harvard
   University-Kaohsiung Medical University Alliance; National Science
   Council (Taiwan) [NSC92-2314-B-037-028]
FX This work was supported by National Institutes of Health grants HL65639,
   HL60788, and GM53249 (to Dr Perrella), a grant from the March of Dimes
   Birth Defects Foundation (to Dr Perrella), and Harvard
   University-Kaohsiung Medical University Alliance and National Science
   Council (Taiwan) grant NSC92-2314-B-037-028 (to Dr Chen).
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NR 42
TC 32
Z9 38
U1 0
U2 10
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7322
EI 1524-4539
J9 CIRCULATION
JI Circulation
PD JAN 20
PY 2009
VL 119
IS 2
BP 261
EP U99
DI 10.1161/CIRCULATIONAHA.108.799536
PG 18
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 396XL
UT WOS:000262625300011
PM 19118250
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Vihma, H
   Pruunsild, P
   Timmusk, T
AF Vihma, Hanna
   Pruunsild, Priit
   Timmusk, Tonis
TI Alternative splicing and expression of human and mouse NFAT genes
SO GENOMICS
LA English
DT Article
DE NFAT; Alternative splicing; Ca2+-regulated transcription factor;
   Calcineurin; Neurons; Brain; Nervous system
ID ACTIVATED T-CELLS; TRANSCRIPTION FACTOR NFATP; NUCLEAR FACTOR;
   FUNCTIONAL-CHARACTERIZATION; HIPPOCAMPAL-NEURONS; CALCINEURIN; FAMILY;
   PATHWAY; ATC; GROWTH
AB Four members of the nuclear factor of activated T cells (NFAT) family (NFATC1, NFATC2, NFATC3, and NFATC4) are Ca2+-regulated transcription factors that regulate several processes in vertebrates, including the development and function of the immune, cardiovascular, musculoskeletal, and nervous systems. Here we describe the structures and alternative splicing of the human and mouse NFAT genes, including novel splice variants for NFATC1, NFATC2, NFATC3, and NFATC4, and show the expression of different NFAT mRNAs in various mouse and human tissues and brain regions by RT-PCR. Our results show that alternatively spliced NFAT mRNAs are expressed differentially and could contribute to the diversity of functions of the NFAT proteins. Since NFAT family members are Ca2+-regulated and have critical roles in neuronal gene transcription in response to electrical activity, we describe the expression of NFATC1, NFATC2, NFATC3, and NFATC4 mRNAs in the adult mouse brain and in the adult human hippocampus using in situ hybridization and show that all NFAT mRNAs are expressed in the neurons of the mouse brain with specific patterns for each NFAT. (C) 2008 Elsevier Inc. All rights reserved
C1 [Vihma, Hanna; Pruunsild, Priit; Timmusk, Tonis] Tallinn Univ Technol, Dept Gene Technol, EE-19086 Tallinn, Estonia.
C3 Tallinn University of Technology
RP Timmusk, T (corresponding author), Tallinn Univ Technol, Dept Gene Technol, Akad Tee 15, EE-19086 Tallinn, Estonia.
EM tonis.timmusk@ttu.ee
RI Timmusk, Tonis/JFJ-9675-2023; Timmusk, Tonis/H-4889-2015
OI Pruunsild, Priit/0000-0001-6823-6683; Vihma, Hanna/0000-0002-6128-636X;
   Timmusk, Tonis/0000-0002-1015-3348
FU Wellcome Trust [067952]; Estonian Ministry of Education [0222602,
   0140143]; Estonian Science Foundation [7257]
FX We thank Enn Joeste and Liina Kiho from North Estonian Regional
   Hospital, Tallinn, for help in collecting tissue samples; Epp Vali for
   technical assistance; and Richard Tamme and Liis Leitsalu for help in
   preparing cryostat sections. This work was supported by the following
   grants to T.T.: Wellcome Trust International Senior Research Fellowship
   (Grant 067952), Estonian Ministry of Education and Research (Grants
   0222602 and 0140143), and Estonian Science Foundation (Grant 7257).
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NR 54
TC 58
Z9 78
U1 0
U2 7
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0888-7543
J9 GENOMICS
JI Genomics
PD NOV
PY 2008
VL 92
IS 5
BP 279
EP 291
DI 10.1016/j.ygeno.2008.06.011
PG 13
WC Biotechnology & Applied Microbiology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Genetics & Heredity
GA 369SY
UT WOS:000260715400004
PM 18675896
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU White, ES
   Baralle, FE
   Muro, AF
AF White, E. S.
   Baralle, F. E.
   Muro, A. F.
TI New insights into form and function of fibronectin splice variants
SO JOURNAL OF PATHOLOGY
LA English
DT Review
DE pulmonary fibrosis; arterial thrombosis; alternative splicing;
   fibronectin isoforms; atherosclerosis; mouse models; transgenic mice
ID PRE-MESSENGER-RNA; GROWTH-FACTOR-BETA; PLATELET THROMBUS FORMATION;
   TOLL-LIKE RECEPTOR-4; GENE KNOCKOUT MOUSE; EXTRA DOMAIN-A; PLASMA
   FIBRONECTIN; EDA EXON; EXTRACELLULAR-MATRIX; CELLULAR FIBRONECTIN
AB The extracellular matrix (ECM) is a highly dynamic structure that not only provides a physical framework for cells within connective tissues, but also imparts instructive signals for development, tissue homeostasis and basic cell functions through its composition and ability to exert mechanical forces. The ECM of tissues is composed of, in addition to proteoglycans and hyaluronic acid, a number of proteins, most of which are generated after alternative splicing of their pre-mRNA. However, the precise function of these protein isoforms is still obscure in most cases. Fibronectin (FN), one of the main components of the ECM, is also one of the best-known examples of a family of proteins generated by alternative splicing, having at least 20 different isoforms in humans. Over the last few years, considerable progress on elucidating the functions of the alternatively spliced FN isoforms has been achieved with the essential development of key engineered mouse strains. Here we summarize the phenotypes of the mouse strains having targeted mutations in the FN gene, which may lead to novel insights linking function of alternatively spliced isoforms of fibronectin to human pathologies. Copyright (C) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
C1 [Baralle, F. E.; Muro, A. F.] Int Ctr Genet Engn & Biotechnol, I-34012 Trieste, Italy.
   [White, E. S.] Univ Michigan, Sch Med, Dept Internal Med, Div Pulm & Crit Care Med, Ann Arbor, MI USA.
C3 International Center for Genetic Engineering & Biotechnology (ICGEB);
   University of Michigan System; University of Michigan
RP Muro, AF (corresponding author), Int Ctr Genet Engn & Biotechnol, Padriciano 99, I-34012 Trieste, Italy.
EM muro@cgeb.org
RI Muro, Andrés/K-3156-2016
OI Baralle, Francisco/0000-0002-4645-2809; White, Eric/0000-0003-4060-8443;
   Muro, Andres Fernando/0000-0002-9628-0494
FU National Institutes of Health [HL083085]; T. Franklin Williams
   Geriatrics Research Development Award; CHEST Foundation; Martin E.
   Galvin Fund and Quest for Breath Foundation
FX We thank Fabiola Porro and Emanuele Buratti for critical discussion.
   This work was supported, in part, by National Institutes of Health Grant
   No. HL083085, a T. Franklin Williams Geriatrics Research Development
   Award from the Association of Specialty professors and the CHEST
   Foundation, and from the Martin E. Galvin Fund and Quest for Breath
   Foundation (all to ESW).
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NR 137
TC 256
Z9 293
U1 1
U2 30
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0022-3417
EI 1096-9896
J9 J PATHOL
JI J. Pathol.
PD SEP
PY 2008
VL 216
IS 1
BP 1
EP 14
DI 10.1002/path.2388
PG 14
WC Oncology; Pathology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Pathology
GA 345AS
UT WOS:000258969000001
PM 18680111
OA Green Accepted, Bronze
DA 2025-04-10
ER

PT J
AU Astrof, S
   Hynes, RO
AF Astrof, Sophie
   Hynes, Richard O.
TI Fibronectins in vascular morphogenesis
SO ANGIOGENESIS
LA English
DT Review
DE Alternative splicing; Angiogenesis; Cardiovascular development;
   Endothelium; Integrins; Pericyte; Vascular smooth muscle
ID BLOOD-VESSEL FORMATION; ALTERNATIVELY SPLICED SEGMENTS;
   SMOOTH-MUSCLE-CELLS; PRE-MESSENGER-RNA; ALPHA-V INTEGRINS; EXTRA
   DOMAIN-A; TUMOR VASCULATURE; MOUSE EMBRYOS; MICE LACKING;
   ENDOTHELIAL-CELLS
AB Fibronectin is an extracellular matrix protein found only in vertebrate organisms containing endothelium-lined vasculature and is required for cardiovascular development in fish and mice. Fibronectin and its splice variants containing EIIIA and EIIIB domains are highly upregulated around newly developing vasculature during embryogenesis and in pathological conditions including atherosclerosis, cardiac hypertrophy, and tumorigenesis. However, their molecular roles in these processes are not entirely understood. We review genetic studies examining functions of fibronectin and its splice variants during embryonic cardiovascular development, and discuss potential roles of fibronectin in vascular disease and tumor angiogenesis.
C1 [Astrof, Sophie] Cornell Univ, Weill Med Coll, Dept Cell & Dev Biol, Dept Med,Greenberg Div Cardiol, New York, NY 10065 USA.
   [Hynes, Richard O.] MIT, Koch Inst Integrat Canc Res, Howard Hughes Med Inst, Cambridge, MA 02139 USA.
C3 Cornell University; Weill Cornell Medicine; Howard Hughes Medical
   Institute; Massachusetts Institute of Technology (MIT)
RP Astrof, S (corresponding author), Cornell Univ, Weill Med Coll, Dept Cell & Dev Biol, Dept Med,Greenberg Div Cardiol, New York, NY 10065 USA.
EM soa2004@med.cornell.edu; rohynes@mit.edu
RI Astrof, Sophie/I-4071-2019
OI Astrof, Sophie/0000-0001-9338-9083
FU American Heart Association [0835556D]; Howard Hughes Medical Institue;
   National Heart Lung and Blood Institue [PO1-HL66105]; American Heart
   Association (AHA) [0835556D] Funding Source: American Heart Association
   (AHA)
FX SA is supported by the Scientist Development grant from the American
   Heart Association # 0835556D. Work in the laboratory of ROH is supported
   by the Howard Hughes Medical Institue and by a grant from the National
   Heart Lung and Blood Institue (PO1-HL66105).
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NR 110
TC 203
Z9 239
U1 2
U2 20
PU SPRINGER
PI DORDRECHT
PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS
SN 0969-6970
EI 1573-7209
J9 ANGIOGENESIS
JI Angiogenesis
PD JUN
PY 2009
VL 12
IS 2
BP 165
EP 175
DI 10.1007/s10456-009-9136-6
PG 11
WC Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 459IK
UT WOS:000267095000007
PM 19219555
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Ryan, KJ
   Charlet-B, N
   Cooper, TA
AF Ryan, KJ
   Charlet-B, N
   Cooper, TA
TI Binding of PurH to a muscle-specific splicing enhancer functionally
   correlates with exon inclusion in vivo
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID PRE-MESSENGER-RNA; DROSOPHILA DOUBLESEX GENE; T ALTERNATIVE EXON;
   GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; SKELETAL-MUSCLE; IMP
   CYCLOHYDROLASE; NONMUSCLE CELLS; 3'-SPLICE SITE; PROTEIN; ELEMENTS
AB Regulated alternative splicing of avian cardiac troponin T (cTNT) pre-mRNA requires multiple intronic elements called muscle-specific splicing enhancers (MSEs) that flank the alternative exon 5 and promote muscle-specific exon inclusion. To understand the function of the MSEs in muscle-specific splicing, we sought to identify trans-acting factors that bind to these elements. MSE3, which is located 66-81 nucleotides downstream of exon 5, assembles a complex that is both sequence- and muscle-specific, Purification and characterization of the MSE3 complex identified one component as 5-aminoimidazole-4-carboxamide ribonucleotideformyltransferase/IMP cyclohydrolase (PurH), an enzyme involved in de novo purine synthesis, Recombinant human PurH protein directly binds MSE3 RNA and PurH is the primary determinant of sequence-specific binding in the native complex. Furthermore, we show a direct correlation between the in vitro binding affinity of both the MSE3 complex and recombinant PurH with functional activation of exon inclusion in vivo. Together, these results strongly suggest that PurH performs a second function as a component of a complex that regulates MSE3-dependent exon inclusion.
C1 Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA.
   Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Baylor College of Medicine
RP Cooper, TA (corresponding author), Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA.
RI Charlet-Berguerand, Nicolas/GZM-6636-2022; Charlet-Berguerand,
   Nicolas/I-6727-2016
OI Charlet-Berguerand, Nicolas/0000-0002-4423-4920
FU NHLBI NIH HHS [HL45565] Funding Source: Medline
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NR 52
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Z9 6
U1 0
U2 2
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0021-9258
J9 J BIOL CHEM
JI J. Biol. Chem.
PD JUL 7
PY 2000
VL 275
IS 27
BP 20618
EP 20626
DI 10.1074/jbc.M909977199
PG 9
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 332QG
UT WOS:000088084500057
PM 10801888
OA hybrid
DA 2025-04-10
ER

PT J
AU Ishii, S
   Nakao, S
   Minamikawa-Tachino, R
   Desnick, RJ
   Fan, JQ
AF Ishii, S
   Nakao, S
   Minamikawa-Tachino, R
   Desnick, RJ
   Fan, JQ
TI Alternative splicing in the α-galactosidase A gene:: Increased exon
   inclusion results in the Fabry cardiac phenotype
SO AMERICAN JOURNAL OF HUMAN GENETICS
LA English
DT Article
ID PRE-MESSENGER-RNA; A-GENE; ATYPICAL VARIANT; POINT MUTATIONS; DISEASE;
   SEQUENCE; EXPRESSION; ENHANCER; ELEMENTS; IDENTIFICATION
AB Fabry disease is an inborn error of glycosphingolipid catabolism, resulting from deficient activity of lysosomal a galactosidase A (alpha-Gal A). A rare alternative splicing that introduces a 57-nucleotide (nt) intronic sequence to the alpha-Gal A transcript from intron 4 of the gene has been identified. In addition, a novel midintronic base substitution that results in substantially increased alternative splicing has been identified in a patient with Fabry disease who has the cardiac variant phenotype. The sequence of the patient's intron 4 contains a single G-->A transversion at genomic nt 9331 (IVS4+919G-->A), located at the 5 4 position of the 3 end of the intronic insertion (nts 9278-9334 in the genomic sequence). Minigene constructs containing the entire intron 4 sequence with G, A, C, or T at nt 9331 within an alpha-Gal A complementary DNA expression vector were prepared and expressed in COS-1 cells. Whereas transfection of the G or T minigenes transcribed predominantly normal-sized transcripts, the transfection of the A or C minigenes produced a large amount of the alternatively spliced transcript. These results suggest that the G A mutation, within an A/C-rich domain, results in increased recognition of the alternative splicing by an A/C-rich enhancer-type exonic splicing enhancer. The intronic mutation was not observed in 100 unrelated unaffected men but was present in 6 unrelated patients with cardiac Fabry disease. Reverse-transcriptase polymerase chain reaction of total RNA of various normal human tissues revealed that the alternatively spliced transcript was present in all of the samples, and especially at a higher ratio in the lung and muscle. The normal transcript was present in the patients' lymphoblasts and resulted in similar to10% residual enzyme activity, leading to a cardiac phenotype of Fabry disease.
C1 Mt Sinai Sch Med, Dept Human Genet, New York, NY 10029 USA.
   Usuki Bio Res Ctr, Oita, Japan.
   Kagoshima Prefectural Kanoya Hosp, Kagoshima, Japan.
   Tokyo Metropolitan Inst Med Sci, Tokyo 113, Japan.
C3 Icahn School of Medicine at Mount Sinai; Tokyo Metropolitan Institute of
   Medical Science
RP Fan, JQ (corresponding author), Mt Sinai Sch Med, Dept Human Genet, Box 1498,5th Ave & 100th St, New York, NY 10029 USA.
RI Tachino, Reiko/Q-9946-2019
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NR 39
TC 135
Z9 142
U1 2
U2 9
PU UNIV CHICAGO PRESS
PI CHICAGO
PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA
SN 0002-9297
J9 AM J HUM GENET
JI Am. J. Hum. Genet.
PD APR
PY 2002
VL 70
IS 4
BP 994
EP 1002
DI 10.1086/339431
PG 9
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 528PL
UT WOS:000174252100016
PM 11828341
OA Bronze, Green Published
DA 2025-04-10
ER

PT J
AU MacLean, DW
   Meedel, TH
   Hastings, KEM
AF MacLean, DW
   Meedel, TH
   Hastings, KEM
TI Tissue-specific alternative splicing of ascidian troponin I isoforms -
   Redesign of a protein isoform-generating mechanism during chordate
   evolution
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID CARDIAC TROPONIN; TRANSGENIC MICE; DEVELOPMENTAL EXPRESSION; STRIATED
   MUSCLES; MESSENGER-RNA; NEURAL CREST; CDNA CLONE; RAT-HEART; GENE; SLOW
AB In vertebrates, troponin I (TnI) exists as shorter and longer isoforms encoded by distinct genes expressed in skeletal and cardiac muscle, respectively. We report that the protochordate ascidian Ciona intestinalis expresses a homologous set of shorter and longer TnI isoforms in body wall muscle and heart, respectively. The heart-specific segment of the ascidian longer TnI isoform shares several sequence features with vertebrate cardiac TnI but lacks the protein kinase A phosphorylation sites implicated in sympatho-adrenal control of cardiac function, In contrast with vertebrates, the ascidian longer and shorter TnI isoforms are produced from a single gene by tissue-specific alternative RNA splicing; remarkably, the molecular mechanism of TnI isoform generation has been entirely reworked during ascidian/vertebrate evolution. Because alternative splicing is the more probable chordate ancestral condition, the long/cardiac versus short/somatic muscle pattern of TnI: isoforms likely existed before the occurrence of the gene duplication events that created the vertebrate TnI gene family. Thus, gene duplication was apparently not the primary engine of isoform diversity in this aspect of TnI gene family evolution; rather, it simply provided an alternative (transcriptional) means of maintaining a previously established system of isoform diversity and tissue specificity based on alternative RNA splicing.
C1 McGill Univ, Dept Biol, Montreal, PQ H3A 2B4, Canada.
   Rhode Isl Coll, Dept Biol, Providence, RI 02908 USA.
   McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada.
C3 McGill University; Rhode Island College; McGill University
RP Hastings, KEM (corresponding author), McGill Univ, Montreal Neurol Inst, 3801 Univ St, Montreal, PQ H3A 2B4, Canada.
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NR 40
TC 36
Z9 41
U1 0
U2 9
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0021-9258
J9 J BIOL CHEM
JI J. Biol. Chem.
PD DEC 19
PY 1997
VL 272
IS 51
BP 32115
EP 32120
DI 10.1074/jbc.272.51.32115
PG 6
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA YM852
UT WOS:000071108000028
PM 9405409
OA hybrid
DA 2025-04-10
ER

PT J
AU Nutter, CA
   Jaworski, E
   Verma, SK
   Perez-Carrasco, Y
   Kuyumcu-Martinez, MN
AF Nutter, Curtis A.
   Jaworski, Elizabeth
   Verma, Sunil K.
   Perez-Carrasco, Yareli
   Kuyumcu-Martinez, Muge N.
TI DEVELOPMENTALLY REGULATED ALTERNATIVE SPLICING IS PERTURBED IN TYPE 1
   DIABETIC SKELETAL MUSCLE
SO MUSCLE & NERVE
LA English
DT Article
DE alternative splicing; muscle development; RNA binding proteins; skeletal
   muscle; type 1 diabetes
ID RNA-BINDING PROTEINS; PRE-MESSENGER-RNA; MYOTONIC-DYSTROPHY; HEART
   DEVELOPMENT; SATELLITE CELL; STEM-CELLS; CALCINEURIN; MECHANISMS;
   RBFOX2; CARDIOMYOPATHY
AB Introduction: Type 1 diabetic patients can develop skeletal muscle weakness and atrophy by molecular mechanisms that are not well understood. Alternative splicing (AS) is critical for gene expression in the skeletal muscle, and its dysregulation is implicated in muscle weakness and atrophy. Therefore, we investigated whether AS patterns are affected in type 1 diabetic skeletal muscle contributing to skeletal muscle defects. Methods: AS patterns were determined by reverse transcription- polymerase chain reaction and levels of RNA binding proteins were assessed by Western blot in type 1 diabetic mouse skeletal muscle and during normal mouse skeletal muscle development. Results: Five genes with critical functions in the skeletal muscle are misspliced in type 1 diabetic skeletal muscle, resembling their AS patterns at embryonic stages. AS of these genes undergoes dramatic transitions during skeletal muscle development, correlating with changes in specific RNA binding proteins. Conclusion: Embryonic spliced variants are inappropriately expressed in type 1 diabetic skeletal muscle.
C1 [Nutter, Curtis A.; Jaworski, Elizabeth; Verma, Sunil K.; Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Biochem & Mol Biol, 301 Univ Blvd, Galveston, TX 77555 USA.
   [Perez-Carrasco, Yareli] Univ Texas Arlington, Dept Biol, Arlington, TX 76019 USA.
   [Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Neurosci & Cell Biol, Galveston, TX 77555 USA.
   [Kuyumcu-Martinez, Muge N.] Univ Texas Med Branch, Inst Translat Sci, Galveston, TX 77555 USA.
C3 University of Texas System; University of Texas Medical Branch
   Galveston; University of Texas System; University of Texas Arlington;
   University of Texas System; University of Texas Medical Branch
   Galveston; University of Texas System; University of Texas Medical
   Branch Galveston
RP Kuyumcu-Martinez, MN (corresponding author), Univ Texas Med Branch, Biochem & Mol Biol, 301 Univ Blvd, Galveston, TX 77555 USA.
EM nmmartin@utmb.edu
RI Verma, Sunil/J-8838-2019
OI Jaworski, Elizabeth/0000-0002-4886-0451
FU March of Dimes [5FY12-21]; American Heart Association [15GRNT22830010];
   UTMB IHII Mini Center; University of Texas Medical Branch; BMB; National
   Institutes of Health/National Heart Lung, and Blood Institute
   [R01HL135031]; American Heart Association (AHA) [15GRNT22830010] Funding
   Source: American Heart Association (AHA)
FX This work was supported in part by the March of Dimes (Award 5FY12-21),
   American Heart Association (Grant 15GRNT22830010), UTMB IHII Mini Center
   (pilot award), University of Texas Medical Branch startup funds, BMB
   (pilot award), the National Institutes of Health/National Heart Lung,
   and Blood Institute (Grant R01HL135031 to M.N.K.-M), and the University
   of Texas Medical Branch (Kempner Fellowship to C.A.N.).
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NR 52
TC 15
Z9 16
U1 0
U2 6
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0148-639X
EI 1097-4598
J9 MUSCLE NERVE
JI Muscle Nerve
PD OCT
PY 2017
VL 56
IS 4
BP 744
EP 749
DI 10.1002/mus.25599
PG 6
WC Clinical Neurology; Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA FH7ME
UT WOS:000411372400022
PM 28164326
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Naing, YT
   Sun, L
AF Naing, Yadanar Than
   Sun, Lei
TI The Role of Splicing Factors in Adipogenesis and Thermogenesis
SO MOLECULES AND CELLS
LA English
DT Review
DE adipogenesis; adipose tissue; splicing; splicing factors; thermogenesis;
   thermogenic adipocytes
ID RNA-BINDING; ADIPOSE-TISSUE; REGULATOR; PROTEINS; PRDM16; FAT;
   DIFFERENTIATION; RECOGNITION; COMPLEXITY; EXPRESSION
AB Obesity is a significant global health risk that can cause a range of serious metabolic problems, such as type 2 diabetes and cardiovascular diseases. Adipose tissue plays a pivotal role in regulating energy and lipid storage. New research has underlined the crucial role of splicing factors in the physiological and functional regulation of adipose tissue. By generating multiple transcripts from a single gene, alternative splicing allows for a greater diversity of the proteome and transcriptome, which subsequently influence adipocyte development and metabolism. In this review, we provide an outlook on the part of splicing factors in adipogenesis and thermogenesis, and investigate how the different spliced isoforms can affect the development and function of adipose tissue.
C1 [Naing, Yadanar Than; Sun, Lei] Duke NUS Med Sch, Cardiovasc & Metab Disorders Program, Singapore 169857, Singapore.
C3 National University of Singapore
RP Sun, L (corresponding author), Duke NUS Med Sch, Cardiovasc & Metab Disorders Program, Singapore 169857, Singapore.
EM sun.lei@duke-nus.edu.sg
OI Than Naing, Yadanar/0009-0004-2841-6363
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NR 58
TC 11
Z9 11
U1 1
U2 10
PU KOREAN SOC MOLECULAR & CELLULAR  BIOLOGY
PI SEOUL
PA 635-4, YUCKSAM-DONG, GANGNAM-GU, SEOUL 135-703, SOUTH KOREA
SN 1016-8478
EI 0219-1032
J9 MOL CELLS
JI Mol. Cells
PD MAY
PY 2023
VL 46
IS 5
BP 268
EP 277
DI 10.14348/molcells.2023.2195
EA DEC 2023
PG 10
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA H5GZ2
UT WOS:000996258100002
PM 37170770
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU George, CH
   Rogers, SA
   Bertrand, BMA
   Tunwell, REA
   Thomas, NL
   Steele, DS
   Cox, EV
   Pepper, C
   Hazeel, CJ
   Claycomb, WC
   Lai, FA
AF George, Christopher H.
   Rogers, Sarah A.
   Bertrand, Benedicte M. A.
   Tunwell, Richard E. A.
   Thomas, N. Lowri
   Steele, Derek S.
   Cox, Eryl V.
   Pepper, Christopher
   Hazeel, Carolyn J.
   Claycomb, William C.
   Lai, F. Anthony
TI Alternative splicing of ryanodine receptors modulates cardiomyocyte
   Ca<SUP>2+</SUP> signaling and susceptibility to apoptosis
SO CIRCULATION RESEARCH
LA English
DT Article
DE ryanodine receptor; Ca(2+); alternative splicing; cardiomyocyte;
   apoptosis
ID CALCIUM-RELEASE CHANNELS; NUCLEOPLASMIC RETICULUM; INTRACELLULAR CA2+;
   MUSCLE-CELL; IDENTIFICATION; VARIANT; RAT; MITOCHONDRIA; EXPRESSION;
   CAFFEINE
AB Ca(2+) release via type 2 ryanodine receptors ( RyR2) regulates cardiac function. Molecular cloning of human RyR2 identified 2 alternatively spliced variants, comprising 30- and 24-bp sequence insertions; yet their role in shaping cardiomyocyte Ca(2+) signaling and cell phenotype is unknown. We profiled the developmental regulation and the tissue and species specificity of these variants and showed that their recombinant expression in HL-1 cardiomyocytes profoundly modulated nuclear and cytoplasmic Ca(2+) release. All splice variants localized to the sarcoplasmic reticulum, perinuclear Golgi apparatus, and to finger-like invaginations of the nuclear envelope ( nucleoplasmic reticulum). Strikingly, the 24-bp splice insertion that was present at low levels in embryonic and adult hearts was essential for targeting RyR2 to an intranuclear Golgi apparatus and promoted the intracellular segregation of this variant. The amplitude variability of nuclear and cytoplasmic Ca(2+) fluxes were reduced in nonstimulated cardiomyocytes expressing both 30- and 24-bp splice variants and were associated with lower basal levels of apoptosis. Expression of RyR2 containing the 24-bp insertion also suppressed intracellular Ca(2+) fluxes following prolonged caffeine exposure ( 1 mmol/L, 16 hours) that protected cells from apoptosis. The antiapoptotic effects of this variant were linked to increased levels of Bcl-2 phosphorylation. In contrast, RyR2 containing the 30- bp insertion, which was abundant in human embryonic heart but was decreased during cardiac development, did not protect cardiomyocytes from caffeine-evoked apoptosis. Thus, we provide the first evidence that RyR2 splice variants exquisitely modulate intracellular Ca(2+) signaling and are key determinants of cardiomyocyte apoptotic susceptibility.
C1 Cardiff Univ, Sch Med, Heart Res Inst, Dept Cardiol, Cardiff CF14 4XN, Wales.
   UCL, Dept Physiol, London WC1E 6BT, England.
   Univ Leeds, Inst Membrane & Syst Biol, Leeds LS2 9JT, W Yorkshire, England.
   Cardiff Univ, Sch Med, Dept Haematol, Cardiff, Wales.
   Louisiana State Univ, Dept Biochem, Baton Rouge, LA 70803 USA.
C3 Cardiff University; University of London; University College London;
   University of Leeds; Cardiff University; Louisiana State University
   System; Louisiana State University
RP George, CH (corresponding author), Cardiff Univ, Sch Med, Heart Res Inst, Dept Cardiol, Heath Pk, Cardiff CF14 4XN, Wales.
EM georgech@cf.ac.uk
RI Pepper, Chris/B-4357-2009; Steele, Derek/D-4633-2009
OI Steele, Derek/0000-0002-1339-784X; Lai, Tony/0000-0003-2852-8547;
   Pepper, Chris/0000-0003-3603-8839; George,
   Christopher/0000-0001-9852-1135; Thomas, Nia Lowri/0000-0001-8822-8576
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U1 1
U2 5
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA
SN 0009-7330
J9 CIRC RES
JI Circ.Res.
PD MAR 30
PY 2007
VL 100
IS 6
BP 874
EP 883
DI 10.1161/01.RES.0000260804.77807.cf
PG 10
WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Hematology
GA 151TE
UT WOS:000245312900019
PM 17322175
DA 2025-04-10
ER

PT J
AU Cieply, B
   Carstens, RP
AF Cieply, Benjamin
   Carstens, Russ P.
TI Functional roles of alternative splicing factors in human disease
SO WILEY INTERDISCIPLINARY REVIEWS-RNA
LA English
DT Review
ID EPITHELIAL-MESENCHYMAL TRANSITION; AMYOTROPHIC-LATERAL-SCLEROSIS;
   FAMILIAL DILATED CARDIOMYOPATHY; MYOTONIC-DYSTROPHY; BREAST-CANCER;
   MOLECULAR CHARACTERIZATION; BINDING-PROTEIN; TREMOR/ATAXIA SYNDROME;
   HEXANUCLEOTIDE REPEAT; REGULATORY NETWORK
AB Alternative splicing (AS) is an important mechanism used to generate greater transcriptomic and proteomic diversity from a finite genome. Nearly all human gene transcripts are alternatively spliced and can produce protein isoforms with divergent and even antagonistic properties that impact cell functions. Many AS events are tightly regulated in a cell-type or tissue-specific manner, and at different developmental stages. AS is regulated by RNA-binding proteins, including cell- or tissue-specific splicing factors. In the past few years, technological advances have defined genome-wide programs of AS regulated by increasing numbers of splicing factors. These splicing regulatory networks (SRNs) consist of transcripts that encode proteins that function in coordinated and related processes that impact the development and phenotypes of different cell types. As such, it is increasingly recognized that disruption of normal programs of splicing regulated by different splicing factors can lead to human diseases. We will summarize examples of diseases in which altered expression or function of splicing regulatory proteins has been implicated in human disease pathophysiology. As the role of AS continues to be unveiled in human disease and disease risk, it is hoped that further investigations into the functions of numerous splicing factors and their regulated targets will enable the development of novel therapies that are directed at specific AS events as well as the biological pathways they impact. WIREs RNA 2015, 6:311-326. doi: 10.1002/wrna.1276 For further resources related to this article, please visit the . Conflict of interest: The authors have declared no conflicts of interest for this article.
C1 [Carstens, Russ P.] Univ Penn, Perelman Sch Med, Dept Renal Med, Philadelphia, PA 19104 USA.
   Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA.
C3 University of Pennsylvania; University of Pennsylvania
RP Carstens, RP (corresponding author), Univ Penn, Perelman Sch Med, Dept Renal Med, Philadelphia, PA 19104 USA.
EM russcars@upenn.edu
OI Carstens, Russ/0000-0002-8083-0412
FU NIH [GM088809, HG006892, AR066741]
FX We thank Tom Bebee and Auinash Kalsotra for review of the manuscript.
   Work in the Carstens Lab is supported by NIH grants GM088809, HG006892,
   and AR066741.
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NR 114
TC 103
Z9 127
U1 0
U2 35
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1757-7004
EI 1757-7012
J9 WIRES RNA
JI Wiley Interdiscip. Rev.-RNA
PD MAY-JUN
PY 2015
VL 6
IS 3
BP 311
EP 326
DI 10.1002/wrna.1276
PG 16
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA CF8KP
UT WOS:000352808400003
PM 25630614
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Takabatake, N
   Souri, M
   Ichinose, A
AF Takabatake, N
   Souri, M
   Ichinose, A
TI Multiple novel transcripts for apolipoprotein(a)-related gene II
   generated by alternative splicing in tissue- and cell type-specific
   manners
SO JOURNAL OF BIOCHEMISTRY
LA English
DT Article
DE alternative splicing; apolipoprotein(a); Kringle domain; plasminogen;
   reverse transcription PCR
ID PLASMINOGEN-RELATED GENE; FIBRINOLYTIC SYSTEM; THROMBOSIS; FAMILIES;
   REGION; SITE
AB Various Kringle 4 (R4) sequences were identified in human genomic clones and genomic DNAs amplified by PCR. These K4s were homologous to those found in the apo(a) gene and thus termed apo(a)-related genes (ARGs), The same sequences were obtained when human peripheral leukocytes were analyzed by reverse transcription-PCR in order to study the expression mode of the ARGs. It was of note that multiple transcripts with three optional exons for an ARG (ARGII) were detected in leukocytes, indicating that they were generated by alternative splicing. All these transcripts possessed the first half of the second K4 sequence, which had been reported to be skipped. The variant products of ARGII are expected to contain an additional region of either 44, 66, or 100 unique amino acids at the C-terminus of a single K4 unit. When normal human tissues and cultured tumor cells were analyzed, the multiple ARGII transcripts were detected at varying levels. The presence of the cellular state-specific alternative splicing machinery may provide not only redundancy but also diversity in the structure/function of ARGII.
C1 Yamagata Univ, Sch Med, Dept Mol Pathol Biochem, Yamagata 9909585, Japan.
C3 Yamagata University
RP Ichinose, A (corresponding author), Yamagata Univ, Sch Med, Dept Mol Pathol Biochem, Iida Nishi 2-2-2, Yamagata 9909585, Japan.
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NR 19
TC 3
Z9 3
U1 0
U2 1
PU JAPANESE BIOCHEMICAL SOC
PI TOKYO
PA ISHIKAWA BLDG-3F, 25-16 HONGO-5-CHOME, BUNKYO-KU, TOKYO, 113, JAPAN
SN 0021-924X
J9 J BIOCHEM-TOKYO
JI J. Biochem. (Tokyo)
PD SEP
PY 1998
VL 124
IS 3
BP 540
EP 546
DI 10.1093/oxfordjournals.jbchem.a022146
PG 7
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 117KA
UT WOS:000075779400009
PM 9722663
DA 2025-04-10
ER

PT J
AU Marcucci, R
   Romano, M
AF Marcucci, Roberto
   Romano, Maurizio
TI Thrombopoietin and its splicing variants: Structure and functions in
   thrombopoiesis and beyond
SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
LA English
DT Review
DE thrombopoietin; alternative splicing; THPO isoform; thrombocythaemia;
   polymorphism; G-rich splicing control element; evolution
ID RECOMBINANT HUMAN THROMBOPOIETIN; MESSENGER-RNA EXPRESSION; C-TERMINAL
   REGION; MEGAKARYOCYTE GROWTH; HEREDITARY THROMBOCYTHEMIA; CHROMOSOMAL
   LOCALIZATION; MPL LIGAND; PLATELET PRODUCTION; GLYCAN DOMAIN;
   BONE-MARROW
AB Since its cloning in 1994, several studies have reported that thrombopoietin (THPO) presents several alternative splicing products that differ from the full-length protein in its 5' UTR, N- or C-terminal regions. Most of these splice variants are evolutionarily conserved and have been detected in different tissues as well as in cell lines. Although the possible functions of the THPO isoforms are still elusive, different clues link them to the peculiar mechanism that regulates THPO production. Moreover, novel fields to explore possible roles of the THPO variants are opened by observations that this hormone can influence the formation of hematopoietic progenitors and its expression occurs in some tumors as well as in tissues not directly related to the thrombopoiesis. In this review, we summarize the structure and functions of THPO through the published evidence on its splicing isoforms and discuss about their involvement with physiopathologic phenomena. (C) 2008 Elsevier B.V. All rights reserved.
C1 [Romano, Maurizio] Univ Trieste, Dept Physiol & Pathol, I-34127 Trieste, Italy.
   [Marcucci, Roberto; Romano, Maurizio] Int Ctr Genet Engn & Biotechnol, I-34012 Trieste, Italy.
C3 University of Trieste; International Center for Genetic Engineering &
   Biotechnology (ICGEB)
RP Romano, M (corresponding author), Univ Trieste, Dept Physiol & Pathol, Via A Fleming 22, I-34127 Trieste, Italy.
EM mromano@icgeb.org
RI Romano, Maurizio/G-9431-2012
OI Romano, Maurizio/0000-0002-4820-2897
FU Telethon [GGP02453] Funding Source: Medline
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NR 56
TC 13
Z9 18
U1 1
U2 6
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0925-4439
EI 0006-3002
J9 BBA-MOL BASIS DIS
JI Biochim. Biophys. Acta-Mol. Basis Dis.
PD JUL-AUG
PY 2008
VL 1782
IS 7-8
BP 427
EP 432
DI 10.1016/j.bbadis.2008.03.007
PG 6
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA 324YJ
UT WOS:000257555000001
PM 18433726
OA Green Submitted, Bronze
DA 2025-04-10
ER

PT J
AU Blechschmidt, S
   Haufe, V
   Benndorf, K
   Zimmer, T
AF Blechschmidt, Steve
   Haufe, Volker
   Benndorf, Klaus
   Zimmer, Thomas
TI Voltage-gated Na<SUP>+</SUP> channel transcript patterns in the
   mammalian heart are species-dependent
SO PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY
LA English
DT Review
DE Na+ channels; Alternative splicing; Cardiomyocytes; Developmental
   regulation; Gene expression
ID CARDIAC SODIUM-CHANNEL; RAT VENTRICULAR MYOCYTES; NA(V)1.5 CHANNEL;
   SINOATRIAL NODE; MOUSE HEART; EXPRESSION; REQUIREMENT; VARIANTS; GENE;
   CONTRACTION
AB In the present study we investigated whether transcription, alternative splicing and developmental regulation of voltage-gated Na+ channels occur in a species-dependent manner in the mammalian heart. The composition of the Na+ channel transcript pool including Na(v)1.1-Na(v)1.5 was analysed by RT-PCR in mouse, rat, pi,g, and human hearts. We found that relative transcript levels of tetrodotoxin (TTX) sensitive channels (Na(v)1.1-Na(v)1.4) decreased with increasing heart size (30% for Mouse, 8% for rat, and 4% for pig/human). Considering transcript levels of individual isoforms, human and pig hearts were ready indistinguishable whereas large differences existed between human and mouse. We also noticed that alternative splicing and age-dependent Na+ channel expression occurred in a species-dependent manner. Unexpectedly, we even observed gender differences in the cardiac levels of TTX sensitive Na+ channels in humans. Our data suggest that species differences could underlie published discrepancies oil the role of TTX sensitive Na+ channels in the heart and that the functions of those minor cardiac isoforms in normal and diseased hearts are best studied in larger mammalian animals. (C) 2009 Elsevier Ltd. All rights reserved.
C1 [Blechschmidt, Steve; Haufe, Volker; Benndorf, Klaus; Zimmer, Thomas] Univ Jena, Inst Physiol 2, D-07743 Jena, Germany.
C3 Friedrich Schiller University of Jena
RP Zimmer, T (corresponding author), Univ Jena, Inst Physiol 2, Kollegiengasse 9, D-07743 Jena, Germany.
EM thomas.zimmer@mti.uni-jena.de
RI Zimmer, Thomas/ISU-6303-2023
OI Benndorf, Klaus/0000-0002-0707-4083
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NR 31
TC 51
Z9 58
U1 1
U2 6
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 0079-6107
J9 PROG BIOPHYS MOL BIO
JI Prog. Biophys. Mol. Biol.
PD OCT-NOV
PY 2008
VL 98
IS 2-3
SI SI
BP 309
EP 318
DI 10.1016/j.pbiomolbio.2009.01.009
PG 10
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA 430CQ
UT WOS:000264966800019
PM 19351521
OA Bronze
DA 2025-04-10
ER

PT J
AU Nakamori, M
   Kimura, T
   Kubota, T
   Matsumura, T
   Sumi, H
   Fujimura, H
   Takahashi, MP
   Sakoda, S
AF Nakamori, M.
   Kimura, T.
   Kubota, T.
   Matsumura, T.
   Sumi, H.
   Fujimura, H.
   Takahashi, M. P.
   Sakoda, S.
TI Aberrantly spliced α-dystrobrevin alters α-syntrophin binding in
   myotonic dystrophy type 1
SO NEUROLOGY
LA English
DT Article
ID PRE-MESSENGER-RNA; SKELETAL-MUSCLE; PROTEIN; TORPEDO; DEFICIENCY;
   EXPRESSION; INTERACTS; ISOFORMS; RECEPTOR; COMPLEX
AB Background: Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by a CTG repeat expansion in the DMPK gene. Aberrant messenger RNA (mRNA) splicing of several genes has been reported to explain some of the symptoms in DM1, but the cause of muscle wasting is still unknown. By contrast, many forms of muscular dystrophy are caused by abnormalities of the dystrophin - glycoprotein complex (DGC). alpha-Dystrobrevin is a key component of the DGC in striated muscle and plays important roles in maturation and signal transduction by interacting with alpha-syntrophin. The goal of this study was to investigate alternative splicing of alpha-dystrobrevin in DM1 and examine alpha-syntrophin binding of different alpha-dystrobrevin splice isoforms.
   Methods: Splicing patterns of alpha-dystrobrevin in DM1 muscle were studied by reverse-transcriptase PCR. Expression of the variant splice isoform was examined by immunoblotting and immunohistochemistry. Alternatively spliced isoforms were expressed in cultured cells to investigate interaction with alpha-syntrophin. alpha-Syntrophin expression was examined by immunoblotting.
   Results: alpha-Dystrobrevin mRNA including exons 11A and 12 was increased in both skeletal and cardiac muscle of DM1 patients. The aberrantly spliced alpha-dystrobrevin isoform was localized to the sarcolemma, and showed increased binding with alpha-syntrophin. Furthermore, levels of alpha-syntrophin associated with the DGC were increased in DM1 muscle.
   Conclusion: Alternative splicing of alpha-dystrobrevin is dysregulated in myotonic dystrophy type 1 (DM1) muscle, resulting in changes in alpha-syntrophin binding. These results raise the possibility that effects on alpha-dystrobrevin splicing may influence signaling in DM1 muscle cells.
C1 [Nakamori, M.; Kimura, T.; Kubota, T.; Sumi, H.; Takahashi, M. P.; Sakoda, S.] Osaka Univ, Grad Sch Med, Dept Neurol, Osaka, Japan.
   [Matsumura, T.; Fujimura, H.] Toneyama Natl Hosp, Dept Neurol, Osaka, Japan.
C3 The University of Osaka
RP Takahashi, MP (corresponding author), 2-2,D-4 Yamadaoka, Osaka 5650871, Japan.
EM mtakahas@neurol.med.osaka-u.ac.jp
RI Takahashi, Masanori/O-8946-2019; Nakamori, Masayuki/ABE-2169-2020
OI Takahashi, Masanori P/0000-0002-5513-5012; Nakamori,
   Masayuki/0000-0003-4714-3044; KUBOTA, TOMOYA/0000-0003-1004-8537
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NR 43
TC 28
Z9 31
U1 0
U2 2
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0028-3878
EI 1526-632X
J9 NEUROLOGY
JI Neurology
PD FEB 26
PY 2008
VL 70
IS 9
BP 677
EP 685
DI 10.1212/01.wnl.0000302174.08951.cf
PG 9
WC Clinical Neurology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 267XS
UT WOS:000253543100004
PM 18299519
DA 2025-04-10
ER

PT J
AU Jin, BX
   Han, YL
   Xu, F
   Wang, JJ
   Zhao, YZ
   Liu, HJ
   Wang, F
   Wang, Z
   Lu, WT
   Wang, MY
   Cui, LL
   Zhao, YN
   Hao, JW
   Chai, GL
AF Jin, Bingxue
   Han, Yilai
   Xu, Fang
   Wang, Junjie
   Zhao, Yunzhi
   Liu, Haijie
   Wang, Fei
   Wang, Ze
   Lu, Wanting
   Wang, Mingyang
   Cui, Lili
   Zhao, Yinan
   Hao, Junwei
   Chai, Guoliang
TI Translatome analysis in acute ischemic stroke: Astrocytes and microglia
   exhibit differences in poststroke alternative splicing of expressed
   transcripts
SO FASEB JOURNAL
LA English
DT Article
DE alternative splicing; astrocyte; microglia; stroke; translatome
ID ANTISENSE OLIGONUCLEOTIDE THERAPIES; MESSENGER-RNA; REACTIVE ASTROCYTES;
   PROFILING APPROACH; CELL; MOUSE
AB Astrocytes and microglia undergo dynamic and complex morphological and functional changes following ischemic stroke, which are instrumental in both inflammatory responses and neural repair. While gene expression alterations poststroke have been extensively studied, investigations into posttranscriptional regulatory mechanisms, specifically alternative splicing (AS), remain limited. Utilizing previously reported Ribo-Tag-seq data, this study analyzed AS alterations in poststroke astrocytes and microglia from young adult male and female mice. Our findings reveal that in astrocytes, compared to the sham group, 109 differential alternative splicing (DAS) events were observed at 4 h poststroke, which increased to 320 at day 3. In microglia, these numbers were 316 and 266, respectively. Interestingly, the disparity between DAS genes and differentially expressed genes is substantial, with fewer than 10 genes shared at both poststroke time points in astrocytes and microglia. Gene ontology enrichment analysis revealed the involvement of these DAS genes in diverse functions, encompassing immune response (Adam8, Ccr1), metabolism (Acsl6, Pcyt2, Myo5a), and developmental cell growth (App), among others. Selective DAS events were further validated by semiquantitative RT-PCR. Overall, this study comprehensively describes the AS alterations in astrocytes and microglia during the hyperacute and acute phases of ischemic stroke and underscores the significance of certain hub DAS events in neuroinflammatory processes.
   Utilizing RiboTag-seq translatome data from ischemic stroke mouse models, this study reveals dynamic alternative splicing (AS) changes in astrocytes and microglia at hyperacute (4 h) and acute (3 days) phases poststroke. These findings highlight the critical roles of AS in regulating poststroke neuroinflammation and morphological and functional transformations of glial cells, offering valuable insights for developing future therapies.image
C1 [Jin, Bingxue; Han, Yilai; Xu, Fang; Wang, Junjie; Zhao, Yunzhi; Liu, Haijie; Wang, Fei; Wang, Ze; Lu, Wanting; Wang, Mingyang; Cui, Lili; Zhao, Yinan; Hao, Junwei; Chai, Guoliang] Capital Med Univ, Xuanwu Hosp, Natl Ctr Neurol Disorders, Dept Neurol, Beijing 100053, Peoples R China.
   [Jin, Bingxue; Han, Yilai; Xu, Fang; Wang, Junjie; Zhao, Yunzhi; Liu, Haijie; Wang, Fei; Wang, Ze; Lu, Wanting; Wang, Mingyang; Cui, Lili; Zhao, Yinan; Hao, Junwei; Chai, Guoliang] Beijing Municipal Geriatr Med Res Ctr, Beijing, Peoples R China.
   [Hao, Junwei; Chai, Guoliang] Minist Educ, Key Lab Neurodegenerat Dis, Beijing, Peoples R China.
   [Chai, Guoliang] Chinese Inst Med Res, Beijing, Peoples R China.
C3 Capital Medical University
RP Hao, JW; Chai, GL (corresponding author), Capital Med Univ, Xuanwu Hosp, Natl Ctr Neurol Disorders, Dept Neurol, Beijing 100053, Peoples R China.
EM haojunwei@vip.163.com; guoliang.chai@xwh.ccmu.edu.cn
RI Wang, Junjie/HMV-8487-2023; Wang, Zhong/ABA-8164-2021
FU National Key Research and Development Program of China [2021YFA1101403];
   National Natural Science Foundation of China (NSFC) [82090043, 82104435,
   82001258]; Project of Construction and Support for high- level
   Innovative Teams of Beijing Municipal Institutions [BPHR20220112]; Youth
   Beijing Scholar [NO.020]; Dengfeng Talent Program [DFL20220701]; Project
   for Innovation and Development of Beijing Municipal Geriatric Medical
   Research Center [11000023T000002041657]; Beijing Municipal Public
   Welfare Development and Reform Pilot Project for Medical Research
   Institutes [JYY2023- 7]; General Science and Technology Programme of
   Beijing Municipal Education Commission [KM202110025020]
FX National Key Research and Development Program of China, Grant/Award
   Number: 2021YFA1101403; National Natural Science Foundation of China
   (NSFC), Grant/Award Number: 82090043, 82104435 and 82001258; the Project
   of Construction and Support for high- level Innovative Teams of Beijing
   Municipal Institutions, Grant/Award Number: BPHR20220112; Youth Beijing
   Scholar, Grant/Award Number: NO.020; Dengfeng Talent Program,
   Grant/Award Number: DFL20220701; the Project for Innovation and
   Development of Beijing Municipal Geriatric Medical Research Center,
   Grant/Award Number: 11000023T000002041657; Beijing Municipal Public
   Welfare Development and Reform Pilot Project for Medical Research
   Institutes, Grant/Award Number: JYY2023- 7; the General Science and
   Technology Programme of Beijing Municipal Education Commission,
   Grant/Award Number: KM202110025020
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NR 77
TC 1
Z9 1
U1 3
U2 6
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0892-6638
EI 1530-6860
J9 FASEB J
JI Faseb J.
PD AUG 15
PY 2024
VL 38
IS 15
AR e23855
DI 10.1096/fj.202400341R
PG 17
WC Biochemistry & Molecular Biology; Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other
   Topics; Cell Biology
GA A5D3A
UT WOS:001282729300001
PM 39096134
OA hybrid
DA 2025-04-10
ER

PT J
AU Schiano, C
   Rienzo, M
   Casamassimi, A
   Soricelli, A
   Napoli, C
AF Schiano, Concetta
   Rienzo, Monica
   Casamassimi, Amelia
   Soricelli, Andrea
   Napoli, Claudio
TI Splicing regulators in endothelial cell differentiation
SO JOURNAL OF CARDIOVASCULAR MEDICINE
LA English
DT Article
DE alternative splicing; cell therapy; human muscleblind-like family;
   mediator complex
ID EMBRYONIC STEM-CELLS; MEDIATOR COMPLEX; PROGENITOR CELLS;
   GENE-EXPRESSION; RNA-SEQ; PLURIPOTENCY; LOCALIZATION; DISEASES; NANOG;
   IDENTIFICATION
AB Aims Alternative splicing represents a key mechanism of gene regulation. Despite its role in regulating cell pluripotency and differentiation being well known, the underlining mechanisms are still poorly studied. Here, we investigated the possible involvement of splicing regulators during the different steps of endothelial cell differentiation through expression studies on human circulating progenitors.
   Methods Total RNAs were extracted from all cells and reverse-transcribed. Semiquantitative and real-time RT-PCR was performed using selective oligonucleotides. Differences between group means were considered significant at P value less than 0.05 and more significant at P value less than 0.01. Protein extracts were incubated with an antibody directed against MED23. Immunoprecipitation of supernatants and pellets was probed with both anti-Muscleblind-like splicing regulator (MBNL) 1 and anti-MBNL2 antibodies.
   Results Several clinical trials demonstrated the safety and efficacy of progenitor cells in regenerative therapy of the cardiovascular system. Particularly, we analyzed the expression of genes belonging to muscleblind family members and MED complex subunits, which are known to be involved during differentiation in other models. This study shows that MED23, MBNL1 and MBNL2 were all expressed at high levels only in differentiated cells. Moreover, immunoprecipitation assays indicated that MED23 is able to bind MBNLs in endothelial cells.
   Conclusion Our data suggest that MED23, MBNL1 and MBNL2 could regulate alternative splicing events activated during differentiation through a common mechanism. Hence, these observations corroborate previous evidence that splicing regulators may have an essential role in the basic apparatus required for cell pluripotency and reprogramming, allowing identification of novel biomarkers to use for early diagnosis in cardiovascular diseases.
C1 [Schiano, Concetta; Napoli, Claudio] IRCCS SDN, Via E Gianturco 113, I-80143 Naples, Italy.
   [Rienzo, Monica; Casamassimi, Amelia; Napoli, Claudio] Univ Campania Luigi Vanvitelli, Dept Biochem Biophys & Gen Pathol, Naples, Italy.
   [Soricelli, Andrea] Univ Naples Parthenope, Dept Diagnost Imaging, Naples, Italy.
   [Napoli, Claudio] Univ Campania Luigi Vanvitelli, UOC Immunohematol Transfus Med & Transplant Immun, Reg Reference Lab Transplant Immunol, Dept Med Surg Neurol Metab & Geriatr Sci, Naples, Italy.
C3 IRCCS Istituto di Ricerca Diagnostica e Nucleare (SDN); Universita della
   Campania Vanvitelli; Parthenope University Naples; Universita della
   Campania Vanvitelli
RP Schiano, C (corresponding author), IRCCS SDN, Via E Gianturco 113, I-80143 Naples, Italy.
EM cschiano@sdn-napoli.it
RI Casamassimi, Amelia/AAD-2816-2020; Schiano, Concetta/GOE-4310-2022;
   Rienzo, Monica/AGS-5718-2022; Schiano, Concetta/K-6431-2016; Soricelli,
   Andrea/C-1133-2009
OI Rienzo, Monica/0000-0002-4496-4894; Schiano,
   Concetta/0000-0002-2570-6910; Soricelli, Andrea/0000-0001-7011-7667
FU Ministero della Salute [GR-2011-02349436, RRC-2015-2360454]; P.O.R.
   Campania FSE
FX The work was supported by grants from 'Ministero della Salute'
   (GR-2011-02349436 and RRC-2015-2360454) and P.O.R. Campania FSE
   2007-2013 to the II University of Naples (C.N.).
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NR 38
TC 8
Z9 8
U1 0
U2 4
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 1558-2027
EI 1558-2035
J9 J CARDIOVASC MED
JI J. Cardiovasc. Med.
PD OCT
PY 2017
VL 18
IS 10
BP 742
EP 749
DI 10.2459/JCM.0000000000000536
PG 8
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA FP5SU
UT WOS:000417683000002
PM 28661931
DA 2025-04-10
ER

PT J
AU Martínez-Campos, E
   Hernández-SanMiguel, E
   López-Sánchez, C
   De Pablo, F
   Hernández-Sánchez, C
AF Martinez-Campos, Enrique
   Hernandez-SanMiguel, Esther
   Lopez-Sanchez, Carmen
   De Pablo, Flora
   Hernandez-Sanchez, Catalina
TI Alternative splicing variants of proinsulin mRNA and the effects of
   excess proinsulin on cardiac morphogenesis
SO FEBS LETTERS
LA English
DT Article
DE Proinsulin; Insulin gene; Alternative splicing; Intron retention;
   Cardiogenesis; Cardiac malformation
ID TRANSLATION; HEART
AB Alternative forms of proinsulin mRNA with differential translational capacities and unknown significance are expressed in several developing tissues and in the adult pancreas. In the chick embryo developing heart, we observed low expression of the translationally active transcript of embryonic proinsulin (Pro1B), and predominant expression of the intron 1-unspliced variant, translationally inactive. In the embryonic mouse heart, intron 1-unspliced isoform appeared after E12.5. This tight regulation is required for normal development, since overexpression of Pro1B resulted in abnormal cardiac morphogenesis in 40% of chick embryos, and was accompanied by changes in gene expression of Amhc1 and Vmhc1. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
C1 [Martinez-Campos, Enrique; Hernandez-SanMiguel, Esther; De Pablo, Flora; Hernandez-Sanchez, Catalina] Ctr Invest Biol CSIC, Dev Differentiat Degenerat Lab 3D, Madrid, Spain.
   [Lopez-Sanchez, Carmen] Univ Extremadura, Fac Med, Badajoz, Spain.
   [De Pablo, Flora; Hernandez-Sanchez, Catalina] CIBERDEM ISCIII, Minist Econ & Competitividad MINECO, Madrid, Spain.
C3 Consejo Superior de Investigaciones Cientificas (CSIC); CSIC - Centro de
   Investigaciones Biologicas (CIB); Universidad de Extremadura; CIBER -
   Centro de Investigacion Biomedica en Red; CIBERDEM; Spanish Ministry of
   Economy & Competitiveness
RP De Pablo, F (corresponding author), CSIC, CIB, Ramiro Maeztu 9, E-28040 Madrid, Spain.
EM fdepablo@cib.csic.es; chernandez@cib.csic.es
RI Hernandez Sanchez, Catalina/N-1737-2014; Lopez-Sanchez,
   Carmen/K-5458-2014; Hernandez-SanMiguel, Esther/H-2767-2015
OI Hernandez Sanchez, Catalina/0000-0002-0846-5019; Martinez-Campos,
   Enrique/0000-0002-7110-3651; Lopez-Sanchez, Carmen/0000-0003-3296-2071;
   Hernandez-SanMiguel, Esther/0000-0003-4135-860X
FU initiatives of the MINECO, Spain [BFU 2010-15868, BFU2007-66350/BFI];
   Junta de Extremadura (FEDER) [CTS005]
FX We thank Cayetana Murillo, Isabel Espinosa-Medina and Patricia Vazquez
   for tissue collection, and Rosa Corcoy, Teresa Suarez and Enrique J. de
   la Rosa for their input during the preparation of the manuscript. We are
   grateful to Mario Garcia de Lacoba (CIB, CSIC) for assistance with the
   calculation and plotting of predicted secondary structures. This study
   was funded by BFU 2010-15868 (to FdeP and C.H.S.) and BFU2007-66350/BFI
   (to C.L.-S), initiatives of the MINECO, Spain, and by the Junta de
   Extremadura (FEDER) CTS005 (to C.L.-S). CIBERDEM is an initiative of the
   Instituto de Salud Carlos III (Spain).
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NR 24
TC 4
Z9 6
U1 0
U2 4
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1873-3468
J9 FEBS LETT
JI FEBS Lett.
PD JUL 11
PY 2013
VL 587
IS 14
BP 2272
EP 2277
DI 10.1016/j.febslet.2013.05.060
PG 6
WC Biochemistry & Molecular Biology; Biophysics; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics; Cell Biology
GA 173VN
UT WOS:000321109800030
PM 23747309
OA Green Submitted
DA 2025-04-10
ER

PT J
AU Ichida, M
   Hakamata, Y
   Hayakawa, M
   Ueno, E
   Ikeda, U
   Shimada, K
   Hamamoto, T
   Kagawa, Y
   Endo, H
AF Ichida, M
   Hakamata, Y
   Hayakawa, M
   Ueno, E
   Ikeda, U
   Shimada, K
   Hamamoto, T
   Kagawa, Y
   Endo, H
TI Differential regulation of exonic regulatory elements for
   muscle-specific alternative splicing during myogenesis and cardiogenesis
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID PRE-MESSENGER-RNA; SYNTHASE GAMMA-SUBUNIT; GREEN FLUORESCENT PROTEIN;
   SR-PROTEINS; PREMESSENGER RNA; ENHANCER COMPLEX; BINDING; EXPRESSION;
   SELECTION; DISTINCT
AB Muscle-specific isoform of the mitochondrial ATP synthase gamma subunit (F(1)gamma) was generated by alternative splicing, and exon 9 of the gene was found to be lacking particularly in skeletal muscle and heart tissue. Recently, we reported that alternative splicing of exon 9 was induced by low serum or acidic media in mouse myoblasts, and that this splicing required de novo protein synthesis of a negative regulatory factor (Ichida, M., Endo, H., Ikeda, U., Matsuda, C., Ueno, E., Shimada, K., and Kagawa, Y. (1998) J. Biol. Chem. 273, 8492-8501; Hayakawa, M, Endo, H., Hamamoto, T., and Kagawa, Y. (1998) Biochem Biophys. Res. Commun. 251, 603-608). In the present report, we identified a cis-acting element on the muscle-specific alternatively spliced exon of F(1)gamma gene by an in vivo splicing system using cultured cells and transgenic mice. We constructed a F(1)gamma wild-type minigene, containing the full-length gene from exon 8 to exon 10, and two mutants; one mutant involved a pyrimidine-rich substitution on exon 9, whereas the other was a purine-rich substitution, abbreviated as F(1)gamma Pudel and F(1)gamma Pu-rich mutants, respectively. Based on an in vivo splicing assay using low serum- or acid-stimulated splicing induction system in mouse myoblasts, Pudel mutation inhibited exon inclusion, indicating that a Pu-del mutation would disrupt an exonic splicing enhancer. On the other hand, the Pu-rich mutation blocked muscle-specific exon exclusion following both inductions. Next, we produced transgenic mice bearing both mutant minigenes and analyzed their splicing patterns in tissues. Based on an analysis of F(1)gamma Pu-del mini-gene transgenic mice, the purine nucleotide of this element was shown to be necessary for exon inclusion in non-muscle tissue. In contrast, analysis of F(1)gamma Pu-rich minigene mice revealed that the F(1)gamma Pu-rich mutant exon had been excluded from heart and skeletal muscle of these transgenic mice, despite the fact mutation of the exon inhibited muscle-specific exon exclusion in myotubes of early embryonic stage. These results suggested that the splicing regulatory mechanism underlying F(1)gamma pre-mRNA differed between myotubes and myofibers during myogenesis and cardiogenesis.
C1 Jichi Med Sch, Dept Biochem, Minami Kawachi, Tochigi 3290498, Japan.
   Jichi Med Sch, Dept Cardiol, Minami Kawachi, Tochigi 3290498, Japan.
   Jichi Med Sch, Expt Med Lab, Minami Kawachi, Tochigi 3290498, Japan.
C3 Jichi Medical University; Jichi Medical University; Jichi Medical
   University
RP Endo, H (corresponding author), Jichi Med Sch, Dept Biochem, Minami Kawachi, Tochigi 3290498, Japan.
RI Hakamata, Yoji/AAF-7759-2020
OI Hayakawa, Morisada/0000-0002-1869-2450; Hakamata,
   Yoji/0000-0002-0138-6692
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NR 40
TC 24
Z9 26
U1 0
U2 6
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0021-9258
J9 J BIOL CHEM
JI J. Biol. Chem.
PD MAY 26
PY 2000
VL 275
IS 21
BP 15992
EP 16001
DI 10.1074/jbc.275.21.15992
PG 10
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 318NX
UT WOS:000087291400053
PM 10821853
OA hybrid
DA 2025-04-10
ER

PT J
AU Yu, CY
   Theusch, E
   Lo, K
   Mangravite, LM
   Naidoo, D
   Kutilova, M
   Medina, MW
AF Yu, Chi-Yi
   Theusch, Elizabeth
   Lo, Kathleen
   Mangravite, Lara M.
   Naidoo, Devesh
   Kutilova, Mariya
   Medina, Marisa W.
TI HNRNPA1 regulates HMGCR alternative splicing and modulates
   cellular cholesterol metabolism
SO HUMAN MOLECULAR GENETICS
LA English
DT Article
ID NUCLEAR RIBONUCLEOPROTEIN A1; MESSENGER-RNA; IN-VIVO; HEPG2 CELLS;
   PROTEIN; GENE; EXON; SIMVASTATIN; EXPRESSION; REDUCTASE
AB 3-hydroxy-3-methylglutaryl-CoenzymeAreductase (HMGCR) encodes the rate-limiting enzyme in the cholesterol biosynthesis pathway and is inhibited by statins, a class of cholesterol-lowering drugs. Expression of an alternatively spliced HMGCR transcript lacking exon 13, HMGCR13(-), has been implicated in the variation of plasma LDL-cholesterol (LDL-C) and is the single most informative molecular marker of LDL-C response to statins. Given the physiological importance of this transcript, our goal was to identify molecules that regulate HMGCR alternative splicing. We recently reported gene expression changes in 480 lymphoblastoid cell lines (LCLs) after in vitro simvastatin treatment, and identified a number of statin-responsive genes involved in mRNA splicing. Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) was chosen for follow-up since rs3846662, an HMGCR SNP that regulates exon 13 skipping, was predicted to alter an HNRNPA1 binding motif. Here, we not only demonstrate that rs3846662 modulates HNRNPA1 binding, but also that sterol depletion of human hepatoma cell lines reduced HNRNPA1 mRNA levels, an effect that was reversed with sterol add-back. Overexpression of HNRNPA1 increased the ratio of HMGCR13(2) to total HMGCR transcripts by both directly increasing exon 13 skipping in an allele-related manner and specifically stabilizing the HMGCR13(2) transcript. Importantly, HNRNPA1 overexpression also diminished HMGCR enzyme activity, enhanced LDL-Cuptake and increased cellular apolipoprotein B (APOB). rs1920045, an SNP associated with HNRNPA1 exon 8 alternative splicing, was also associated with smaller statin-induced reduction in total cholesterol from two independent clinical trials. These results suggest that HNRNPA1 plays a role in the variation of cardiovascular disease risk and statin response.
C1 [Yu, Chi-Yi; Theusch, Elizabeth; Lo, Kathleen; Naidoo, Devesh; Kutilova, Mariya; Medina, Marisa W.] Childrens Hosp, Oakland Res Inst, Oakland, CA 94609 USA.
   [Mangravite, Lara M.] Sage Bionetworks, Seattle, WA 98109 USA.
C3 Children's Hospital Oakland Research Institute; Children's Hospital Los
   Angeles
RP Medina, MW (corresponding author), Childrens Hosp, Oakland Res Inst, 5700 Martin Luther King Jr Way, Oakland, CA 94609 USA.
EM mwmedina@chori.org
OI Theusch, Elizabeth/0000-0002-5678-759X
FU NIH [R01 HL104133, U19 HL069757]
FX This work was supported by the NIH (R01 HL104133, U19 HL069757).
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NR 50
TC 53
Z9 60
U1 0
U2 5
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0964-6906
EI 1460-2083
J9 HUM MOL GENET
JI Hum. Mol. Genet.
PD JAN 15
PY 2014
VL 23
IS 2
BP 319
EP 332
DI 10.1093/hmg/ddt422
PG 14
WC Biochemistry & Molecular Biology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Genetics & Heredity
GA AA1EX
UT WOS:000330840400004
PM 24001602
OA Green Published, Bronze
DA 2025-04-10
ER

PT J
AU McGlinchey, JCP
   Tummala, H
   Lester, DH
AF McGlinchey, Jonathan C. P.
   Tummala, Hemanth
   Lester, Douglas H.
TI Correction of the Pathogenic Alternative Splicing, Caused by the Common
   GNB3 c.825C&gt;T Allele, Using a Novel, Antisense Morpholino
SO NUCLEIC ACID THERAPEUTICS
LA English
DT Article
ID PROTEIN BETA-3 SUBUNIT; C825T POLYMORPHISM; GENE POLYMORPHISM;
   BLOOD-PRESSURE; 825T ALLELE; CARDIOVASCULAR-DISEASE; ERECTILE
   DYSFUNCTION; ACE I/D; ASSOCIATION; OBESITY
AB The very common GNB3 c.825C>T polymorphism (rs5443) is present in approximately half of all human chromosomes. Significantly, the presence of the GNB3 825T allele has been strongly associated with predisposition to essential hypertension. Paradoxically the presence of the GNB3 825T allele, in exon 10, introduces a pathogenic alternative RNA splice site into the middle of exon 9. To attempt to correct this pathogenic aberrant splicing, we, therefore, bioinformatically designed, using a Gene Tools (R) algorithm, a GNB3-specific, antisense morpholino. It was hoped that this morpholino would behave in vitro as either a potential splice blocker and/or exon skipper, to both bind and inhibit/reduce the aberrant splicing of the GNB3 825T allele. On transfecting a human lymphoblast cell line homozygous for the 825T allele, with this antisense morpholino, we encouragingly observed both a significant reduction (from similar to 58% to similar to 5%) in the production of the aberrant smaller GNB3 transcript, and a subsequent increase in the normal GNB3 transcript (from similar to 42% to similar to 95%). Our results demonstrate the potential use of a GNB3-specific antisense morpholino, as a pharmacogenetic therapy for essential hypertension.
C1 [McGlinchey, Jonathan C. P.; Lester, Douglas H.] Abertay Univ, Sch Sci Engn & Technol, Dundee DD1 1HG, Scotland.
   [McGlinchey, Jonathan C. P.] Ninewells Hosp, Dept Haematol, Blood Sci Lab, Dundee, Scotland.
   [Tummala, Hemanth] Queen Mary Univ London, Barts & London Childrens Hosp, Barts & London Sch Med & Dent, Ctr Paediat, London, England.
C3 University of Dundee; University of London; Queen Mary University London
RP Lester, DH (corresponding author), Abertay Univ, Sch Sci Engn & Technol, Dundee DD1 1HG, Scotland.
EM d.lester@abertay.ac.uk
RI Tummala, Hemanth/ABC-8367-2020
OI Tummala, Hemanth/0000-0002-1413-745X
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NR 61
TC 0
Z9 0
U1 0
U2 2
PU MARY ANN LIEBERT, INC
PI NEW ROCHELLE
PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA
SN 2159-3337
EI 2159-3345
J9 NUCLEIC ACID THER
JI Nucl. Acid Ther.
PD AUG
PY 2016
VL 26
IS 4
BP 257
EP 265
DI 10.1089/nat.2015.0571
PG 9
WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Medicine,
   Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Research &
   Experimental Medicine
GA DT0ZL
UT WOS:000381211400007
PM 27028457
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Xue, LL
   Wang, F
   Xiong, LL
   Du, RL
   Zhou, HL
   Zou, Y
   Wu, MX
   Yang, MA
   Dai, J
   He, MX
   Wang, TH
AF Xue, Lu-Lu
   Wang, Fang
   Xiong, Liu-Lin
   Du, Ruo-Lan
   Zhou, Hao-Li
   Zou, Yu
   Wu, Ma-Xiu
   Yang, Ming-An
   Dai, Jing
   He, Man-Xi
   Wang, Ting-Hua
TI A single-nucleotide polymorphism induced alternative splicing in
   Tacr3 involves in hypoxic-ischemic brain damage
SO BRAIN RESEARCH BULLETIN
LA English
DT Article
DE Hypoxic ischemic encephalopathy; Tachykinin receptor 3;
   Single-nucleotide polymorphism; Alternative splicing; Gene ontology
ID HYPOGONADOTROPIC HYPOGONADISM; RECEPTOR ANTAGONISTS; NEUROKININ-B; TERM
   INFANT; RISK; ASSOCIATION; CANCER; MUTATION; INJURY; GENES
AB Single-nucleotide polymorphism (SNP) and Alternative splicing (AS) were found to be implicated in certain diseases, nevertheless, the contributions of mRNA SNPs and AS to pathogenesis in developing rat brains with hypoxic-ischemic encephalopathy (HIE) remained largely vague. Additionally, the disease associated with Tacr3 was normosmic congenital hypogonadotropic hypogonadism, while the relationship between HIE and Tacr3 remained largely elusive. The current study was designed to investigate the differentially expressed mRNAs and related SNPs as well as AS in neonatal rats subjected to HIE to identify if the exhibition of AS was associated with SNPs under pathological condition. Firstly, we used postnatal day 7 Sprague-Dawley rats to construct neonatal HIE model, and analyzed the expression profiles of SNP mRNA in hypoxic-ischemic (HI) and sham brains by using RNA sequencing. Then four genes, including Mdfic, Lpp, Bag3 and Tacr3, connecting with HIE and exhibiting SNPs and AS were identified by bioinformatics analysis. Moreover, combined with exonic splicing enhancer (ESE) and alternative splice site predictor (ASSP) analysis, we found that Tacr3 is associated specifically with HIE through 258547789 G > A SNP in inside the Alt First Exon and 258548573 G > A SNP in outside the Alt First Exon. Taken together, our study provides new evidence to understand the role of Tacr3 in HIE and it is possibly a potential target for the treatment of HIE in future clinic trial.
C1 [Xue, Lu-Lu; Wang, Ting-Hua] Sichuan Univ, West China Hosp, Translat Neurosci Ctr, Inst Neurol Dis,Dept Anesthesiol, Chengdu 610041, Peoples R China.
   [Xue, Lu-Lu; Du, Ruo-Lan; Wang, Ting-Hua] Kunming Med Univ, Inst Neurosci, Anim Zool Dept, Kunming 650031, Yunnan, Peoples R China.
   [Xiong, Liu-Lin] Zunyi Med Univ, Dept Anesthesiol, Affiliated Hosp, Zunyi 563000, Guizhou, Peoples R China.
   [Zhou, Hao-Li; Zou, Yu; Wu, Ma-Xiu; Dai, Jing; He, Man-Xi] Univ Elect Sci & Technol China, Clin Hosp, MOE Key Lab Neuroinformat, Chengdu Brain Sci Inst, Chengdu, Peoples R China.
   [Wang, Fang] Kunming Med Univ, Dept Sci & Technol, Kunming 650031, Yunnan, Peoples R China.
   [Yang, Ming-An] San Diego State Univ, Sch Publ Hlth, Div Biostat & Epidemiol, San Diego, CA 92182 USA.
C3 Sichuan University; Kunming Medical University; Zunyi Medical
   University; University of Electronic Science & Technology of China;
   Kunming Medical University; California State University System; San
   Diego State University
RP He, MX; Wang, TH (corresponding author), Sichuan Univ, West China Hosp, Translat Neurosci Ctr, Inst Neurol Dis,Dept Anesthesiol, Chengdu 610041, Peoples R China.
EM 2357622298@qq.com; wangtinghua@vip.163.com
RI Xue, Lulu/GWD-0455-2022; dai, jing/GVS-5395-2022
FU program Innovative Research Team in Science and Technology in Yunnan
   province [2017HC007]; National Natural Science Foundation of China
   [81471268, 81560215]
FX This study was supported by grant from the program Innovative Research
   Team in Science and Technology in Yunnan province (2017HC007) and
   National Natural Science Foundation of China (Grant No 81471268 and
   Grant No 81560215).
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NR 52
TC 6
Z9 6
U1 0
U2 7
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 0361-9230
EI 1873-2747
J9 BRAIN RES BULL
JI Brain Res. Bull.
PD JAN
PY 2020
VL 154
BP 106
EP 115
DI 10.1016/j.brainresbull.2019.11.001
PG 10
WC Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA KE7SC
UT WOS:000508750400012
PM 31722250
OA hybrid
DA 2025-04-10
ER

PT J
AU Tran, H
   Gourrier, N
   Lemercier-Neuillet, C
   Dhaenens, CM
   Vautrin, A
   Fernandez-Gomez, FJ
   Arandel, L
   Carpentier, C
   Obriot, H
   Eddarkaoui, S
   Delattre, L
   Van Brussels, E
   Holt, I
   Morris, GE
   Sablonnière, B
   Buée, L
   Charlet-Berguerand, N
   Schraen-Maschke, S
   Furling, D
   Behm-Ansmant, I
   Branlant, C
   Caillet-Boudin, ML
   Sergeant, N
AF Tran, Helene
   Gourrier, Nathalie
   Lemercier-Neuillet, Camille
   Dhaenens, Claire-Marie
   Vautrin, Audrey
   Fernandez-Gomez, Francisco Jose
   Arandel, Ludovic
   Carpentier, Celine
   Obriot, Helene
   Eddarkaoui, Sabiha
   Delattre, Lucie
   Van Brussels, Edwige
   Holt, Ian
   Morris, Glenn E.
   Sablonniere, Bernard
   Buee, Luc
   Charlet-Berguerand, Nicolas
   Schraen-Maschke, Susanna
   Furling, Denis
   Behm-Ansmant, Isabelle
   Branlant, Christiane
   Caillet-Boudin, Marie-Laure
   Sergeant, Nicolas
TI Analysis of Exonic Regions Involved in Nuclear Localization, Splicing
   Activity, and Dimerization of Muscleblind-like-1 Isoforms
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID EXPANDED-REPEAT TRANSCRIPTS; CARDIAC TROPONIN-T; PRE-MESSENGER-RNA;
   MYOTONIC-DYSTROPHY; CUG REPEATS; IN-VIVO; PROTEINS; MBNL1; GENE;
   DROSOPHILA
AB Muscleblind-like-1 (MBNL1) is a splicing regulatory factor controlling the fetal-to-adult alternative splicing transitions during vertebrate muscle development. Its capture by nuclear CUG expansions is one major cause for type 1 myotonic dystrophy (DM1). Alternative splicing produces MBNL1 isoforms that differ by the presence or absence of the exonic regions 3, 5, and 7. To understand better their respective roles and the consequences of the deregulation of their expression in DM1, here we studied the respective roles of MBNL1 alternative and constitutive exons. By combining genetics, molecular and cellular approaches, we found that (i) the exon 5 and 6 regions are both needed to control the nuclear localization of MBNL1; (ii) the exon 3 region strongly enhances the affinity of MBNL1 for its pre-mRNA target sites; (iii) the exon 3 and 6 regions are both required for the splicing regulatory activity, and this function is not enhanced by an exclusive nuclear localization of MBNL1; and finally (iv) the exon 7 region enhances MBNL1-MBNL1 dimerization properties. Consequently, the abnormally high inclusion of the exon 5 and 7 regions in DM1 is expected to enhance the potential of MBNL1 of being sequestered with nuclear CUG expansions, which provides new insight into DM1 pathophysiology.
C1 [Gourrier, Nathalie; Vautrin, Audrey; Behm-Ansmant, Isabelle; Branlant, Christiane] Nancy Univ, Lab Lab ARN Ribonucl Particles Maturat Struct Fun, Unite Mixte Rech 7214, CNRS,Fac Sci, F-54506 Vandoeuvre Les Nancy, France.
   [Sergeant, Nicolas] Univ Lille Nord France, INSERM, U837, USDL,IMPRT, F-59045 Lille, France.
   [Tran, Helene; Dhaenens, Claire-Marie; Fernandez-Gomez, Francisco Jose; Carpentier, Celine; Obriot, Helene; Eddarkaoui, Sabiha; Delattre, Lucie; Van Brussels, Edwige; Sablonniere, Bernard; Buee, Luc; Schraen-Maschke, Susanna; Caillet-Boudin, Marie-Laure; Sergeant, Nicolas] Univ Lille 2, Univ Lille Nord France, Inst Predict Med & Therapeut Res, Fac Med,Jean Pierre Aubert Res Ctr, F-59045 Lille, France.
   [Lemercier-Neuillet, Camille; Furling, Denis] Univ Paris 06, Unite Mixte 76, Inst Myol, F-75013 Paris, France.
   [Lemercier-Neuillet, Camille; Arandel, Ludovic; Furling, Denis] CNRS, Unite Mixte Rech 7215, F-75013 Paris, France.
   [Lemercier-Neuillet, Camille; Arandel, Ludovic; Furling, Denis] INSERM, U974, F-75013 Paris, France.
   [Charlet-Berguerand, Nicolas] IGBMC, F-67404 Illkirch Graffenstaden, France.
   [Holt, Ian; Morris, Glenn E.] Robert Jones & Agnes Hunt Orthopaed Hosp, Wolfson Ctr Inherited Neuromuscular Dis, Owestry, England.
   [Holt, Ian; Morris, Glenn E.] Keele Univ, Inst Sci & Technol Med, Keele, Staffs, England.
C3 Centre National de la Recherche Scientifique (CNRS); Universite de
   Lorraine; Institut National de la Sante et de la Recherche Medicale
   (Inserm); Universite de Lille; Institut National de la Sante et de la
   Recherche Medicale (Inserm); Universite de Lille; Sorbonne Universite;
   Centre National de la Recherche Scientifique (CNRS); Institut National
   de la Sante et de la Recherche Medicale (Inserm); Institut National de
   la Sante et de la Recherche Medicale (Inserm); Keele University
RP Branlant, C (corresponding author), Nancy Univ, Lab Lab ARN Ribonucl Particles Maturat Struct Fun, Unite Mixte Rech 7214, CNRS,Fac Sci, BP 70239, F-54506 Vandoeuvre Les Nancy, France.
EM christiane.branlant@maem.uhp-nancy.fr; nicolas.sergeant@inserm.fr
RI Charlet-Berguerand, Nicolas/GZM-6636-2022; BEHM-ANSMANT,
   Isabelle/B-1406-2012; Tran, Vu Hoang/AAT-9423-2021; Fernández-Gómez,
   Francisco/GOP-0463-2022; Furling, Denis/M-2346-2017; Sergeant,
   Nicolas/O-5467-2017; Charlet-Berguerand, Nicolas/I-6727-2016; BUEE,
   Luc/B-3126-2010
OI Furling, Denis/0000-0001-7912-4409; Fernandez-Gomez, Francisco
   Jose/0000-0002-7891-8634; DHAENENS, Claire-Marie/0000-0003-4719-4124;
   SCHRAEN, Susanna/0000-0002-7247-4809; Sergeant,
   Nicolas/0000-0003-1448-124X; Behm-Ansmant, Isabelle/0000-0001-8909-0660;
   Branlant, Christiane/0000-0003-4728-5499; Charlet-Berguerand,
   Nicolas/0000-0002-4423-4920; BUEE, Luc/0000-0002-6261-4230
FU Association Francaise contre les Myopathies [14269, 15047]; Agence
   Nationale de Recherche Neuro-SplicedeTau BLAN [1114 01]; EU [FP6];
   Centre National de la Recherche Scientifique; Institut National pour la
   Sante et la Recherche Medicale; French Ministry for Youth, National
   Education and Research; Lorraine Region
FX This work was supported by the Association Francaise contre les
   Myopathies Grants 14269 and 15047, the Agence Nationale de Recherche
   Neuro-SplicedeTau BLAN 1114 01, the EURASNET EU Contract FP6, life
   sciences, genomics and biotechnology for health, the Centre National de
   la Recherche Scientifique, the Institut National pour la Sante et la
   Recherche Medicale, the French Ministry for Youth, National Education
   and Research, and the Lorraine Region.
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NR 37
TC 59
Z9 78
U1 0
U2 4
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD MAY 6
PY 2011
VL 286
IS 18
DI 10.1074/jbc.M110.194928
PG 12
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 756ON
UT WOS:000290022800081
PM 21454535
OA hybrid, Green Published
DA 2025-04-10
ER

PT J
AU Yao, XM
   Wang, CH
   Song, BL
   Yang, XY
   Wang, ZZ
   Qi, W
   Lin, ZX
   Chang, CCY
   Chang, TY
   Li, BL
AF Yao, XM
   Wang, CH
   Song, BL
   Yang, XY
   Wang, ZZ
   Qi, W
   Lin, ZX
   Chang, CCY
   Chang, TY
   Li, BL
TI Two human ACAT2 mRNA variants produced by alternative splicing and
   coding for novel isoenzymes
SO ACTA BIOCHIMICA ET BIOPHYSICA SINICA
LA English
DT Article
DE ACAT2 gene; alternative splicing; ACAT2 mRNA variant; isoenzyme
ID A-CHOLESTEROL ACYLTRANSFERASE; HUMAN ACYL-COA; HAMSTER OVARY CELLS;
   TRANSCRIPTIONAL ACTIVATION; DIFFERENT CHROMOSOMES; HUMAN LIVER;
   COENZYME; GENE; MACROPHAGES; EXPRESSION
AB Acyl coenzyme A:cholesterol acyltransferase 2 (ACAT2) plays an important role in cholesterol absorption. Human ACAT2 is highly expressed in small intestine and fetal liver, but its expression is greatly diminished in adult liver. The full-length human ACAT2 mRNA encodes a protein, designated ACAT2a, with 522 amino acids. We have previously reported the organization of the human ACAT2 gene and the differentiation-dependent promoter activity in intestinal Caco-2 cells. In the Current work, two human ACAT2 mRNA variants produced by alternative splicing are cloned and predicted to encode two novel ACAT2 isoforms, named ACAT2b and ACAT2c, with 502 and 379 amino acids, respectively. These mRNA variants differ from ACAT2a mRNA by lack of the exon 4 (ACAT2b mRNA) and exons 4-5 plus 8-9-10 (ACAT2c mRNA). Significantly, comparable amounts of the alternatively spliced ACAT2 mRNA variants were detected by RTPCR, and Western blot analysis confirmed the presence of their corresponding proteins in human liver and intestine cells. Furthermore, phosphorylation and enzymatic activity analyses demonstrated that the novel isoenzymes ACAT2b and ACAT2c lacked the phosphorylatable site SLLD, and their enzymatic activities reduced to 25%-35% of that of ACAT2a. These evidences indicate that alternative splicing produces two human ACAT2 mRNA variants that encode the novel ACAT2 isoenzymes. Our findings might help to understand the regulation of the ACAT2 gene expression under certain physiological and pathological conditions.
C1 Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Mol Biol, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China.
   Shanghai Jiao Tong Univ, Dept Biochem & Technol, Shanghai 200030, Peoples R China.
   Dartmouth Coll Sch Med, Dept Biochem, Hanover, NH 03756 USA.
C3 Chinese Academy of Sciences; Center for Excellence in Molecular Cell
   Science, CAS; Shanghai Jiao Tong University; Dartmouth College
RP Chinese Acad Sci, Shanghai Inst Biol Sci, State Key Lab Mol Biol, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China.
EM blli@sibs.ac.cn
RI Wang, Xinhua/ISR-8520-2023; Yao, Xuemei/IQS-1334-2023
OI Chang, Ta-Yuan/0000-0002-3249-0468; Song, Bao-Liang/0000-0002-6397-5935;
   li, bo liang/0000-0002-7123-5638
FU NHLBI NIH HHS [HL60306] Funding Source: Medline
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NR 35
TC 2
Z9 5
U1 1
U2 10
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 1672-9145
EI 1745-7270
J9 ACTA BIOCH BIOPH SIN
JI Acta Biochim. Biophys. Sin.
PD DEC
PY 2005
VL 37
IS 12
BP 797
EP 806
DI 10.1111/j.1745-7270.2005.00118.x
PG 10
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA 995RA
UT WOS:000234120300002
PM 16331323
DA 2025-04-10
ER

PT J
AU Xie, ZW
   Chen, YX
   Long, CF
   Qi, YX
   Yao, QP
AF Xie, Zhi-Wei
   Chen, Yuan-Xiu
   Long, Cai-Feng
   Qi, Ying-Xin
   Yao, Qing-Ping
TI Cyclic stretch induces VEGFA alternative splicing via
   Serine/Arginine-Rich Splicing Factor 1
SO CELLULAR AND MOLECULAR BIOLOGY
LA English
DT Article
DE Hypertension; Cyclic stretch; Vascular endothelial growth factor A;
   Vascular smooth muscle cells; Serine/arginine-richsplicing factor 1
ID ENDOTHELIAL GROWTH-FACTOR; SMOOTH-MUSCLE-CELLS; EXPRESSION;
   PROLIFERATION; HYPERTENSION; MECHANISMS; AUTOCRINE; VARIANTS; ISOFORM;
   BREAST
AB Abnormal proliferation of vascular smooth muscle cells (VSMCs) induced by high cyclic stretch is crucial in the vascular remodeling during hypertension. Vascular endothelial growth factor A (VEGFA) alternative splicing plays important roles in the pathological process of vascular diseases and remodeling. However, the roles of VEGFA isoforms in modulating VSMC functions in response to cyclic stretch remain unclear. We hypothesize that high cyclic stretch may induce VEGFA alternative splicing via Serine/arginine-rich splicing factor 1 (SRSF1) which subsequently induce VSMC proliferation. In the present research, hypertensive rat model was established using the abdominal aortic constriction method. In comparison with sham-operated group, immunohistology staining showed translocation of SRSF1 into nuclei in hypertensive rat thoracic aorta, and RT-PCR detected a shift of VEGFA expression pattern, including the increased expression of VEGFA120 and VEGFA164, but not VEGFA188. Then VSMCs were subjected to cyclic stretch in vitro using a Flexercell strain unit. VEGFA ELISA assay showed 15% cyclic stretch increased the secretion of VEGFA which significantly increased proliferation of VSMCs. Western blot and immunofluorescence detected accumulation of SRSF1 in nuclei after 15% cyclic stretch application. Furthermore, SRSF1-specific siRNA transfection reversed the VEGFA secretion induced by pathological high cyclic stretch. Our present results suggested that pathologically high cyclic stretch induces the shuttling of SRSF1 which results in the secretive pattern splicing of VEGFA and finally contributes to the proliferation of VSMCs.
C1 [Xie, Zhi-Wei; Chen, Yuan-Xiu; Long, Cai-Feng; Qi, Ying-Xin; Yao, Qing-Ping] Shanghai Jiao Tong Univ, Inst Mechanobiol & Med Engn, Sch Life Sci & Biotechnol, Shanghai, Peoples R China.
C3 Shanghai Jiao Tong University
RP Yao, QP (corresponding author), Shanghai Jiao Tong Univ, Inst Mechanobiol & Med Engn, Sch Life Sci & Biotechnol, Shanghai, Peoples R China.
EM qpyao@sjtu.edu.cn
FU National Natural Science Foundation of China [11625209, 11772198]
FX This research was supported by grants from the National Natural Science
   Foundation of China, Nos. 11625209 and 11772198.
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NR 32
TC 0
Z9 1
U1 0
U2 8
PU C M B  ASSOC
PI POITIERS
PA 34 BOULEVARD SOLFERINO, 86000 POITIERS, FRANCE
SN 0145-5680
EI 1165-158X
J9 CELL MOL BIOL
JI Cell. Mol. Biol.
PY 2018
VL 64
IS 7
BP 43
EP 50
DI 10.14715/cmb/2018.64.7.8
PG 8
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA GN4RW
UT WOS:000439020900008
PM 29974845
OA Bronze
DA 2025-04-10
ER

PT J
AU Suzuki, H
   Jin, Y
   Otani, H
   Yasuda, K
   Inoue, K
AF Suzuki, H
   Jin, Y
   Otani, H
   Yasuda, K
   Inoue, K
TI Regulation of alternative splicing of α-actinin transcript by Bruno-like
   proteins
SO GENES TO CELLS
LA English
DT Article
ID RNA-BINDING PROTEINS; PRE-MESSENGER-RNA; MYOTONIC-DYSTROPHY; 3-HYBRID
   SYSTEM; XENOPUS-EMBRYOS; ELAV; FAMILY; LOCALIZATION; MECHANISMS;
   EXPRESSION
AB Background: The Bruno-like or CELF proteins, such as mammalian CUGBP1 and Etr-3, Xenopus EDEN-BP, and Drosophila Bruno (Bru), are regulators of gene expression at the post-transcriptional level, and contain three RNA-recognition motifs (RPMs). It has been shown that mammalian CUGBP1 and Etr-3 regulate alternative splicing of cardiac troponin T pre-mRNA via binding to CUG-triplet repeats.
   Results: Using in vitro selection and UV-crosslinking experiments, we found that zebrafish Bruno-like proteins bound to repeat elements of uridine and purine (termed UREs). It is known that non-muscle (NM) and smooth muscle (SM) exons of the rat alpha-actinin gene are used in a mutually exclusive manner. Transfection experiments in mammalian cells showed that zebrafish Brul and Etr-3 induced the muscle-specific splicing of rat alpha-actinin pre-mRNA via binding to the URE at the branch point upstream of the NM exon. In contrast, zebrafish Etr-1 promoted skipping of both the NM and SM exons in a manner which was not dependent on URE-binding.
   Conclusions: Our results showed that Bruno-like proteins bind to UREs and regulate the alternative splicing of alpha-actinin pre-mRNA. Members of the Bruno family play multiple roles in splicing regulation.
C1 Nara Inst Sci & Technol, Grad Sch Biol Sci, Ikoma 6300101, Japan.
C3 Nara Institute of Science & Technology
RP Nara Inst Sci & Technol, Grad Sch Biol Sci, Ikoma 6300101, Japan.
EM kunio@bs.aist-nara.ac.jp
RI JIN, Yui/AGO-9517-2022
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Z9 67
U1 0
U2 10
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1356-9597
EI 1365-2443
J9 GENES CELLS
JI Genes Cells
PD FEB
PY 2002
VL 7
IS 2
BP 133
EP 141
DI 10.1046/j.1356-9597.2001.00506.x
PG 9
WC Cell Biology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Genetics & Heredity
GA 530PZ
UT WOS:000174369300004
PM 11895477
DA 2025-04-10
ER

PT J
AU Felkin, LE
   Narita, T
   Germack, R
   Shintani, Y
   Takahashi, K
   Sarathchandra, P
   López-Olañeta, MM
   Gómez-Salinero, JM
   Suzuki, K
   Barton, PJR
   Rosenthal, N
   Lara-Pezzi, E
AF Felkin, Leanne E.
   Narita, Takuya
   Germack, Renee
   Shintani, Yasunori
   Takahashi, Kunihiko
   Sarathchandra, Padmini
   Lopez-Olaneta, Marina M.
   Gomez-Salinero, Jesus M.
   Suzuki, Ken
   Barton, Paul J. R.
   Rosenthal, Nadia
   Lara-Pezzi, Enrique
TI Calcineurin Splicing Variant Calcineurin Aβ1 Improves Cardiac Function
   After Myocardial Infarction Without Inducing Hypertrophy
SO CIRCULATION
LA English
DT Article
DE amino acids; calcineurin; mice, transgenic; myocardial infarction;
   signal transduction
ID HEART-FAILURE; IN-VIVO; PROTEIN; ACTIVATION; APOPTOSIS; ASSOCIATION;
   EXPRESSION; KINASE-1; PATHWAY; STRESS
AB Background-Calcineurin is a calcium-regulated phosphatase that plays a major role in cardiac hypertrophy. We previously described that alternative splicing of the calcineurin A beta (CnA beta) gene generates the CnA beta 1 isoform, with a unique C-terminal region that is different from the autoinhibitory domain present in all other CnA isoforms. In skeletal muscle, CnA beta 1 is necessary for myoblast proliferation and stimulates regeneration, reducing fibrosis and accelerating the resolution of inflammation. Its role in the heart is currently unknown.
   Methods and Results-We generated transgenic mice overexpressing CnA beta 1 in postnatal cardiomyocytes under the control of the alpha-myosin heavy chain promoter. In contrast to previous studies using an artificially truncated calcineurin, CnA beta 1 overexpression did not induce cardiac hypertrophy. Moreover, transgenic mice showed improved cardiac function and reduced scar formation after myocardial infarction, with reduced neutrophil and macrophage infiltration and decreased expression of proinflammatory cytokines. Immunoprecipitation and Western blot analysis showed interaction of CnA beta 1 with the mTOR complex 2 and activation of the Akt/SGK cardioprotective pathway in a PI3K-independent manner. In addition, gene expression profiling revealed that CnA beta 1 activated the transcription factor ATF4 downstream of the Akt/mTOR pathway to promote the amino acid biosynthesis program, to reduce protein catabolism, and to induce the antifibrotic and antiinflammatory factor growth differentiation factor 15, which protects the heart through Akt activation.
   Conclusions-Calcineurin A beta 1 shows a unique mode of action that improves cardiac function after myocardial infarction, activating different cardioprotective pathways without inducing maladaptive hypertrophy. These features make CnA beta 1 an attractive candidate for the development of future therapeutic approaches. (Circulation. 2011; 123: 2838-2847.)
C1 [Lopez-Olaneta, Marina M.; Gomez-Salinero, Jesus M.; Lara-Pezzi, Enrique] Ctr Nacl Invest Cardiovasc, Cardiovasc Dev Biol Dept, Madrid 28029, Spain.
   [Felkin, Leanne E.; Germack, Renee; Sarathchandra, Padmini; Suzuki, Ken; Barton, Paul J. R.; Rosenthal, Nadia; Lara-Pezzi, Enrique] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Heart Sci Ctr, London, England.
   [Narita, Takuya; Shintani, Yasunori; Takahashi, Kunihiko; Suzuki, Ken] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.
   [Rosenthal, Nadia] European Mol Biol Lab, Mouse Biol Unit, Rome, Italy.
   [Barton, Paul J. R.] Royal Brompton & Harefield NHS Fdn Trust, NIHR Cardiovasc Biomed Res Unit, London, England.
C3 Centro Nacional de Investigaciones Cardiovasculares (CNIC); Imperial
   College London; University of London; Queen Mary University London;
   European Molecular Biology Laboratory (EMBL); Royal Brompton & Harefield
   NHS Foundation Trust
RP Lara-Pezzi, E (corresponding author), Ctr Nacl Invest Cardiovasc, Cardiovasc Dev Biol Dept, Melchor Fernandez Almagro 3, Madrid 28029, Spain.
EM elara@cnic.es
RI Rosenthal, Nadia/O-7009-2015; Lara-Pezzi, Enrique/E-2350-2015
OI Lara-Pezzi, Enrique/0000-0002-2743-1033; Barton, Paul Jeremy
   Richard/0000-0002-1165-7767; Felkin, Leanne/0000-0003-1402-8314;
   Shintani, Yasunori/0000-0001-9579-0727; Rosenthal,
   Nadia/0000-0002-7599-7365
FU British Heart Foundation [PG/07/020/22503]; Spanish Ministry of Science
   and Innovation [BFU2009-10016]; National Institutes of Health Research,
   Cardiovascular Biomedical Research Unit at the Royal Brompton;
   Hare-field NHS Foundation Trust; Imperial College; Spanish Fondo
   Nacional de Investigaciones Sanitarias [EIF-040545, ERG-239158,
   CP08/00144]; MRC [G1000461, G0600872] Funding Source: UKRI
FX This project was funded by a British Heart Foundation grant
   PG/07/020/22503 (to Drs Barton, Lara-Pezzi, Rosenthal, and Suzuki), a
   Spanish Ministry of Science and Innovation grant BFU2009-10016 (to Dr
   Lara-Pezzi), and the National Institutes of Health Research,
   Cardiovascular Biomedical Research Unit at the Royal Brompton and
   Hare-field NHS Foundation Trust and Imperial College (to Dr Barton). Dr
   Lara-Pezzi was also supported by a Marie Curie Intra-European Fellowship
   (EIF-040545), a Marie Curie Reintegration grant (ERG-239158), and a
   national grant from the Spanish Fondo Nacional de Investigaciones
   Sanitarias (CP08/00144).
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NR 26
TC 44
Z9 50
U1 1
U2 9
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA
SN 0009-7322
J9 CIRCULATION
JI Circulation
PD JUN 21
PY 2011
VL 123
IS 24
BP 2838
EP 2847
DI 10.1161/CIRCULATIONAHA.110.012211
PG 10
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 779QM
UT WOS:000291795200017
PM 21632490
OA Bronze, Green Accepted
DA 2025-04-10
ER

PT J
AU Li, RQ
   Huang, TC
   Zhou, JP
   Liu, XS
   Li, G
   Zhang, YM
   Guo, YL
   Li, FS
   Li, Y
   Liesz, A
   Li, PY
   Wang, ZH
   Wan, JQ
AF Li, Ruqi
   Huang, Tianchen
   Zhou, Jianpo
   Liu, Xiansheng
   Li, Gan
   Zhang, Yueman
   Guo, Yunlu
   Li, Fengshi
   Li, Yan
   Liesz, Arthur
   Li, Peiying
   Wang, Zhenghong
   Wan, Jieqing
TI Mef2c Exacerbates Neuron Necroptosis via Modulating Alternative Splicing
   of Cflar in Ischemic Stroke With Hyperlipidemia
SO CNS NEUROSCIENCE & THERAPEUTICS
LA English
DT Article
DE alternative splicing; Cflar; hyperlipidemia; Mef2c; necroptosis; stroke
ID CELL-DEATH; BRAIN-INJURY; APOPTOSIS; ACTIVATION; PROTEIN; BINDING;
   MODEL; FLIP
AB AimHyperlipidemia is a common comorbidity of stroke patients, elucidating the mechanism that underlies the exacerbated ischemic brain injury after stroke with hyperlipidemia is emerging as a significant clinical problem due to the growing proportion of hyperlipidemic stroke patients.MethodsMice were fed a high-fat diet for 12 weeks to induce hyperlipidemia. Transient middle cerebral artery occlusion was induced as a mouse model of ischemic stroke. Emx1Cre mice were crossed with Mef2cfl/fl mice to specifically deplete Mef2c in neurons.ResultsWe reported that hyperlipidemia significantly aggravated neuronal necroptosis and exacerbated long-term neurological deficits following ischemic stroke in mice. Mechanistically, Cflar, an upstream necroptotic regulator, was alternatively spliced into pro-necroptotic isoform (CflarR) in ischemic neurons of hyperlipidemic mice. Neuronal Mef2c was a transcription factor modulating Cflar splicing and upregulated by hyperlipidemia following stroke. Neuronal specific Mef2c depletion reduced cerebral level of CflarR and cFLIPR (translated by CflarR), while mitigated neuron necroptosis and neurological deficits following stroke in hyperlipidemic mice.ConclusionsOur study highlights the pathogenic role of CflarR splicing mediated by neuronal Mef2c, which aggravates neuron necroptosis following stroke with comorbid hyperlipidemia and proposes CflarR splicing as a potential therapeutic target for hyperlipidemic stroke patients.
C1 [Li, Ruqi; Huang, Tianchen; Zhou, Jianpo; Liu, Xiansheng; Li, Gan; Li, Fengshi; Wan, Jieqing] Shanghai Jiao Tong Univ, Renji Hosp, Cerebrovasc Dis Ctr, Dept Neurosurg,Sch Med, Shanghai, Peoples R China.
   [Zhang, Yueman; Guo, Yunlu; Li, Yan; Li, Peiying; Wang, Zhenghong] Shanghai Jiao Tong Univ, Renji Hosp, Dept Anesthesiol, Key Lab Minist Educ,Sch Med, Shanghai, Peoples R China.
   [Zhang, Yueman; Guo, Yunlu; Li, Yan; Li, Peiying] Shanghai Jiao Tong Univ, Renji Hosp, Clin Res Ctr, Sch Med, Shanghai, Peoples R China.
   [Liesz, Arthur] LMU, Univ Hosp, Inst Stroke & Dementia Res ISD, Munich, Germany.
   [Liesz, Arthur] Munich Cluster Syst Neurol SyNergy, Munich, Germany.
C3 Shanghai Jiao Tong University; Shanghai Jiao Tong University; Shanghai
   Jiao Tong University; University of Munich; University of Munich
RP Wan, JQ (corresponding author), Shanghai Jiao Tong Univ, Renji Hosp, Cerebrovasc Dis Ctr, Dept Neurosurg,Sch Med, Shanghai, Peoples R China.; Wang, ZH (corresponding author), Shanghai Jiao Tong Univ, Renji Hosp, Dept Anesthesiol, Key Lab Minist Educ,Sch Med, Shanghai, Peoples R China.
EM wangzhenghong@renji.com; jieqingwan@126.com
RI Li, Ruqi/JXX-6226-2024; Liesz, Arthur/HLX-0311-2023
FU Deutsche Forschungsgemeinschaft [PW2020E-2]; Health and Family Planning
   Project of Pudong Health Committee of Shanghai [82371317, 82171279];
   National Natural Science Foundation of China [201409002500]; Science and
   Technology Innovation Plan of the Shanghai Science and Technology
   Commission [M-0671, U22A20295]; NSFC [EXC 2145 SyNergy-ID 390857198,
   LI-2534/6-1, LI-2534/7-1]; Deutsche Forschungsgemeinschaft (DFG, German
   Research Foundation) under Germany's Excellence Strategy within the
   framework of the Munich Cluster for Systems Neurology
FX Dr. J.W. is supported by the Health and Family Planning Project of
   Pudong Health Committee of Shanghai (PW2020E-2), the National Natural
   Science Foundation of China (NSFC, 82371317, 82171279) and Science and
   Technology Innovation Plan of the Shanghai Science and Technology
   Commission (201409002500). Dr. Z.W. is supported by NSFC (82071290). Dr.
   P.L. is supported by NSFC (M-0671, U22A20295), Dr. A.L. is supported by
   the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
   under Germany's Excellence Strategy within the framework of the Munich
   Cluster for Systems Neurology (EXC 2145 SyNergy-ID 390857198) and under
   the grants LI-2534/6-1 and LI-2534/7-1. We acknowledge the kind
   technical support and supply of pRIPK3 antibody from Dr. Junying Yuan's
   Lab in Interdisciplinary Research Center on Biology and Chemistry,
   Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
   Shanghai 201203, China.
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NR 60
TC 0
Z9 0
U1 4
U2 4
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1755-5930
EI 1755-5949
J9 CNS NEUROSCI THER
JI CNS Neurosci. Ther.
PD DEC
PY 2024
VL 30
IS 12
AR e70144
DI 10.1111/cns.70144
PG 11
WC Neurosciences; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology; Pharmacology & Pharmacy
GA O7D5U
UT WOS:001372689800001
PM 39648651
OA gold
DA 2025-04-10
ER

PT J
AU Kerr, NCH
   Holmes, FE
   Wynick, D
AF Kerr, NCH
   Holmes, FE
   Wynick, D
TI Novel Isoforms of the sodium channels Nav1.8 and
   Nav1.5 are produced by a conserved mechanism in mouse and rat
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID FEBRILE SEIZURES PLUS; MESSENGER-RNA; NA+ CHANNEL; GENOMIC ORGANIZATION;
   MOLECULAR-CLONING; GENERALIZED EPILEPSY; CODING SEQUENCE; EXPRESSION;
   SCN5A; GENE
AB The voltage-gated sodium channel Na(v)1.8 is only expressed in subsets of neurons in dorsal root ganglia (DRG) and trigeminal and nodose ganglia. We have isolated mouse partial length Na(v)1.8 cDNA clones spanning the exon 17 sequence, which have 17 nucleotide substitutions and 12 predicted amino acid differences from the published sequence. The absence of a mutually exclusive alternative exon 17 was confirmed by sequencing 4.1 kilobases of genomic DNA spanning exons 16-18 of Scn10a. A novel cDNA isoform was identified, designated Na(v)1.8c, which results from alternative 3'-splice site selection at a CAG/CAG motif to exclude the codon for glutamine 1031 within the interdomain cytoplasmic loop IDII/III. The ratio of Na(v)1.8c (CAG-skipped) to Na(v)1.8 (CAG-inclusive) mRNA in mouse is similar to2:1 in adult DRG, trigeminal ganglion, and neonatal DRG. A Na(v)1.8c isoform also occurs in rat DRG, but is less common. Of the two other tetrodotoxin-resistant channels, no analogous alternative splicing of mouse Na(v)1.9 was detected, whereas rare alternative splicing of Na(v)1.5 at a CAG/CAG motif resulted in the introduction of a CAG trinucleotide. This isoform, designated Na(v)1.5c, is conserved in rat and encodes an additional glutamine residue that disrupts a putative CK2 phosphorylation site. In summary, novel isoforms of Na(v)1.8 and Na(v)1.5 are each generated by alternative splicing at CAG/CAG motifs, which result in the absence or presence of predicted glutamine residues within the interdomain cytoplasmic loop IDII/III. Mutations of sodium channels within this cytoplasmic loop have previously been demonstrated to alter electrophysiological properties and cause cardiac arrhythmias and epilepsy.
C1 LINE, Bristol BS1 3NY, Avon, England.
   NeuroTargets Ltd, Surrey Technol Ctr, Surrey GU2 7YG, England.
C3 University of Bristol
RP LINE, Dorothy Hodgkin Bldg,Whitson St, Bristol BS1 3NY, Avon, England.
EM d.wynick@bristol.ac.uk
FU MRC [G0300028] Funding Source: UKRI; Medical Research Council
   [G0300028(65120), G0300028] Funding Source: Medline
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NR 73
TC 45
Z9 54
U1 1
U2 5
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI ROCKVILLE
PA 11200 ROCKVILLE PIKE, SUITE 302, ROCKVILLE, MD, UNITED STATES
SN 0021-9258
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD JUN 4
PY 2004
VL 279
IS 23
BP 24826
EP 24833
DI 10.1074/jbc.M401281200
PG 8
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 824RA
UT WOS:000221702500113
PM 15047701
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Wang, LJ
   Lei, MG
   Zuo, B
   Xu, DQ
   Ren, ZQ
   Xiong, YZ
AF Wang, Linjie
   Lei, Minggang
   Zuo, Bo
   Xu, Dequan
   Ren, Zhuqing
   Xiong, Yuanzhu
TI Multiple alternative splicing and differential expression of
   actinin-associated LIM protein (ALP) during porcine skeletal muscle
   development in vitro and in vivo
SO MEAT SCIENCE
LA English
DT Article
DE ALP; Alternative splicing; Skeletal muscle; Pig; Satellite cells
ID FIBER CHARACTERISTICS; VENTRICULAR-FUNCTION; MEAT QUALITY; LARGE WHITE;
   PDZ; GROWTH; DOMAIN; CYTOSKELETON; MOTIF
AB The actinin-associated LIM protein (ALP) is co-localized with alpha-actinin at the Z-discs and plays a critical role in the integration of cytoskeletal architecture and transcriptional regulation. Here we report that five isoforms of the porcine ALP were generated in skeletal muscle by alternative splicing. All of ALP isoforms were predominantly expressed in skeletal muscle except for ALP2. These isoforms had different expression profiles during the prenatal and postnatal period of the porcine skeletal muscle development and between the two breeds. Moreover, ALP1 and ALP3 were expressed at higher levels in soleus and masseter muscles compared with longissimus dorsi and bicepsfemoris muscles in Yorkshire pigs. Expression analysis in porcine satellite cells showed that all isoforms were induced in differentiated porcine satellite cells, suggesting a role of them in myogenic differentiation. These results provide new insight into roles of regulation at level of splicing of the ALP in governing porcine skeletal muscle development. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved.
C1 [Xiong, Yuanzhu] Huazhong Agr Univ, Key Lab Swine Genet & Breeding, Minist Agr, Coll Anim Sci, Wuhan 430070, Hubei, Peoples R China.
   Huazhong Agr Univ, Key Lab Agr Anim Genet Breeding & Reprod, Minist Educ, Coll Anim Sci, Wuhan 430070, Hubei, Peoples R China.
C3 Huazhong Agricultural University; Ministry of Agriculture & Rural
   Affairs; Huazhong Agricultural University
RP Xiong, YZ (corresponding author), Huazhong Agr Univ, Key Lab Swine Genet & Breeding, Minist Agr, Coll Anim Sci, Wuhan 430070, Hubei, Peoples R China.
EM yuanzhu010@yahoo.com.cn
FU 973 Programme [2006CB102102]; National High Technology Research and
   Development Program [2006AA10Z1D6]
FX This work was supported by the Grants from 973 (2006CB102102) Programme,
   National High Technology Research and Development Program
   (2006AA10Z1D6).
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NR 29
TC 8
Z9 9
U1 0
U2 10
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 0309-1740
EI 1873-4138
J9 MEAT SCI
JI Meat Sci.
PD APR
PY 2010
VL 84
IS 4
BP 655
EP 661
DI 10.1016/j.meatsci.2009.10.027
PG 7
WC Food Science & Technology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Food Science & Technology
GA 569JI
UT WOS:000275592000012
PM 20374839
DA 2025-04-10
ER

PT J
AU Lorenz, M
   Hewing, B
   Hui, JY
   Zepp, A
   Baumann, G
   Bindereif, A
   Stangl, V
   Stangl, K
AF Lorenz, Mario
   Hewing, Bernd
   Hui, Jingyi
   Zepp, Angela
   Baumann, Gert
   Bindereif, Albrecht
   Stangl, Verena
   Stangl, Karl
TI Alternative splicing in intron 13 of the human eNOS gene: a potential
   mechanism for regulating eNOS activity
SO FASEB JOURNAL
LA English
DT Article
DE NOS; endothelium NO; CA repeats
ID NITRIC-OXIDE SYNTHASE; PRE-MESSENGER-RNA; CA-REPEAT; EXPRESSION;
   PROTEINS; DISEASE; INHIBITION; ACTIVATION; ISOFORMS; SUBUNIT
AB NO, the product of endothelial NOS ( eNOS), is a major regulator of vascular homeostasis and a critical factor in preventing cardiovascular diseases. We previously established a positive correlation between the number of variable CA repeats in intron 13 of human eNOS and the risk of coronary artery disease, and demonstrated that these polymorphic CA repeats function as a length-dependent splicing enhancer. By 5'-RACE polymerase chain reaction (PCR), we detected three splice variants containing novel 3' splice sites within intron 13 - termed eNOS13A, eNOS13B, and eNOS13C - which share the first 13 exons of human eNOS and the same polyadenylation site at the end of the novel exon. When translated, all these splice variants would result in truncated proteins lacking eNOS activity. Coexpression of full- length eNOS with eNOS13A diminished eNOS enzyme activity in COS- 7 cells by formation of heterodimers. The splice variants were expressed in endothelial cells and various human tissues. Finally, we demonstrate, using minigene transfection, that the expression of the eNOS13A splice variant is increased with high CA repeat numbers in intron 13. These data suggest a new mechanism for the regulation of eNOS activity and NO production in the cardiovascular system by truncated, dominant- negative splice variants of human eNOS.
C1 Charite Univ Med Berlin, CCM, Med Klin Schwerpunkt Kardiol & Angiol, D-10117 Berlin, Germany.
   Univ Giessen, Inst Biochem, Giessen, Germany.
C3 Berlin Institute of Health; Free University of Berlin; Humboldt
   University of Berlin; Charite Universitatsmedizin Berlin; Justus Liebig
   University Giessen
RP Stangl, K (corresponding author), Charite Univ Med Berlin, CCM, Med Klin Schwerpunkt Kardiol & Angiol, Charite Pl 1, D-10117 Berlin, Germany.
EM karl.stangl@charite.de
OI Lorenz, Mario/0000-0001-5267-4101
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NR 32
TC 38
Z9 41
U1 0
U2 2
PU FEDERATION AMER SOC EXP BIOL
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA
SN 0892-6638
J9 FASEB J
JI Faseb J.
PD MAY
PY 2007
VL 21
IS 7
BP 1556
EP 1564
DI 10.1096/fj.06-7434com
PG 9
WC Biochemistry & Molecular Biology; Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other
   Topics; Cell Biology
GA 162VG
UT WOS:000246117000030
PM 17264164
DA 2025-04-10
ER

PT J
AU Chang, PA
   Wang, ZX
   Long, DX
   Qin, WZ
   Wei, CY
   Wu, YJ
AF Chang, Ping-An
   Wang, Zhan-Xiang
   Long, Ding-Xin
   Qin, Wen-zhen
   Wei, Chen-ying
   Wu, Yi-Jun
TI Identification of two novel splicing variants of murine NTE-related
   esterase
SO GENE
LA English
DT Article
DE NTE-related esterase; Splice variant; Esterase activity; Endoplasmic
   reticulum; Nutritional regulation
ID NEUROPATHY TARGET ESTERASE; PROTEIN; RNA; NEURODEGENERATION; MECHANISMS
AB NTE-related esterase (NRE) is an insulin-regulated lysophospholipase with homology to neuropathy target esterase (NTE), which plays a role in energy metabolism. Here, we reported two alternative splicing variants of the murine NRE (mNRE) gene, termed mNREV1 and mNREV2. Genomic organization analysis indicated that 5' splice site of mNRE intron 33 was changed in both mNREV1 and mNREV2, and mNRE exon 21 was deleted in mNREV2. mNREV1 had the same protein domains with mNRE, while mNREV2 lacked the patatin domain in the C-terminal catalytic region. Green fluorescent protein-mNREV1 or mNREV2 fusion proteins localized to the endoplasmic reticulum. mNREV1 and mNRE exhibited equal hydrolytic activity to the substrate phenyl valerate, whereas mNREV2 did not have any catalytic activity. The expression profiles of mNRE and its splicing isoforms in white adipose tissue, cardiac muscle, skeletal muscle, and testis tissues were further analyzed by real time quantitative-PCR in fed and fasted states, which indicated that the major isoform of mNRE mRNA generated switched from mNREV2 to mNREV1 during fasting. Thus there was a nutritional regulation of mNRE expression at the mRNA levels via alternative splicing. (C) 2012 Elsevier B.V. All rights reserved.
C1 [Chang, Ping-An; Qin, Wen-zhen; Wei, Chen-ying] Chongqing Univ Posts & Telecommun, Coll Bioinformat, Key Lab Mol Biol, Chongqing 400065, Peoples R China.
   [Wang, Zhan-Xiang] Xiamen Univ, Hosp Xiamen 1, Dept Neurosurg, Xiamen 361001, Peoples R China.
   [Long, Ding-Xin; Wu, Yi-Jun] Chinese Acad Sci, Inst Zool, Mol Toxicol Lab, Beijing 100101, Peoples R China.
   [Long, Ding-Xin] Univ S China, Sch Publ Hlth, Hengyang 421001, Peoples R China.
C3 Chongqing University of Posts & Telecommunications; Xiamen University;
   Chinese Academy of Sciences; Institute of Zoology, CAS; University of
   South China
RP Chang, PA (corresponding author), Chongqing Univ Posts & Telecommun, Coll Bioinformat, Key Lab Mol Biol, Chongqing 400065, Peoples R China.
EM changpingan@yahoo.com.cn
RI Wang, Zhanxiang/K-4162-2016
FU National Natural Science Foundation of China [30870298]; Natural Science
   Foundation of CQ CSTC [2010885410]; Science and Technology Bureau
   Foundation of Xiamen City [J00067-2010]; Program for Excellent Talents
   in Chongqing Higher Education Institutions
FX This work was supported by grants from the National Natural Science
   Foundation of China (No. 30870298) and the Natural Science Foundation
   Project of CQ CSTC (CSTC, 2010885410), by Science and Technology Bureau
   Foundation of Xiamen City (No. J00067-2010), and by Program for
   Excellent Talents in Chongqing Higher Education Institutions (to PA
   Chang).
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NR 26
TC 4
Z9 6
U1 0
U2 11
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0378-1119
EI 1879-0038
J9 GENE
JI Gene
PD APR 15
PY 2012
VL 497
IS 2
BP 164
EP 171
DI 10.1016/j.gene.2012.01.064
PG 8
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 922YH
UT WOS:000302584300005
PM 22326266
DA 2025-04-10
ER

PT J
AU Spletter, ML
   Schnorrer, F
AF Spletter, Maria L.
   Schnorrer, Frank
TI Transcriptional regulation and alternative splicing cooperate in muscle
   fiber-type specification in flies and mammals
SO EXPERIMENTAL CELL RESEARCH
LA English
DT Review
DE Drosophila; Muscle; Sarcomere; Transcription; Alternative splicing
ID SKELETAL-MUSCLE; FLIGHT-MUSCLE; FIBRILLAR MUSCLE; ADULT MUSCLE; PEVK
   DOMAIN; TITIN; ELASTICITY; GENE; EXPRESSION; SALL1
AB Muscles coordinate body movements throughout the animal kingdom. Each skeletal muscle is built of large, multi-nucleated cells, called myofibers, which are classified into several functionally distinct types. The typical fiber-type composition of each muscle arises during development, and in mammals is extensively adjusted in response to postnatal exercise. Understanding how functionally distinct muscle fiber-types arise is important for unraveling the molecular basis of diseases from cardiomyopathies to muscular dystrophies. In this review, we focus on recent advances in Drosophila and mammals in understanding how muscle fiber-type specification is controlled by the regulation of transcription and alternative splicing. We illustrate the cooperation of general myogenic transcription factors with muscle fiber-type specific transcriptional regulators as a basic principle for fiber-type specification, which is conserved from flies to mammals. We also examine how regulated alternative splicing of sarcomeric proteins in both flies and mammals can directly instruct the physiological and biophysical differences between fiber-types. Thus, research in Drosophila can provide important mechanistic insight into muscle fiber specification, which is relevant to homologous processes in mammals and to the pathology of muscle diseases. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.
C1 [Spletter, Maria L.; Schnorrer, Frank] Max Planck Inst Biochem, D-82152 Martinsried, Germany.
C3 Max Planck Society
RP Schnorrer, F (corresponding author), Max Planck Inst Biochem, Klopferspitz 18, D-82152 Martinsried, Germany.
EM schnorrer@biochem.mpg.de
RI Spletter, Maria/T-5917-2018; Schnorrer, Frank/AIE-3578-2022
OI Spletter, Maria/0000-0002-2068-3350; Schnorrer,
   Frank/0000-0002-9518-7263
FU Max Planck Society; Career Development Award by the Human Frontier
   Science Programme; NIH-F32 [5F32-AR062477]; EMBO; Humboldt postdoctoral
   fellowships
FX We are very grateful to Cornelia Schonbauer for providing data for Fig.
   1 and to Alexander Stark and Daniel Gerlach for help with the sequencing
   traces and splice junction reads used in Fig. 2a and b. We thank
   Cornelia Schonbauer and Nina Vogt for critical comments on the
   manuscript. This work was supported by the Max Planck Society, a Career
   Development Award by the Human Frontier Science Programme to ES., and
   NIH-F32 (5F32-AR062477), EMBO and Humboldt postdoctoral fellowships to
   M.L.S.
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NR 76
TC 41
Z9 43
U1 0
U2 18
PU ELSEVIER INC
PI SAN DIEGO
PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0014-4827
EI 1090-2422
J9 EXP CELL RES
JI Exp. Cell Res.
PD FEB 1
PY 2014
VL 321
IS 1
BP 90
EP 98
DI 10.1016/j.yexcr.2013.10.007
PG 9
WC Oncology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology; Cell Biology
GA AA5RL
UT WOS:000331157200014
PM 24145055
OA Green Published, Green Accepted, hybrid
DA 2025-04-10
ER

PT J
AU Elton, TS
   Martin, MM
AF Elton, TS
   Martin, MM
TI Alternative splicing:: a novel mechanism to fine-tune the expression and
   function of the human AT1 receptor
SO TRENDS IN ENDOCRINOLOGY AND METABOLISM
LA English
DT Review
ID ANGIOTENSIN-II RECEPTOR; SMOOTH-MUSCLE-CELLS; RIBOSOME ENTRY SITE;
   MESSENGER-RNA; TYPE-1 RECEPTOR; GENE-EXPRESSION; GENOMIC ORGANIZATION;
   CARDIAC FIBROBLASTS; SIGNAL-TRANSDUCTION; MOLECULAR-CLONING
AB Activation of the angiotensin II type 1 (AT(1)) receptor is closely involved in the pathogenesis of cardiovascular diseases; therefore, aberrant regulation of the production of this receptor might play a role in these disorders. Currently, there is strong evidence to suggest that the predominant mechanism regulating the number of AT(1) receptors is the modulation of mRNA stability. Here, we discuss the importance of alternative splicing as an additional post-transcriptional mechanism regulating human AT(1) receptor number and function.
C1 Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA.
C3 Brigham Young University
RP Elton, TS (corresponding author), Brigham Young Univ, Dept Chem & Biochem, C100 Benson Sci Bldg, Provo, UT 84602 USA.
EM terry_elton@byu.edu
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NR 60
TC 28
Z9 33
U1 0
U2 0
PU ELSEVIER SCIENCE LONDON
PI LONDON
PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND
SN 1043-2760
J9 TRENDS ENDOCRIN MET
JI Trends Endocrinol. Metab.
PD MAR
PY 2003
VL 14
IS 2
BP 66
EP 71
AR PII S1043-2760(02)00038-3
DI 10.1016/S1043-2760(02)00038-3
PG 6
WC Endocrinology & Metabolism
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Endocrinology & Metabolism
GA 658PJ
UT WOS:000181729100006
PM 12591176
DA 2025-04-10
ER

PT J
AU Cooper, TA
AF Cooper, TA
TI Muscle-specific splicing of a heterologous exon mediated by a single
   muscle-specific splicing enhancer from the cardiac troponin T gene
SO MOLECULAR AND CELLULAR BIOLOGY
LA English
DT Article
ID PRE-MESSENGER-RNA; ALTERNATIVE EXON; SKELETAL-MUSCLE; BINDING-PROTEIN;
   SELECTION; SITES; IDENTIFICATION; SEQUENCES; ELEMENTS
AB The chicken cardiac troponin T (cTNT) gene contains a single 30-nucleotide alternative exon that is included in embryonic striated muscle and skipped in the adult. Transient-transfection analysis of cTNT minigenes in muscle and fibroblast cell cultures previously identified four muscle-specific splicing enhancers (MSEs) that promote exon inclusion specifically in embryonic striated muscle cultures. Three MSEs located in the intron downstream from the alternative exon were sufficient for muscle-specific exon inclusion. In the present study, the boundaries of these MSEs were defined by scanning mutagenesis, allowing analysis of individual elements in gain-of-function experiments. Concatamers of MSE2 were necessary and sufficient to promote muscle-specific inclusion of a heterologous exon, indicating that it is a target for muscle-specific regulation. Sequences present in MSE2 are also found in MSE4, suggesting that these two MSEs act in a similar manner, MSE3 appears to be different from MSE2 and MSE4 yet is able to functionally replace both of these elements, demonstrating functional redundancy of elements that are likely to bind different factors. MSE2 and MSE4 each contain a novel sequence motif that is found adjacent to a number of alternative exons that undergo regulated splicing in striated muscle, suggesting a common role for this element in muscle-specific regulation.
C1 Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA.
   Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA.
C3 Baylor College of Medicine; Baylor College of Medicine
RP Cooper, TA (corresponding author), Baylor Coll Med, Dept Pathol, 1 Baylor Plaza, Houston, TX 77030 USA.
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NR 33
TC 44
Z9 47
U1 0
U2 4
PU AMER SOC MICROBIOLOGY
PI WASHINGTON
PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA
SN 0270-7306
J9 MOL CELL BIOL
JI Mol. Cell. Biol.
PD AUG
PY 1998
VL 18
IS 8
BP 4519
EP 4525
DI 10.1128/MCB.18.8.4519
PG 7
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 102WX
UT WOS:000074950000012
PM 9671461
OA Green Published
DA 2025-04-10
ER

PT J
AU Ab Hakim, NH
   Kounishi, T
   Alam, AHMK
   Tsukahara, T
   Suzuki, H
AF Ab Hakim, Nor Hakimah
   Kounishi, Toshiki
   Alam, A. H. M. Khurshid
   Tsukahara, Toshifumi
   Suzuki, Hitoshi
TI Alternative splicing of Mef2c promoted by Fox-1 during neural
   differentiation in P19 cells
SO GENES TO CELLS
LA English
DT Article
ID EMBRYONAL CARCINOMA-CELLS; TRACT-BINDING-PROTEIN; MUSCLE DEVELOPMENT;
   RNA RECOGNITION; GENE-EXPRESSION; TRANSCRIPTION; BRAIN; NEURONS; INTRON;
   NOVA
AB Mef2c protein is one of the MADS-box type transcription factors involved in muscular differentiation and synaptic formation. Previously, it has been reported that the Mef2c gene is responsible for three alternative splicing regulations. Here, we investigated the alternative splicing variants of Mef2c during neural differentiation of P19 cells and during cardio muscular differentiation of P19 clone 6 (P19CL6). We detected that two Mef2c mRNA isoforms, using exon alpha 1 with and without the gamma region at exon 10, are mainly produced in immature P19 cells. Remarkably, Mef2c isoforms containing exon beta specifically appeared in the neural cell stage. Because most transcripts contain exon beta in the neural cell stage and in the brain, this suggests that the alternative splicing of exon beta is highly regulated. Among known regulators, Fox-1 was specifically expressed in the neural cell stage in correlation with Mef2c exon beta. Fox-1 promoted exon beta inclusion in transfection experiments using Mef2c beta minigene. Moreover, we found that the promotion required RNA-binding activity of Fox-1 and GCAUG sequence located in adjacent intron of exon beta. Taken together, our results suggest that Fox-1, expressed specifically in the neural cell stage, promoted Mef2c exon beta inclusion via the GCAUG.
C1 [Ab Hakim, Nor Hakimah; Kounishi, Toshiki; Alam, A. H. M. Khurshid; Tsukahara, Toshifumi; Suzuki, Hitoshi] Japan Adv Inst Sci & Technol, Ctr Nano Mat Technol, Nomi, Ishikawa 9231211, Japan.
   [Ab Hakim, Nor Hakimah; Kounishi, Toshiki; Alam, A. H. M. Khurshid] Japan Adv Inst Sci & Technol, Grad Sch Mat Sci, Nomi, Ishikawa 9231211, Japan.
C3 Japan Advanced Institute of Science & Technology (JAIST); Japan Advanced
   Institute of Science & Technology (JAIST)
RP Suzuki, H (corresponding author), Japan Adv Inst Sci & Technol, Ctr Nano Mat Technol, 1-1 Asahidai, Nomi, Ishikawa 9231211, Japan.
EM suzuki-h@jaist.ac.jp
OI Alam, AHM Khurshid/0000-0003-2690-6559
FU Japan Society for the Promotion of Science of Japan; Ministry of Health,
   Labor and Welfare of Japan; Panasonic Scholarship Inc.
FX We thank Dr Douglas L. Black for anti-Fox serum and Ms Mary A. Mooradian
   for scientific English correction. This research was supported in part
   by a Grant-in-Aid for Scientific Research (B) from the Japan Society for
   the Promotion of Science of Japan (to T. T.), and Grant-in-Aid from the
   Ministry of Health, Labor and Welfare of Japan (to H. S). N.H.A.H. is a
   recipient of a Panasonic Scholarship Inc.
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NR 39
TC 34
Z9 38
U1 0
U2 7
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1356-9597
EI 1365-2443
J9 GENES CELLS
JI Genes Cells
PD MAR
PY 2010
VL 15
IS 3
BP 255
EP 267
DI 10.1111/j.1365-2443.2009.01378.x
PG 13
WC Cell Biology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology; Genetics & Heredity
GA 564ID
UT WOS:000275205600008
PM 20141540
OA Bronze
DA 2025-04-10
ER

PT J
AU Gjerga, E
   Dewenter, M
   Britto-Borges, T
   Grosso, J
   Stein, F
   Eschenbach, J
   Rettel, M
   Backs, J
   Dieterich, C
AF Gjerga, Enio
   Dewenter, Matthias
   Britto-Borges, Thiago
   Grosso, Johannes
   Stein, Frank
   Eschenbach, Jessica
   Rettel, Mandy
   Backs, Johannes
   Dieterich, Christoph
TI Transverse aortic constriction multi-omics analysis uncovers
   pathophysiological cardiac molecular mechanisms
SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION
LA English
DT Article
ID PROTEOME; PACKAGE
AB Time-course multi-omics data of a murine model of progressive heart failure (HF) induced by transverse aortic constriction (TAC) provide insights into the molecular mechanisms that are causatively involved in contractile failure and structural cardiac remodelling. We employ Illumina-based transcriptomics, Nanopore sequencing and mass spectrometry-based proteomics on samples from the left ventricle (LV) and right ventricle (RV, RNA only) of the heart at 1, 7, 21 and 56 days following TAC and Sham surgery. Here, we present Transverse Aortic COnstriction Multi-omics Analysis (TACOMA), as an interactive web application that integrates and visualizes transcriptomics and proteomics data collected in a TAC time-course experiment. TACOMA enables users to visualize the expression profile of known and novel genes and protein products thereof. Importantly, we capture alternative splicing events by assessing differential transcript and exon usage as well. Co-expression-based clustering algorithms and functional enrichment analysis revealed overrepresented annotations of biological processes and molecular functions at the protein and gene levels. To enhance data integration, TACOMA synchronizes transcriptomics and proteomics profiles, enabling cross-omics comparisons. With TACOMA (https://shiny.dieterichlab.org/app/tacoma), we offer a rich web-based resource to uncover molecular events and biological processes implicated in contractile failure and cardiac hypertrophy. For example, we highlight: (i) changes in metabolic genes and proteins in the time course of hypertrophic growth and contractile impairment; (ii) identification of RNA splicing changes in the expression of Tpm2 isoforms between RV and LV; and (iii) novel transcripts and genes likely contributing to the pathogenesis of HF. We plan to extend these data with additional environmental and genetic models of HF to decipher common and distinct molecular changes in heart diseases of different aetiologies.Database URL: https://shiny.dieterichlab.org/app/tacoma
C1 [Gjerga, Enio; Britto-Borges, Thiago; Eschenbach, Jessica; Dieterich, Christoph] Univ Hosp Heidelberg, Klaus Tschira Inst Integrat Computat Cardiol, Sect Bioinformat & Syst Cardiol, INF 669, D-69120 Heidelberg, Germany.
   [Gjerga, Enio; Britto-Borges, Thiago; Eschenbach, Jessica; Dieterich, Christoph] Univ Hosp Heidelberg, Dept Internal Med 3, Cardiol Angiol & Pneumol, INF 669, D-69120 Heidelberg, Germany.
   [Gjerga, Enio; Dewenter, Matthias; Britto-Borges, Thiago; Grosso, Johannes; Eschenbach, Jessica; Backs, Johannes; Dieterich, Christoph] German Ctr Cardiovasc Res DZHK, Partner Site Heidelberg, D-69120 Heidelberg, Germany.
   [Dewenter, Matthias; Grosso, Johannes; Backs, Johannes] Heidelberg Univ, Inst Expt Cardiol, Med Fac Heidelberg, INF 669, D-69120 Heidelberg, Germany.
   [Dewenter, Matthias; Backs, Johannes] Heidelberg Univ Hosp, Internal Med 8, INF 669, D-69120 Heidelberg, Germany.
   [Stein, Frank; Rettel, Mandy] European Mol Biol Lab, Meyerhofstr 1, D-69117 Heidelberg, Germany.
   [Stein, Frank] European Mol Biol Lab, Prote Core Facil, Meyerhofstr 1, D-69117 Heidelberg, Germany.
   [Backs, Johannes] Heidelberg Univ, Helmholtz Inst Translat Angiocardiosci HI TAC, MDC, D-69120 Heidelberg, Germany.
C3 Ruprecht Karls University Heidelberg; Ruprecht Karls University
   Heidelberg; German Centre for Cardiovascular Research; Ruprecht Karls
   University Heidelberg; Ruprecht Karls University Heidelberg; European
   Molecular Biology Laboratory (EMBL); European Molecular Biology
   Laboratory (EMBL); Ruprecht Karls University Heidelberg
RP Dieterich, C (corresponding author), Univ Hosp Heidelberg, Klaus Tschira Inst Integrat Computat Cardiol, Sect Bioinformat & Syst Cardiol, INF 669, D-69120 Heidelberg, Germany.; Dieterich, C (corresponding author), Univ Hosp Heidelberg, Dept Internal Med 3, Cardiol Angiol & Pneumol, INF 669, D-69120 Heidelberg, Germany.; Dieterich, C (corresponding author), German Ctr Cardiovasc Res DZHK, Partner Site Heidelberg, D-69120 Heidelberg, Germany.
EM christoph.dieterich@med.uni-heidelberg.de
RI Dieterich, Christoph/ABF-8459-2021; Britto-Borges, Thiago/J-4953-2016
OI Dieterich, Christoph/0000-0001-9468-6311
FU Klaus Tschira Stiftung gGmbH [00.013.2021]; Deutsche
   Forschungsgemeinschaft [DFG, German Research Foundation [464424253];
   Ministry of Science, Research; Arts Baden-Wuerttemberg (MWK); German
   Research Foundation (DFG) [INST 35/1314-1 FUGG, INST 35/1503-1 FUGG]
FX Klaus Tschira Stiftung gGmbH (grant 00.013.2021 to E.G., T.B.B. and
   C.D.); Deutsche Forschungsgemeinschaft [DFG, German Research Foundation
   - SFB 1550 - Project-ID 464424253 to C.D. (sub-projects B07 and INF),
   M.D. (sub-project S02) and to J.B. (sub-projects A01 and B07)]. The
   authors gratefully acknowledge the data storage service SDS@hd supported
   by the Ministry of Science, Research and the Arts Baden-Wuerttemberg
   (MWK) and the German Research Foundation (DFG) through grant INST
   35/1314-1 FUGG and INST 35/1503-1 FUGG.
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NR 37
TC 0
Z9 0
U1 1
U2 1
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 1758-0463
J9 DATABASE-OXFORD
JI Database
PD JUL 25
PY 2024
VL 2024
AR baae060
DI 10.1093/database/baae060
EA JUL 2024
PG 10
WC Mathematical & Computational Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Mathematical & Computational Biology
GA ZL9K8
UT WOS:001275570500001
PM 39051433
OA gold
DA 2025-04-10
ER

PT J
AU Yamamoto, T
   Sano, R
   Miura, A
   Imasaka, M
   Naito, Y
   Nishiguchi, M
   Ihara, K
   Otani, N
   Kominato, Y
   Ohmuraya, M
   Kuroyanagi, H
   Nishio, H
AF Yamamoto, Takuma
   Sano, Rie
   Miura, Aya
   Imasaka, Mai
   Naito, Yoshiro
   Nishiguchi, Minori
   Ihara, Kensuke
   Otani, Naruhito
   Kominato, Yoshihiko
   Ohmuraya, Masaki
   Kuroyanagi, Hidehito
   Nishio, Hajime
TI I536T variant of RBM20 affects splicing of cardiac structural
   proteins that are causative for developing dilated cardiomyopathy
SO JOURNAL OF MOLECULAR MEDICINE-JMM
LA English
DT Article
DE Sudden death; RBM20; Cardiomyopathy; Alternative splicing; Postmortem
   examination
ID SUDDEN UNEXPLAINED DEATH; POSTMORTEM GENETIC-ANALYSIS; UNEXPECTED DEATH;
   TITIN; MUTATIONS; AUTOPSY; INFANCY
AB RBM20 is one of the genes predisposing to dilated cardiomyopathy (DCM). Variants in the RS domain have been reported in many DCM patients, but the pathogenicity of variants within the RNA-recognition motif remains unknown. Two human patients with the I536T-RBM20 variant without an apparent DCM phenotype were identified in sudden death cohorts. A splicing reporter assay was performed, and an I538T knock-in mouse model (Rbm20(I538T)) was generated to determine the significance of this variant. The reporter assay demonstrated that the human I536T variant affected the TTN splicing pattern compared to wild-type. In the mouse experiments, Rbm20(I538T) mice showed different splicing patterns in Ttn, Ldb3, Camk2d, and Ryr2. The expressions of Casq1, Mybpc2, and Myot were upregulated in Rbm20(I538T) mice, but Rbm20(I538T) mice showed neither DCM nor cardiac dysfunction on histopathological examination and ultrasound echocardiography. The I536T-RBM20 (I538T-Rbm20) variant changes gene splicing and affects gene expression, but the splicing and expression changes in Ttn and Ca handling genes such as Casq1, Camk2d, and Ryr2 do not cause DCM morphology in the mouse model. Key messages center dot Two human patients with the I536T-RBM20 variant without a DCM phenotype were identified. center dot A splicing reporter assay demonstrated that the variant affected the TTN splicing. center dot Rbm20(I538T) mice showed neither DCM nor cardiac dysfunction. center dot Rbm20(I538T) mice showed different splicing patterns and the gene expressions.
C1 [Yamamoto, Takuma; Miura, Aya; Nishiguchi, Minori; Nishio, Hajime] Hyogo Med Univ, Dept Legal Med, 1-1 Mukogawa Cho, Nishinomiya, Hyogo 6638501, Japan.
   [Sano, Rie; Kominato, Yoshihiko] Gunma Univ, Dept Legal Med, Grad Sch Med, Gunma 3718511, Japan.
   [Imasaka, Mai; Ohmuraya, Masaki] Hyogo Med Univ, Dept Genet, Nishinomiya, Hyogo 6638501, Japan.
   [Naito, Yoshiro] Hyogo Med Univ, Dept Cardiovasc & Renal Med, Nishinomiya, Hyogo 6638501, Japan.
   [Ihara, Kensuke] Tokyo Med & Dent Univ, Med Res Inst, Dept Bioinformat Pharmacol, Tokyo 1138510, Japan.
   [Otani, Naruhito] Hyogo Med Univ, Dept Publ Hlth, Nishinomiya, Hyogo 6638501, Japan.
   [Kuroyanagi, Hidehito] Univ Ryukyus, Grad Sch Med, Dept Biochem, Nishihara, Okinawa 9030215, Japan.
C3 Hyogo Medical University; Gunma University; Hyogo Medical University;
   Hyogo Medical University; Institute of Science Tokyo; Tokyo Medical &
   Dental University (TMDU); Hyogo Medical University; University of the
   Ryukyus
RP Yamamoto, T (corresponding author), Hyogo Med Univ, Dept Legal Med, 1-1 Mukogawa Cho, Nishinomiya, Hyogo 6638501, Japan.
EM tk-yamamoto@hyo-med.ac.jp
RI Miura, Aya/MBG-6981-2025
OI yamamoto, takuma/0000-0001-5690-885X
FU JSPS KAKENHI [JP20H03958, JP20K07659, JP20K21385]; Takeda Science
   Foundation; Grants-in-Aid for Scientific Research [20K08467, 20K21697,
   20K21385, 20H03958, 20K10551] Funding Source: KAKEN
FX This work was supported in part by grants from JSPS KAKENHI (JP20H03958
   to T.Y., JP20K07659 and JP20K21385 to H.K.) and Takeda Science
   Foundation.
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NR 38
TC 6
Z9 9
U1 0
U2 1
PU SPRINGER HEIDELBERG
PI HEIDELBERG
PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY
SN 0946-2716
EI 1432-1440
J9 J MOL MED
JI J. Mol. Med.
PD DEC
PY 2022
VL 100
IS 12
BP 1741
EP 1754
DI 10.1007/s00109-022-02262-8
EA OCT 2022
PG 14
WC Genetics & Heredity; Medicine, Research & Experimental
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity; Research & Experimental Medicine
GA 6L1AF
UT WOS:000864043500001
PM 36198914
OA hybrid, Green Published
DA 2025-04-10
ER

PT J
AU Medina, MW
   Krauss, RM
AF Medina, Marisa Wong
   Krauss, Ronald M.
TI The Role of HMGCR Alternative Splicing in Statin Efficacy
SO TRENDS IN CARDIOVASCULAR MEDICINE
LA English
DT Review
ID HUMAN GENE-EXPRESSION; LIPOPROTEIN CHOLESTEROL RESPONSE; ABNORMAL
   STEROL-METABOLISM; COENZYME-A REDUCTASE; COA REDUCTASE;
   LYMPHOBLASTOID-CELLS; INDUCED CYTOTOXICITY; THERAPY; GENOME; SIMVASTATIN
AB Statins, or 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, are widely prescribed to lower plasma cholesterol levels and reduce cardiovascular disease risk. Despite the well-documented efficacy of statins, there is large interindividual variation in response. Using a panel of immortalized lymphocyte cell lines incubated with simvastatin, we recently found that the magnitude of expression of an alternatively spliced HMGCR transcript lacking exon 13 was inversely correlated with in vivo reductions of total cholesterol, low-density lipoprotein cholesterol, apoB, and triglycerides after statin treatment of the individuals from whom the cells were derived. This review will discuss the potential significance of alternative splicing as a mechanism contributing to variation in statin efficacy as well as the use of immortalized lymphocyte cell lines for identifying pharmacogenetically relevant polymorphisms and molecular mechanisms. (Trends Cardiovasc Med 2009;19:173-177) (C) 2009, Elsevier Inc.
C1 [Medina, Marisa Wong; Krauss, Ronald M.] Childrens Hosp Oakland Res Inst, Oakland, CA 94609 USA.
C3 University of California System; University of California San Francisco;
   UCSF Medical Center; UCSF Benioff Children's Hospital Oakland;
   Children's Hospital Oakland Research Institute
RP Medina, MW (corresponding author), Childrens Hosp Oakland Res Inst, 5700 Martin Luther King Jr Way, Oakland, CA 94609 USA.
EM mwmedina@chori.org
RI Krauss, Ronald M./LTD-4078-2024
FU NHLBI NIH HHS [U01 HL069757-09, U01 HL069757] Funding Source: Medline
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NR 37
TC 47
Z9 55
U1 0
U2 4
PU ELSEVIER SCIENCE LONDON
PI LONDON
PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND
SN 1050-1738
J9 TRENDS CARDIOVAS MED
JI Trends Cardiovasc. Med.
PD JUL
PY 2009
VL 19
IS 5
BP 173
EP 177
AR PII S1050-1738(09)00156-X
DI 10.1016/j.tcm.2009.10.003
PG 5
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 626SY
UT WOS:000279988500006
PM 20005478
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Chand, HS
   Ness, SA
   Kisiel, W
AF Chand, HS
   Ness, SA
   Kisiel, W
TI Identification of a novel human tissue factor splice variant that is
   upregulated in tumor cells
SO INTERNATIONAL JOURNAL OF CANCER
LA English
DT Article
DE tissue factor; alternative splicing; cancer
ID FACTOR EXPRESSION; ANGIOGENESIS; METASTASIS; RECEPTOR; ACTIVATION;
   MECHANISMS; CARCINOMA
AB Tissue factor (TF) is a transmembrane glycoprotein that serves as the prime initiator of blood coagulation and plays a critical role in thrombosis and hemostasis. In addition, a variety of tumor cells overexpress cell-surface TF, which appears to be important for tumor angiogenesis and metastasis. To elucidate the mechanism involved in the upregulation of TF in human tumor cells, a comprehensive analysis of TF mRNA from various normal and tumor cells was performed. The results of these studies indicate that, in addition to possessing a normal full-length TF transcript and minor levels of an alternatively spliced transcript known as alternatively-spliced tissue factor (asTF) (Bogdanov et al, Nat Me 2003;9:458-62), human tumor cells express additional full-length TF transcripts that are also generated by alternative splicing. Reverse transcripts-polymerase chain reaction (RT-PCR) and 5'-rapid amplification of cDNA ends- (5'-RACE) based analyses of cytoplasmic RNA from normal and tumor cells revealed that there is alternative splicing of the first intron between exon I and exon II resulting in 2 additional TF transcripts. One of the transcripts has an extended exon I with inclusion of most of the first TF intron (955 bp), while the second transcript is formed by the insertion of a 495 bp sequence, referred to as exon IA, derived from an internal sequence of the first intron. The full length TF transcript with alternatively spliced novel exon IA, referred to as alternative exon 1A-tissue factor (TF-A), represented similar to 1% of the total TF transcripts in normal cells, but constituted 7-10% of the total TF transcript in tumor cells. Quantitative real-time RT-PCR analysis indicated that cultured human tumor cells contain 10-25-fold more copy numbers of TF-A in comparison to normal, untransformed cells. We propose that high-level expression of the novel TF-A transcript, preferentially in tumor cells, may have utility in the diagnosis and staging of a variety of solid tumors. (c) 2005 Wiley-Liss, Inc.
C1 Univ New Mexico, Hlth Sci Ctr, Dept Pathol, Albuquerque, NM 87131 USA.
   Univ New Mexico, Hlth Sci Ctr, Dept Mol Genet & Microbiol, Albuquerque, NM USA.
C3 University of New Mexico's Health Sciences Center; University of New
   Mexico; University of New Mexico; University of New Mexico's Health
   Sciences Center
RP Univ New Mexico, Hlth Sci Ctr, Dept Pathol, Albuquerque, NM 87131 USA.
EM wkisiel@salud.unm.edu
RI Ness, Scott/AAV-4009-2020; Chand, Hitendra/AAE-7975-2020
OI Chand, Hitendra/0000-0002-0574-9307; Ness, Scott/0000-0001-6965-8909
FU NCI NIH HHS [CA58443, R01 CA058443] Funding Source: Medline; NHLBI NIH
   HHS [HL64119] Funding Source: Medline
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NR 30
TC 43
Z9 54
U1 0
U2 1
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0020-7136
EI 1097-0215
J9 INT J CANCER
JI Int. J. Cancer
PD APR 1
PY 2006
VL 118
IS 7
BP 1713
EP 1720
DI 10.1002/ijc.21550
PG 8
WC Oncology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Oncology
GA 024RV
UT WOS:000236214700015
PM 16217771
OA Bronze
DA 2025-04-10
ER

PT J
AU Kone, BC
AF Kone, BC
TI Molecular biology of natriuretic peptides and nitric oxide synthases
SO CARDIOVASCULAR RESEARCH
LA English
DT Review
DE natriuretic peptide; G proteins; nitric oxide; endothelial factors;
   endothelial function; signal transduction
ID CORONARY-ARTERY DISEASE; ACTIVATED PROTEIN-KINASE; ENDOTHELIAL NO
   SYNTHASE; MESSENGER-RNA STABILITY; SMOOTH-MUSCLE CELLS; MISSENSE
   GLU298ASP VARIANT; HUMAN HEART-FAILURE; MICE LACKING; IN-VIVO;
   SKELETAL-MUSCLE
AB Natriuretic peptides and nitric oxide play important roles in cardiovascular and renal physiology and disease. The natriuretic peptides - atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide - comprise a family of proteins that participate in the integrated control of intravascular volume and arterial blood pressure. The natriuretic peptides differentially bind distinct classes of receptors that signal through different mechanisms. Membrane-bound, guanylyl cyclase-coupled natriuretic peptide receptors (A- and B-types) mediate natriuretic peptide effects through the production of 3 ' ,5 ' -cyclic guanosine monophosphate (cGMP). C-Type natriuretic peptide receptors, which lack the guanylyl cyclase domain, alter target cell function through Gi protein-coupled inhibition of membrane adenylyl cyclase activity, and also serve to clear circulating natriuretic peptides. The expression of the natriuretic peptides and their receptors are subject to complex controls. Similar structural and regulatory diversity exists for the nitric oxide synthases. The three nitric oxide synthase genes are regulated by a variety of mechanisms ranging from alternative splicing and alternative promoter usage to complex post-translational controls. This review highlights the molecular diversity of the natriuretic peptides and nitric oxide synthases and explores recent insights into their regulation. (C) 2001 Elsevier Science BY. All rights reserved.
C1 Univ Texas, Sch Med, Dept Internal Med, Div Renal Dis & Hypertens, Houston, TX 77030 USA.
   Univ Texas, Sch Med, Dept Integrat Biol Pharmacol & Physiol, Div Renal Dis & Hypertens, Houston, TX 77030 USA.
C3 University of Texas System; University of Texas System
RP Kone, BC (corresponding author), Univ Texas, Sch Med, Dept Internal Med, Div Renal Dis & Hypertens, 6431 Fannin,MSB 4-138, Houston, TX 77030 USA.
FU NIDDK NIH HHS [DK50745, DK47981] Funding Source: Medline; NIGMS NIH HHS
   [GM20529] Funding Source: Medline
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NR 171
TC 96
Z9 112
U1 0
U2 6
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0008-6363
J9 CARDIOVASC RES
JI Cardiovasc. Res.
PD AUG 15
PY 2001
VL 51
IS 3
BP 429
EP 441
DI 10.1016/S0008-6363(01)00327-3
PG 13
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 465KR
UT WOS:000170588600007
PM 11476733
OA Bronze
DA 2025-04-10
ER

PT J
AU Leroy, O
   Dhaenens, CM
   Schraen-Maschke, S
   Belarbi, K
   Delacourte, A
   Andreadis, A
   Sablonnière, B
   Buée, L
   Sergeant, N
   Caillet-Boudin, ML
AF Leroy, Olivier
   Dhaenens, Claire-Marie
   Schraen-Maschke, Suzanna
   Belarbi, Karim
   Delacourte, Andre
   Andreadis, Athena
   Sablonniere, Bernard
   Buee, Luc
   Sergeant, Nicolas
   Caillet-Boudin, Marie-Laure
TI ETR-3 represses tau exons 2/3 inclusion, a splicing event abnormally
   enhanced in myotonic dystrophy type I
SO JOURNAL OF NEUROSCIENCE RESEARCH
LA English
DT Article
DE myotonic dystrophy; splicing; microtubule-associated Tau; insulin
   receptor; ETR-3
ID EXPANDED-REPEAT TRANSCRIPTS; RNA-BINDING PROTEINS; MESSENGER-RNA;
   MUSCLEBLIND PROTEINS; APOLIPOPROTEIN-E; NUCLEAR FOCI; CELF FAMILY;
   HUMAN-BRAIN; TAU; EXPRESSION
AB Altered splicing of transcripts, including the insulin receptor (IR) and the cardiac troponin (cTNT), is a key feature of myotonic dystrophy type I (DM1). CELF and MBNL splicing factor members regulate the splicing of those transcripts. We have previously described an alteration of Tau exon 2 splicing in DM1 brain, resulting in the favored exclusion of exon 2. However, the factors required for alternative splicing of Tau exon 2 remain undetermined. Here we report a decreased expression of CELF family member and MBNL transcripts in DM1 brains as assessed by RT-PCR. By using cellular models with a control- or DM1-like splicing pattern of Tau transcripts, we demonstrate that ETR-3 promotes selectively the exclusion of Tau exon 2. These results together with the analysis of Tau exon 6 and IR exon 11 splicing in brain, muscle, and cell models suggest that DM1 splicing alteration of several transcripts involves various factors. (c) 2006 Wiley-Liss, Inc.
C1 INSERM, U815, F-59045 Lille, France.
   Univ Lille 2, Fac Med, Lille, France.
   Univ Massachusetts, Sch Med, Shriver Ctr, Waltham, MA USA.
C3 Institut National de la Sante et de la Recherche Medicale (Inserm);
   Universite de Lille; University of Massachusetts System
RP Caillet-Boudin, ML (corresponding author), INSERM, U815, Pl Verdun, F-59045 Lille, France.
EM caillet@lille.inserm.fr
RI belarbi, karim/G-4467-2013; Sergeant, Nicolas/O-5467-2017; belarbi,
   karim/T-9461-2018; BUEE, Luc/B-3126-2010
OI SCHRAEN, Susanna/0000-0002-7247-4809; DHAENENS,
   Claire-Marie/0000-0003-4719-4124; Sergeant, Nicolas/0000-0003-1448-124X;
   belarbi, karim/0000-0002-0027-1172; BUEE, Luc/0000-0002-6261-4230;
   Sablonniere, Bernard/0000-0003-0384-4076
FU NICHD NIH HHS [P01 HD05515] Funding Source: Medline; NINDS NIH HHS [R01
   NS38051] Funding Source: Medline
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NR 42
TC 43
Z9 53
U1 0
U2 1
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0360-4012
EI 1097-4547
J9 J NEUROSCI RES
JI J. Neurosci. Res.
PD SEP
PY 2006
VL 84
IS 4
BP 852
EP 859
DI 10.1002/jnr.20980
PG 8
WC Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 080YI
UT WOS:000240284000015
PM 16862542
DA 2025-04-10
ER

PT J
AU Ricci, M
   Xu, YJ
   Hammond, HL
   Willoughby, DA
   Nathanson, L
   Rodriguez, MM
   Vatta, M
   Lipshultz, SE
   Lincoln, J
AF Ricci, Marco
   Xu, Yanji
   Hammond, Harriet L.
   Willoughby, David A.
   Nathanson, Lubov
   Rodriguez, Maria M.
   Vatta, Matteo
   Lipshultz, Steven E.
   Lincoln, Joy
TI Myocardial Alternative RNA Splicing and Gene Expression Profiling in
   Early Stage Hypoplastic Left Heart Syndrome
SO PLOS ONE
LA English
DT Article
ID FAILURE; VENTRICLE; SETS
AB Hypoplastic Left Heart Syndrome (HLHS) is a congenital defect characterized by underdevelopment of the left ventricle and pathological compensation of the right ventricle. If untreated, HLHS is invariably lethal due to the extensive increase in right ventricular workload and eventual failure. Despite the clinical significance, little is known about the molecular pathobiological state of HLHS. Splicing of mRNA transcripts is an important regulatory mechanism of gene expression. Tissue specific alterations of this process have been associated with several cardiac diseases, however, transcriptional signature profiles related to HLHS are unknown. In this study, we performed genome-wide exon array analysis to determine differentially expressed genes and alternatively spliced transcripts in the right ventricle (RV) of six neonates with HLHS, compared to the RV and left ventricle (LV) from non-diseased control subjects. In HLHS, over 180 genes were differentially expressed and 1800 were differentially spliced, leading to changes in a variety of biological processes involving cell metabolism, cytoskeleton, and cell adherence. Additional hierarchical clustering analysis revealed that differential gene expression and mRNA splicing patterns identified in HLHS are unique compared to non-diseased tissue. Our findings suggest that gene expression and mRNA splicing are broadly dysregulated in the RV myocardium of HLHS neonates. In addition, our analysis identified transcriptome profiles representative of molecular biomarkers of HLHS that could be used in the future for diagnostic and prognostic stratification to improve patient outcome.
C1 [Ricci, Marco] Univ Miami, Miller Sch Med, Div Cardiothorac Surg, Miami, FL 33136 USA.
   [Ricci, Marco; Rodriguez, Maria M.; Lipshultz, Steven E.] Jackson Mem Hosp, Holtz Childrens Hosp, Miami, FL 33136 USA.
   [Xu, Yanji] Shaun & Lilly Int LLC, Palm City, FL USA.
   [Hammond, Harriet L.; Lincoln, Joy] Ohio State Univ, Dept Pediat, Nationwide Childrens Hosp, Ctr Cardiovasc & Pulm Res, Columbus, OH 43210 USA.
   [Willoughby, David A.] Ocean Ridge Biosci LLC, Palm Beach Gardens, FL USA.
   [Nathanson, Lubov] Univ Miami, Miller Sch Med, Inst Human Genom, Miami, FL 33136 USA.
   [Rodriguez, Maria M.] Univ Miami, Miller Sch Med, Dept Pathol, Miami, FL 33136 USA.
   [Vatta, Matteo] Texas Childrens Hosp, Baylor Coll Med, Div Pediat Cardiol, Houston, TX 77030 USA.
   [Vatta, Matteo] Baylor Coll Med, Dept Mol Physiol & Biophys, Houston, TX 77030 USA.
   [Lipshultz, Steven E.] Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33136 USA.
C3 University of Miami; University System of Ohio; Ohio State University;
   Nationwide Childrens Hospital; Research Institute at Nationwide
   Children's Hospital; Center for Cardiovascular & Pulmonary Research;
   University of Miami; University of Miami; Baylor College of Medicine;
   Baylor College Medical Hospital; Baylor College of Medicine; University
   of Miami
RP Ricci, M (corresponding author), Univ Miami, Miller Sch Med, Div Cardiothorac Surg, Miami, FL 33136 USA.
EM mricci@med.miami.edu
RI Nathanson, Lubov/ABC-2642-2021
OI Nathanson, Lubov/0000-0003-1038-9083; Lincoln, Joy/0000-0003-1517-6888
FU private University of Miami; National Heart, Lung, and Blood Institute
   [R01HL091878]
FX Study supported by private University of Miami research Fund (Jonathan
   and Eileen Otto Research Fund) and National Heart, Lung, and Blood
   Institute R01HL091878 (JL). The funders had no role in study design,
   data collection and analysis, decision to publish, or preparation of the
   manuscript.
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NR 28
TC 24
Z9 25
U1 0
U2 11
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD JAN 27
PY 2012
VL 7
IS 1
AR e29784
DI 10.1371/journal.pone.0029784
PG 11
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 911GB
UT WOS:000301704200001
PM 22299024
OA Green Submitted, gold, Green Published
DA 2025-04-10
ER

PT J
AU Hurtado, C
   Prociuk, M
   Maddaford, TG
   Dibrov, E
   Mesaeli, N
   Hryshko, LV
   Pierce, GN
AF Hurtado, C
   Prociuk, M
   Maddaford, TG
   Dibrov, E
   Mesaeli, N
   Hryshko, LV
   Pierce, GN
TI Cells expressing unique Na<SUP>+</SUP>/Ca2<SUP>+</SUP> exchange (NCX1)
   splice variants exhibit different susceptibilities to Ca<SUP>2+</SUP>
   overload
SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
LA English
DT Article
DE NCX1.1; NCX1.3; ouabain; ischemia
ID CARDIAC NA+-CA2+ EXCHANGER; SODIUM-CALCIUM EXCHANGE; SARCOLEMMAL
   MEMBRANE PATCHES; MOLECULAR DETERMINANTS; VENTRICULAR MYOCYTES;
   CA2+-BINDING DOMAIN; FUNCTIONAL-ANALYSIS; DYNAMIC PROPERTIES; NA/CA
   EXCHANGER; STEADY-STATE
AB The Na+/Ca2(+) exchanger (NCX) NCX1 exhibits tissue-specific alternative splicing. Such NCX splice variants as NCX1.1 and NCX1.3 are also differentially regulated by Na+ and Ca2+, although the physiological implications of these regulatory characteristics are unclear. On the basis of their distinct regulatory profiles, we hypothesized that cells expressing these different splice variants might exhibit unique responses to conditions promoting Ca2+ overload, such as during exposure to cardiac glycosides or simulated ischemia. NCX1.1 or NCX1.3 was expressed in human embryonic kidney (HEK)-293 cells or rat neonatal ventricular cardiomyocytes (NVC), and expression was confirmed by Western blotting and immunocytochemical analyses. HEK-293 cells lacked NCX1 protein before transfection. With use of adenoviral vectors, neonatal cardiomyocytes were induced to overexpress the NCX1.1 splice variant by nearly twofold, whereas the NCX1.3 isoform was expressed on the endogenous NCX1.1 background. Total expression was comparable for NCX1.1 and NCX1.3. Exposure of NVC to ouabain induced a significant increase in cellular Ca2+, an effect that was exaggerated in cells overexpressing NCX1.1, but not NCX1.3. The increase in intracellular Ca2+ was inhibited by 5 mu M KB-R7943. Cardiomyocytes overexpressing NCX1.1 also exhibited a greater accumulation of intracellular Ca2+ in response to simulated ischemia than did cells expressing NCX1.3. Similar responses were observed in HEK-293 cells where NCX1.1 was expressed. We conclude that expression of the NCX1.3 splice variant protects against severe Ca2+ overload, whereas NCX1.1 promotes Ca2+ overload in response to cardiac glycosides and ischemic challenges. These results highlight the importance of ionic regulation in controlling NCX1 activity under conditions that promote Ca2+\ overload.
C1 St Boniface Gen Hosp, Res Ctr, Div Stroke & Vasc Dis, Winnipeg, MB R2H 2A6, Canada.
   St Boniface Gen Hosp, Res Ctr, Inst Cardiovasc Sci, Winnipeg, MB R2H 2A6, Canada.
   Univ Manitoba, Fac Med, Dept Physiol & Biochem, Winnipeg, MB, Canada.
   Univ Manitoba, Fac Med, Dept Med Genet, Winnipeg, MB, Canada.
   Univ Manitoba, Fac Pharm, Dept Med Genet, Winnipeg, MB R3T 2N2, Canada.
   Univ Manitoba, Fac Pharm, Dept Physiol & Biochem, Winnipeg, MB R3T 2N2, Canada.
C3 University of Manitoba; Children's Hospital Research Institute of
   Manitoba; University of Manitoba; Children's Hospital Research Institute
   of Manitoba; University of Manitoba; University of Manitoba; University
   of Manitoba; University of Manitoba
RP Pierce, GN (corresponding author), St Boniface Gen Hosp, Res Ctr, Div Stroke & Vasc Dis, 351 Tache Ave, Winnipeg, MB R2H 2A6, Canada.
OI Hryshko, Larry/0000-0003-1079-8549; Mesaeli, Nasrin/0000-0003-1456-4643;
   Pierce, Grant/0000-0001-7674-0142
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NR 35
TC 34
Z9 38
U1 1
U2 2
PU AMER PHYSIOLOGICAL SOC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0363-6135
J9 AM J PHYSIOL-HEART C
JI Am. J. Physiol.-Heart Circul. Physiol.
PD MAY
PY 2006
VL 290
IS 5
BP H2155
EP H2162
DI 10.1152/ajpheart.00958.2005
PG 8
WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Physiology
GA 030WD
UT WOS:000236664900054
PM 16399865
DA 2025-04-10
ER

PT J
AU Hämäläinen, RH
   Joensuu, T
   Kallijärvi, J
   Lehesjoki, AE
AF Hämäläinen, RH
   Joensuu, T
   Kallijärvi, J
   Lehesjoki, AE
TI Characterisation of the mulibrey nanism-associated TRIM37 gene::
   Transcription initiation, promoter region and alternative splicing
SO GENE
LA English
DT Article
DE TRIM37; mulibrey nanism; transcription initiation; promoter; alternative
   splicing; expression
ID PROTAMINE-2 MESSENGER-RNA; COILED-COIL PROTEIN; TRANSLATIONAL CONTROL;
   UNTRANSLATED REGION; GENOMIC NOISE; EXPRESSION; FAMILY; DECAY;
   SURVEILLANCE; MECHANISMS
AB The TRIM37 gene encodes a peroxisomal protein of unknown function. Mutations in TRIM37 underlie mulibrey nanism, a rare autosomal recessively inherited disorder with severe growth failure of prenatal onset, constrictive pericardium, hepatomegaly and characteristic dysmorphic features. Eleven mulibrey nanism-associated mutations have been identified. We here characterised TRIM37 further by mapping the transcription initiation site and promoter region as well as by analysing splice variants. By primer extension analysis, several transcription initiation sites were localised to a region between -246 and -373 relative to the ATG codon for translation initiation. Basal promoter activity was mapped within 600 nucleotides upstream from the translation initiation site using promoter-luciferase reporter constructs. Several alternative splice variants of TRIM37 exist in databases. Most of these predict non-functional protein products, are expressed at low levels and are thus likely to be targets for nonsense-mediated mRNA decay. A novel splice variant, TRIM37b, with an alternative termination codon and 3'untranslated region (UTR) transcribed from an exon 16 kb downstream from exon 24, predicts an identical protein product with the previously identified transcript, TRIM37a. As seen by Northern blot analysis and quantitative real-time PCR, both transcripts are highly expressed in testis, whereas in other tissues TRIM37a is prominent. The 3'UTR of the PPM1E gene in the opposite strand overlaps TRIM37b. These data suggest that TRIM37 expression is regulated by several mechanisms: through nonsense surveillance of non-functional transcripts, as well as through 3'UTR regulatory sequences and/or naturally occurring antisense RNAs especially in testis. (c) 2005 Elsevier B.V. All rights reserved.
C1 Univ Helsinki, Biomedicum, Ctr Neurosci, Folkhalsan Inst Genet, FIN-00014 Helsinki, Finland.
   Univ Helsinki, Biomedicum, Ctr Neurosci, Dept Med Genet, FIN-00014 Helsinki, Finland.
C3 University of Helsinki; University of Helsinki
RP Univ Helsinki, Biomedicum, Ctr Neurosci, Folkhalsan Inst Genet, POB 63,Haartmaninkatu 8, FIN-00014 Helsinki, Finland.
EM anna-elina.lehesjoki@helsinki.fi
RI Kallijarvi, Jukka/AAV-5091-2021; Lehesjoki, Anna-Elina/JPK-4409-2023;
   Joensuu, Tarja/F-3059-2011; Martikainen, Riikka/AAR-8397-2020; Coffey,
   Aidan/AAE-6034-2020; Ross, Paul/A-7584-2015
OI Coffey, Aidan/0000-0003-4116-9913; McAuliffe,
   Olivia/0000-0003-2508-205X; Edwards, Robert/0000-0001-8383-8949;
   Callanan, Michael/0000-0002-4545-8651; Lehesjoki,
   Anna-Elina/0000-0003-4014-3113; Ross, Paul/0000-0003-4876-8839;
   Kallijarvi, Jukka/0000-0003-3773-7025
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NR 31
TC 11
Z9 12
U1 1
U2 4
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0378-1119
EI 1879-0038
J9 GENE
JI Gene
PD JAN 17
PY 2006
VL 366
IS 1
BP 180
EP 188
DI 10.1016/j.gene.2005.08.008
PG 9
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA 026TL
UT WOS:000236365100020
PM 16310976
DA 2025-04-10
ER

PT J
AU Eisenreich, A
   Rauch, U
AF Eisenreich, Andreas
   Rauch, Ursula
TI Regulation and Differential Role of the Tissue Factor Isoforms in
   Cardiovascular Biology
SO TRENDS IN CARDIOVASCULAR MEDICINE
LA English
DT Article
ID DNA TOPOISOMERASE-I; FACTOR EXPRESSION; ENDOTHELIAL-CELLS;
   MESSENGER-RNA; FACTOR VIIA; INHIBITION; BLOOD; ANGIOGENESIS; EFFICACY;
   PATHWAY
AB Alternative pre-mRNA splicing is an essential mechanism regulating protein diversity and functional plasticity of the proteome in response to environmental changes. Several factors are involved in this regulatory mechanism, such as serine/arginine-rich (SR) proteins, the Cdc2-like kinase (Clk) family, the dual-specificity tyrosine phosphorylation regulated kinases, the SR protein kinases (SRPK) 1 and 2, the protein kinase B (PKB,Akt), and the DNA topoisomerase I (DNA topo I). Dynamic changes of the phosphorylation state of SR proteins, mediated by the kinases mentioned previously, play an important role in alternative splicing regulation. Through alternative splicing of the tissue factor (TF) pre-mRNA, two naturally occurring forms of TF, the primary initiator of blood coagulation, are expressed in humans-soluble alternatively spliced (as)TF and membrane-bound "full length" (fl)TF. Both isoforms are known to circulate in blood. flTF, rather than asTF, appears to be the major contributor to the thrombogenicity of vascular wall and blood. asTF has been linked more closely to increased cell survival and angiogenesis. We found the expression of asTF and flTF to be reduced in the myocardium of patients with dilated cardiomyopathy, indicating a role of TF in maintaining myocardial structure. Moreover, we demonstrated proinflammatory cytokines to immediately upregulate the expression of both TF isoforms, which was differentially regulated by SR proteins as well as Clks and DNA topo I. We and others have shown that asTF induces cell proliferation, survival, and angiogenesis via signaling pathways different from flTF-induced effects. These data indicate that both TF isoforms influence diverse processes in cardiovascular (patho)biology and are potential targets for antithrombotic, pro-survival, and proangiogenic therapeutic strategies. (Trends Cardiovasc Med 2010;20:199-203) (C) 2010 Elsevier Inc. All rights reserved.
C1 [Eisenreich, Andreas; Rauch, Ursula] Charite, Ctr Herz & Kreislaufmed, D-12200 Berlin, Germany.
C3 Berlin Institute of Health; Free University of Berlin; Humboldt
   University of Berlin; Charite Universitatsmedizin Berlin
RP Rauch, U (corresponding author), Charite, Ctr Herz & Kreislaufmed, Campus Benjamin Franklin,Hindenburgdamm 30, D-12200 Berlin, Germany.
EM ursula.rauch@charite.de
OI Eisenreich, Andreas/0000-0001-7169-3615; Eisenreich,
   Andreas/0000-0002-0615-7901
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NR 41
TC 19
Z9 22
U1 0
U2 6
PU ELSEVIER SCIENCE LONDON
PI LONDON
PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND
SN 1050-1738
J9 TRENDS CARDIOVAS MED
JI Trends Cardiovasc. Med.
PD AUG
PY 2010
VL 20
IS 6
BP 199
EP 203
AR PII S1050-1738(11)00062-4
PG 5
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA 864FI
UT WOS:000298222000004
PM 22137642
DA 2025-04-10
ER

PT J
AU Nakamori, M
   Kimura, T
   Fujimura, H
   Takahashi, MP
   Sakoda, S
AF Nakamori, Masayuki
   Kimura, Takashi
   Fujimura, Harutoshi
   Takahashi, Masanori P.
   Sakoda, Saburo
TI Altered mRNA splicing of dystrophin in type 1 myotonic dystrophy
SO MUSCLE & NERVE
LA English
DT Article
DE cardiac muscle; dystrophin; myotonic dystrophy; skeletal muscle;
   splicing
ID SKELETAL-MUSCLE; MUSCULAR-DYSTROPHY; LOCALIZATION; EXPRESSION; RECEPTOR;
   HEART; MODEL; GENE
AB Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by a CTG repeat expansion in the DMPK gene. Aberrant mRNA splicing of several genes has been reported to contribute to some of the symptoms, including myotonia and insulin resistance, but the cause of muscle wasting is unknown. Dystrophin is a cytoskeletal protein that is required for structural stability and signaling at the sarcolemma and has several spliced isoforms. We investigated the alternative splicing of dystrophin in skeletal and cardiac muscle of DM1 patients by using reverse transcriptase-polymerase chain reaction and found that dystrophin isoforms lacking exon 71 or 78, which is suggested to encode an important region for protein binding and hydrophobicity, were significantly increased. We suggest that the aberrantly spliced dystrophin is responsible for the muscle wasting in DM1.
C1 Osaka Univ, Grad Sch Med, Dept Neurol, Suita, Osaka 5650871, Japan.
   Hyogo Coll Med, Dept Internal Med, Div Neurol, Hyogo, Japan.
   Toneyama Natl Hosp, Dept Neurol, Osaka, Japan.
C3 The University of Osaka; Hyogo Medical University
RP Takahashi, MP (corresponding author), Osaka Univ, Grad Sch Med, Dept Neurol, D-4,2-2 Yamadaoka, Suita, Osaka 5650871, Japan.
EM mtakahas@neurol.med.osaka-u.ac.jp
RI Takahashi, Masanori/O-8946-2019; Nakamori, Masayuki/ABE-2169-2020
OI Nakamori, Masayuki/0000-0003-4714-3044; Takahashi, Masanori
   P/0000-0002-5513-5012
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NR 26
TC 31
Z9 36
U1 0
U2 3
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0148-639X
EI 1097-4598
J9 MUSCLE NERVE
JI Muscle Nerve
PD AUG
PY 2007
VL 36
IS 2
BP 251
EP 257
DI 10.1002/mus.20809
PG 7
WC Clinical Neurology; Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 194RU
UT WOS:000248362300014
PM 17487865
DA 2025-04-10
ER

PT J
AU Occhi, G
   Rampazzo, A
   Beffagna, G
   Danieli, GA
AF Occhi, G
   Rampazzo, A
   Beffagna, G
   Danieli, GA
TI Identification and characterization of heart-specific splicing of human
   neurexin 3 mRNA (NRXN3)
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE neurexins; alternative splicing; heart transcript; expression pattern
ID ALPHA; RECEPTOR; SMART
AB Three neurexin (NRXN) genes are known in humans, each transcribed from two promoters and extensively spliced at five canonical positions, thus generating thousands of isoforms. For NRXN3, only neuronal expression was reported so far. We reported here on the expression of NRXN3 in additional tissues (lung, pancreas, heart, placenta, liver, and kidney) and on the identification and characterization of heart-specific splicing variants of NRXN3. Cardiac isoforms of NRXN3 probably participate in a complex involving dystroglycan and proteins of extracellular matrix, involved in intercellular connections. (C) 2002 Elsevier Science (USA). All rights reserved.
C1 Univ Padua, Dept Biol, I-35131 Padua, Italy.
C3 University of Padua
RP Univ Padua, Dept Biol, Via U Bassi 58-B, I-35131 Padua, Italy.
EM danieli@bio.unipd.it
RI Occhi, Gianluca/AAJ-1125-2020
OI Occhi, Gianluca/0000-0003-4065-4677
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NR 12
TC 19
Z9 28
U1 0
U2 10
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD OCT 18
PY 2002
VL 298
IS 1
BP 151
EP 155
AR PII S0006-291X(02)02403-8
DI 10.1016/S0006-291X(02)02403-8
PG 5
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA 607LF
UT WOS:000178792500024
PM 12379233
DA 2025-04-10
ER

PT J
AU Rizzacasa, B
   Morini, E
   Pucci, S
   Murdocca, M
   Novelli, G
   Amati, F
AF Rizzacasa, Barbara
   Morini, Elena
   Pucci, Sabina
   Murdocca, Michela
   Novelli, Giuseppe
   Amati, Francesca
TI LOX-1 and Its Splice Variants: A New Challenge for Atherosclerosis and
   Cancer-Targeted Therapies
SO INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
LA English
DT Review
DE OLR1; alternative splicing; atherosclerosis; cancer
ID LOW-DENSITY-LIPOPROTEIN; OXIDIZED LDL RECEPTOR-1; HUMAN LECTIN-LIKE;
   CARNITINE PALMITOYLTRANSFERASE-I; SINGLE NUCLEOTIDE POLYMORPHISMS; FOAM
   CELL-FORMATION; NF-KAPPA-B; MYOTONIC-DYSTROPHY; CARDIOVASCULAR-DISEASE;
   ENDOTHELIAL RECEPTOR
AB Alternative splicing (AS) is a process in which precursor messenger RNA (pre-mRNA) splicing sites are differentially selected to diversify the protein isoform population. Changes in AS patterns have an essential role in normal development, differentiation and response to physiological stimuli. It is documented that AS can generate both risk and protective splice variants that can contribute to the pathogenesis of several diseases including atherosclerosis. The main endothelial receptor for oxidized low-density lipoprotein (ox-LDLs) is LOX-1 receptor protein encoded by the OLR1 gene. When OLR1 undergoes AS events, it generates three variants: OLR1, OLR1D4 and LOXIN. The latter lacks exon 5 and two-thirds of the functional domain. Literature data demonstrate a protective role of LOXIN in pathologies correlated with LOX-1 overexpression such as atherosclerosis and tumors. In this review, we summarize recent developments in understanding of OLR1 AS while also highlighting data warranting further investigation of this process as a novel therapeutic target.
C1 [Rizzacasa, Barbara; Morini, Elena; Pucci, Sabina; Murdocca, Michela; Novelli, Giuseppe; Amati, Francesca] Univ Roma Tor Vergata, Dept Biomed & Prevent, Via Montpellier 1, I-00133 Rome, Italy.
C3 University of Rome Tor Vergata
RP Amati, F (corresponding author), Univ Roma Tor Vergata, Dept Biomed & Prevent, Via Montpellier 1, I-00133 Rome, Italy.
EM barbara.rizzacasa@gmail.com; morinielena.em@gmail.com;
   sabina.pucci@uniroma2.it; miky.murdi@hotmail.it;
   novelli@med.uniroma2.it; amati@med.uniroma2.it
RI Novelli, Giuseppe/A-5195-2013; Amati, Francesca/J-8439-2012
OI Novelli, Giuseppe/0000-0002-7781-602X; Amati,
   Francesca/0000-0003-2209-2156
FU Fondazione Roma [CDS-2013-00000333]; Bando Ateneo "Consolidate
   Foundations" [AmiRNA E82F16000570005]
FX This work was supported by grants from Fondazione Roma
   (CDS-2013-00000333 to Giuseppe Novelli) and from Bando Ateneo
   "Consolidate Foundations" (AmiRNA E82F16000570005 to Francesca Amati).
   We would like to thank Jacob Hess (Leon H. Charney Division of
   Cardiology, Department of Medicine, New York University, New York City,
   NY, USA) for the revision of this manuscript.
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NR 226
TC 33
Z9 34
U1 2
U2 15
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 1422-0067
J9 INT J MOL SCI
JI Int. J. Mol. Sci.
PD FEB
PY 2017
VL 18
IS 2
AR 290
DI 10.3390/ijms18020290
PG 32
WC Biochemistry & Molecular Biology; Chemistry, Multidisciplinary
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Chemistry
GA EM6YD
UT WOS:000395457700059
PM 28146073
OA Green Submitted, gold, Green Published
DA 2025-04-10
ER

PT J
AU Liu, SQ
   Zhou, M
   Ruan, Z
   Wang, YA
   Chang, C
   Sasaki, M
   Rajaram, V
   Lemoff, A
   Nambiar, K
   Wang, JNE
   Hatanpaa, KJ
   Luo, WB
   Dawson, TM
   Dawson, VL
   Wang, YF
AF Liu, Shuiqiao
   Zhou, Mi
   Ruan, Zhi
   Wang, Yanan
   Chang, Calvin
   Sasaki, Masayuki
   Rajaram, Veena
   Lemoff, Andrew
   Nambiar, Kalyani
   Wang, Jennifer E.
   Hatanpaa, Kimmo J.
   Luo, Weibo
   Dawson, Ted M.
   Dawson, Valina L.
   Wang, Yingfei
TI AIF3 splicing switch triggers neurodegeneration
SO MOLECULAR NEURODEGENERATION
LA English
DT Article
DE AIF; Mitochondrial dysfunction; AIF3 splicing; Neurodegeneration
ID APOPTOSIS-INDUCING-FACTOR; POLYMERASE-1-DEPENDENT CELL-DEATH;
   MITOCHONDRIAL DYSFUNCTION; MUTATION; ISOFORM; EXPRESSION; DYSPLASIA;
   SPECTRUM; ATROPHY; BINDING
AB Background Apoptosis-inducing factor (AIF), as a mitochondrial flavoprotein, plays a fundamental role in mitochondrial bioenergetics that is critical for cell survival and also mediates caspase-independent cell death once it is released from mitochondria and translocated to the nucleus under ischemic stroke or neurodegenerative diseases. Although alternative splicing regulation of AIF has been implicated, it remains unknown which AIF splicing isoform will be induced under pathological conditions and how it impacts mitochondrial functions and neurodegeneration in adult brain. Methods AIF splicing induction in brain was determined by multiple approaches including 5 ' RACE, Sanger sequencing, splicing-specific PCR assay and bottom-up proteomic analysis. The role of AIF splicing in mitochondria and neurodegeneration was determined by its biochemical properties, cell death analysis, morphological and functional alterations and animal behavior. Three animal models, including loss-of-function harlequin model, gain-of-function AIF3 knockin model and conditional inducible AIF splicing model established using either Cre-loxp recombination or CRISPR/Cas9 techniques, were applied to explore underlying mechanisms of AIF splicing-induced neurodegeneration. Results We identified a nature splicing AIF isoform lacking exons 2 and 3 named as AIF3. AIF3 was undetectable under physiological conditions but its expression was increased in mouse and human postmortem brain after stroke. AIF3 splicing in mouse brain caused enlarged ventricles and severe neurodegeneration in the forebrain regions. These AIF3 splicing mice died 2-4 months after birth. AIF3 splicing-triggered neurodegeneration involves both mitochondrial dysfunction and AIF3 nuclear translocation. We showed that AIF3 inhibited NADH oxidase activity, ATP production, oxygen consumption, and mitochondrial biogenesis. In addition, expression of AIF3 significantly increased chromatin condensation and nuclear shrinkage leading to neuronal cell death. However, loss-of-AIF alone in harlequin or gain-of-AIF3 alone in AIF3 knockin mice did not cause robust neurodegeneration as that observed in AIF3 splicing mice. Conclusions We identified AIF3 as a disease-inducible isoform and established AIF3 splicing mouse model. The molecular mechanism underlying AIF3 splicing-induced neurodegeneration involves mitochondrial dysfunction and AIF3 nuclear translocation resulting from the synergistic effect of loss-of-AIF and gain-of-AIF3. Our study provides a valuable tool to understand the role of AIF3 splicing in brain and a potential therapeutic target to prevent/delay the progress of neurodegenerative diseases.
C1 [Liu, Shuiqiao; Zhou, Mi; Ruan, Zhi; Wang, Yanan; Rajaram, Veena; Wang, Jennifer E.; Hatanpaa, Kimmo J.; Luo, Weibo; Wang, Yingfei] Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA.
   [Liu, Shuiqiao; Zhou, Mi; Ruan, Zhi; Wang, Yanan; Wang, Jennifer E.; Wang, Yingfei] Univ Texas Southwestern Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA.
   [Chang, Calvin; Sasaki, Masayuki; Nambiar, Kalyani; Dawson, Ted M.; Dawson, Valina L.; Wang, Yingfei] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Neuroregenerat Program, Baltimore, MD 21205 USA.
   [Chang, Calvin; Sasaki, Masayuki; Nambiar, Kalyani; Dawson, Ted M.; Dawson, Valina L.; Wang, Yingfei] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Stem Cell Program, Baltimore, MD 21205 USA.
   [Sasaki, Masayuki; Dawson, Ted M.; Dawson, Valina L.; Wang, Yingfei] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA.
   [Lemoff, Andrew] Univ Texas Southwestern Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA.
   [Luo, Weibo] Univ Texas Southwestern Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA.
   [Dawson, Ted M.; Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA.
   [Dawson, Valina L.] Johns Hopkins Univ, Sch Med, Physiol, Baltimore, MD 21205 USA.
C3 University of Texas System; University of Texas Southwestern Medical
   Center Dallas; University of Texas System; University of Texas
   Southwestern Medical Center Dallas; Johns Hopkins University; Johns
   Hopkins University; Johns Hopkins University; University of Texas
   System; University of Texas Southwestern Medical Center Dallas;
   University of Texas System; University of Texas Southwestern Medical
   Center Dallas; Johns Hopkins University; Johns Hopkins University
RP Wang, YF (corresponding author), Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA.; Dawson, VL; Wang, YF (corresponding author), Johns Hopkins Univ, Sch Med, Inst Cell Engn, Neuroregenerat Program, Baltimore, MD 21205 USA.; Dawson, VL; Wang, YF (corresponding author), Johns Hopkins Univ, Sch Med, Inst Cell Engn, Stem Cell Program, Baltimore, MD 21205 USA.
EM vdawson@jhmi.edu; yingfei.wang@utsouthwestern.edu
RI ruan, zhi/AAC-5421-2019; Dawson, Ted/AFQ-7553-2022; Shan,
   Luchen/KUF-3891-2024; Dawson, Valina/Y-9757-2019; Ruan, Zhi/P-7829-2016
OI Ruan, Zhi/0000-0003-3587-9425
FU National Institutes of Health (NIH) [NS078049, R35GM124693,
   R01AG066166]; Darrell K Royal Research Fund; American Heart Association
   (AHA) NCRP Scientist Development Grant [12SDG11900071]; Welch Foundation
   [I-1939-20170325, I-1903-20190330]; CPRIT-HIHR [RP170671]; TIBIR pilot
   Grant; University of Texas (UT) Southwestern Medical Center Startup
   funds; UT Rising Stars; NIH [R00CA168746, DA000266, R01/R37 NS067525];
   American Heart Association (AHA) [12SDG11900071] Funding Source:
   American Heart Association (AHA); National Institute of General Medical
   Sciences [R35GM124693] Funding Source: NIH RePORTER; National Institute
   of Neurological Disorders and Stroke [R37NS067525] Funding Source: NIH
   RePORTER
FX This work was supported by grants from the National Institutes of Health
   (NIH) NS078049, R35GM124693, and R01AG066166, Darrell K Royal Research
   Fund, American Heart Association (AHA) NCRP Scientist Development Grant
   12SDG11900071, Welch Foundation (I-1939-20170325), CPRIT-HIHR RP170671,
   TIBIR pilot Grant, the University of Texas (UT) Southwestern Medical
   Center Startup funds and UT Rising Stars to Y.W., NIH R00CA168746, Welch
   Foundation I-1903-20190330 to W.L.; and NIH DA000266 and R01/R37
   NS067525, to T.M.D. and V.L.D. T.M.D. is the Leonard and Madlyn Abramson
   Professor in Neurodegenerative Diseases.
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NR 47
TC 6
Z9 6
U1 3
U2 21
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
EI 1750-1326
J9 MOL NEURODEGENER
JI Mol. Neurodegener.
PD APR 14
PY 2021
VL 16
IS 1
AR 25
DI 10.1186/s13024-021-00442-7
PG 24
WC Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA RN6ZB
UT WOS:000640499900002
PM 33853653
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Yu, Y
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AF Yu, Ying
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   Porter, Tom E.
   Liu, George E.
   Song, Jiuzhou
TI Alternative splicing variants and DNA methylation status of BDNF
   in inbred chicken lines
SO BRAIN RESEARCH
LA English
DT Article
DE Chicken; BDNF; Alternative splicing variant; DNA methylation; Marek's
   disease
ID NEUROTROPHIC FACTOR; MAREKS-DISEASE; BRAIN; GENES; EXPRESSION;
   RESISTANCE; PATTERNS; PROTEIN
AB Brain-derived neurotrophic factor (BDNF) has multiple alternative splicing variants and plays diverse biological functions in mammals, including neuronal survival, cholesterol metabolism, cell differentiation and tumor development. However, genomic structures of chicken BDNF (cBDNF) variants and its potential functions are still undefined. Here, we characterized two novel alternative splicing variants of cBDNF, cBDNF1 and cBDNF2, via combining comparative genomics methods and molecular techniques in inbred chicken line 6(3) and line 7(2), which have been developed to be resistant and susceptible, respectively, to Marek's disease tumor since 1939. Both cBDNFs consist of a bipartite transcript, with different 51 exons, exon I (298 bp) in cBDNF1 and exon II (286 bp) in cBDNF2, each of which is spliced to the common 3' exon IV. Exon I and IV are highly conserved between chicken and mammals, whereas exon II is unique for chicken. The amino acid sequence of cBDNF1 contains 8 additional amino acids in the N terminal compared to cBDNF2. cBDNF1 and cBDNF2 were only expressed in the hypothalamus among eight tissues, and cBDNF2 showed lower expression than that of cBDNF1 in both lines. The expression level of cBDNF1 was significantly higher in line 7(2) than in line 6(3) (P < 0.01). Notably, the DNA methylation levels on the cis-regulatory region of cBDNF1 was negatively correlated with its expression level, which suggests that the mRNA expression level of cBDNF1 may be related to the DNA methylation status in the chickens. We also discussed a potential role of variant cBDNF1 in MD tumor resistance and susceptibility. (C) 2009 Elsevier B.V. All rights reserved.
C1 [Yu, Ying; Byerly, Mardi S.; Porter, Tom E.; Song, Jiuzhou] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA.
   [Zhang, Huanmin; Bacon, Larry D.] ARS, USDA, Avian Dis & Oncol Lab, E Lansing, MI 48823 USA.
   [Liu, George E.] ARS, USDA, Bovine Funct Genom Lab, Beltsville, MD 20705 USA.
C3 University System of Maryland; University of Maryland College Park;
   United States Department of Agriculture (USDA); United States Department
   of Agriculture (USDA)
RP Song, JZ (corresponding author), Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA.
EM songj88@umd.edu
RI Song, Jiuzhou/AAD-6440-2020; Zhang, Huanmin/M-9792-2019; Liu,
   George/K-3371-2019
OI Porter, Tom/0000-0003-1168-9045; Liu, George/0000-0003-0192-6705
FU USDA-NRI [2008-00870]
FX We thank Dr. Wansheng Liu for his many helpful discussions, Mary Rogier,
   Fei Tian and Apratim Mitra for manuscript modifications. The authors are
   grateful to the foundation for international exchange program of
   excellent scholar of China and the support by USDA-NRI 2008-00870.
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NR 42
TC 14
Z9 18
U1 0
U2 9
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0006-8993
EI 1872-6240
J9 BRAIN RES
JI Brain Res.
PD MAY 7
PY 2009
VL 1269
BP 1
EP 10
DI 10.1016/j.brainres.2009.01.071
PG 10
WC Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 448XI
UT WOS:000266294900001
PM 19269281
DA 2025-04-10
ER

PT J
AU Chen, CY
   Ai, HS
   Ren, J
   Li, WB
   Li, PH
   Qiao, RM
   Ouyang, J
   Yang, M
   Ma, JW
   Huang, LS
AF Chen, Congying
   Ai, Huashui
   Ren, Jun
   Li, Wanbo
   Li, Pinghua
   Qiao, Ruimin
   Ouyang, Jing
   Yang, Ming
   Ma, Junwu
   Huang, Lusheng
TI A global view of porcine transcriptome in three tissues from a full-sib
   pair with extreme phenotypes in growth and fat deposition by paired-end
   RNA sequencing
SO BMC GENOMICS
LA English
DT Article
DE novel transcript unit; alternative splicing; gene boundary; miRNA;
   differentially expressed gene; complex trait; pig
ID GENOME-WIDE ASSOCIATION; QUANTITATIVE TRAIT LOCI; SKELETAL-MUSCLE;
   IN-VIVO; EXPRESSION PROFILES; MICRORNAS; MUTATION; MICE; GENERATION;
   IDENTIFICATION
AB Background: Elucidation of the pig transcriptome is essential for interpreting functional elements of the genome and understanding the genetic architecture of complex traits such as fat deposition, metabolism and growth.
   Results: Here we used massive parallel high-throughput RNA sequencing to generate a high-resolution map of the porcine mRNA and miRNA transcriptome in liver, longissimus dorsi and abdominal fat from two full-sib F-2 hybrid pigs with segregated phenotypes on growth, blood physiological and biochemical parameters, and fat deposition. We obtained 8,508,418-10,219,332 uniquely mapped reads that covered 78.0% of the current annotated transcripts and identified 48,045-122,931 novel transcript fragments, which constituted 17,085-29,499 novel transcriptional active regions in six tested samples. We found that about 18.8% of the annotated genes showed alternative splicing patterns, and alternative 3' splicing is the most common type of alternative splicing events in pigs. Cross-tissue comparison revealed that many transcriptional events are tissue-differential and related to important biological functions in their corresponding tissues. We also detected a total of 164 potential novel miRNAs, most of which were tissue-specifically identified. Integrated analysis of genome-wide association study and differential gene expression revealed interesting candidate genes for complex traits, such as IGF2, CYP1A1, CKM and CES1 for heart weight, hemoglobin, pork pH value and serum cholesterol, respectively.
   Conclusions: This study provides a global view of the complexity of the pig transcriptome, and gives an extensive new knowledge about alternative splicing, gene boundaries and miRNAs in pigs. Integrated analysis of genome wide association study and differential gene expression allows us to find important candidate genes for porcine complex traits.
C1 [Huang, Lusheng] Jiangxi Agr Univ, Key Lab Anim Biotechnol Jiangxi Prov, Nanchang 330045, Peoples R China.
   Jiangxi Agr Univ, Minist Agr China, Nanchang 330045, Peoples R China.
C3 Jiangxi Agricultural University; Ministry of Agriculture & Rural
   Affairs; Jiangxi Agricultural University
RP Huang, LS (corresponding author), Jiangxi Agr Univ, Key Lab Anim Biotechnol Jiangxi Prov, Nanchang 330045, Peoples R China.
EM Lushenghuang@hotmail.com
RI Chen, Congying/AFU-8515-2022; Ai, Huashui/JGC-9331-2023
FU National Natural Science Foundation of China [31160225]; National Basic
   Research Program of China [2006CB102103]
FX We thank Zujing Han, Zhiyu Peng from BGI Shenzhen, China for their
   assistances on data analysis. This work was supported by National
   Natural Science Foundation of China (31160225) and National Basic
   Research Program of China (2006CB102103).
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   BLAT SOFTWARE
NR 63
TC 89
Z9 101
U1 0
U2 35
PU BMC
PI LONDON
PA CAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
SN 1471-2164
J9 BMC GENOMICS
JI BMC Genomics
PD SEP 10
PY 2011
VL 12
AR 448
DI 10.1186/1471-2164-12-448
PG 16
WC Biotechnology & Applied Microbiology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Genetics & Heredity
GA 831OH
UT WOS:000295740500001
PM 21906321
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Gough, PJ
   Greaves, DR
   Gordon, S
AF Gough, PJ
   Greaves, DR
   Gordon, S
TI A naturally occurring isoform of the human macrophage scavenger receptor
   (SR-A) gene generated by alternative splicing blocks modified LDL uptake
SO JOURNAL OF LIPID RESEARCH
LA English
DT Article
DE macrophage; scavenger receptor; alternative splicing; atherosclerosis;
   dominant negative mutant
ID LOW-DENSITY-LIPOPROTEIN; HAMSTER OVARY CELLS; DELTA T-CELLS; CHOLESTEROL
   DEPOSITION; EXPRESSION CLONING; LIGAND-BINDING; DOMAINS; ADHESION;
   FAMILY; METABOLISM
AB The class A macrophage scavenger receptors (SR-A) are macrophage-specific trimeric integral membrane glycoproteins that have been implicated in many macrophage associated physiological and pathological processes including atherosclerosis, Alzheimer's disease, and host defense. There are two forms of the receptor that have been previously cloned, and both are generated by alternative splicing of a single gene. Here we report the cloning of a third, alternatively spliced isoform of the human SR-A gene (type III hSR-A). The novel isoform is expressed in the human monocytic leukemia cell line THP-1 and also in primary human monocyte derived macrophages. When expressed in CHO-K1 cells, type III hSR-A does not internalize AcLDL despite hating the domain shown to mediate this function in type I and II hSR-A. We show that type III protein has alter ed intracellular processing and is trapped within the endoplasmic reticulum, making it unable to perform endocytosis. Type III protein acts as a dominant negative isoform by reducing modified LDL uptake in CHO cells stably expressing either type I or type II SR-A. The demonstration that a naturally occurring splice variant of SR-A mRNA can act as a dominant negative isoform suggests a novel mechanism for regulation of scavenger receptor activity in macrophages.
C1 Univ Oxford, Sir William Dunn Sch Pathol, Oxford OX1 3RE, England.
C3 University of Oxford
RP Gough, PJ (corresponding author), Univ Oxford, Sir William Dunn Sch Pathol, S Parks Rd, Oxford OX1 3RE, England.
OI Greaves, David/0000-0003-2856-9410
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NR 36
TC 93
Z9 107
U1 0
U2 1
PU LIPID RESEARCH INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA
SN 0022-2275
J9 J LIPID RES
JI J. Lipid Res.
PD MAR
PY 1998
VL 39
IS 3
BP 531
EP 543
PG 13
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA ZF386
UT WOS:000072892300006
PM 9548586
DA 2025-04-10
ER

PT J
AU Cattin, ME
   Deeke, SA
   Dick, SA
   Verret-Borsos, ZJA
   Tennakoon, G
   Gupta, R
   Mak, E
   Roeske, CL
   Weldrick, JJ
   Megeney, LA
   Burgon, PG
AF Cattin, Marie-Elodie
   Deeke, Shelley A.
   Dick, Sarah A.
   Verret-Borsos, Zachary J. A.
   Tennakoon, Gayashan
   Gupta, Rishi
   Mak, Esther
   Roeske, Cassandra L.
   Weldrick, Jonathan J.
   Megeney, Lynn A.
   Burgon, Patrick G.
TI Expression of murine muscle-enriched A-type lamin-interacting protein
   (MLIP) is regulated by tissue-specific alternative transcription start
   sites
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
DE alternative splicing; brain; heart; gene expression; intracellular
   trafficking; protein-protein interaction; skeletal muscle; cellular
   localization; MLIP; transcriptional start site; muscle-enriched
   lamin-interacting protein; transcriptional regulation; splice variant;
   tissue-specific expression; protein isoform
ID IDENTIFICATION; CIP
AB Muscle-enriched lamin-interacting protein (Mlip) is an alternatively spliced gene whose splicing specificity is dictated by tissue type. MLIP is most abundantly expressed in brain, cardiac, and skeletal muscle. In the present study, we systematically mapped the transcriptional start and stop sites of murine Mlip. Rapid amplification of cDNA ends (RACE) of Mlip transcripts from the brain, heart, and skeletal muscle revealed two transcriptional start sites (TSSs), exon 1a and exon 1b, and only one transcriptional termination site. RT-PCR analysis of the usage of the two identified TSSs revealed that the heart utilizes only exon 1a for MLIP expression, whereas the brain exclusively uses exon 1b TSS. Loss of Mlip exon 1a in mice resulted in a 7-fold increase in the prevalence of centralized nuclei in muscle fibers with the Mlip exon1a-deficient satellite cells on single fibers exhibiting a significant delay in commitment to a MYOD-positive phenotype. Furthermore, we demonstrate that the A-type lamin-binding domain in MLIP is encoded in exon 1a, indicating that MLIP isoforms generated with exon 1b TSS lack the A-type lamin-binding domain. Collectively these findings suggest that Mlip tissue-specific expression and alternative splicing play a critical role in determining MLIP's functions in mice.
C1 [Cattin, Marie-Elodie; Deeke, Shelley A.; Verret-Borsos, Zachary J. A.; Tennakoon, Gayashan; Gupta, Rishi; Mak, Esther; Roeske, Cassandra L.; Weldrick, Jonathan J.; Burgon, Patrick G.] Univ Ottawa, Heart Inst, 40 Ruskin St, Ottawa, ON K1Y 4W7, Canada.
   [Dick, Sarah A.; Megeney, Lynn A.] Ottawa Hosp, Sprott Ctr Stem Cell Res, Regenerat Med Program, Res Inst, Ottawa, ON K1H 8L6, Canada.
   [Deeke, Shelley A.; Dick, Sarah A.; Weldrick, Jonathan J.; Megeney, Lynn A.; Burgon, Patrick G.] Univ Ottawa, Fac Med, Dept Cellular & Mol Med, Ottawa, ON K1N 6N5, Canada.
   [Megeney, Lynn A.; Burgon, Patrick G.] Univ Ottawa, Fac Med, Dept Med, Ottawa, ON K1N 6N5, Canada.
   [Cattin, Marie-Elodie] Servier Res Inst, 125 Chemin Ronde, F-78290 Croissy Sur Seine, France.
C3 University of Ottawa; University of Ottawa Heart Institute; University
   of Ottawa; Ottawa Hospital Research Institute; University of Ottawa;
   University of Ottawa; Servier; Institut de Recherches Internationales
   Servier
RP Burgon, PG (corresponding author), Univ Ottawa, Heart Inst, 40 Ruskin St, Ottawa, ON K1Y 4W7, Canada.
EM patrick.burgon@icloud.com
RI Burgon, Patrick/ABB-1027-2021
OI Dick, Sarah A/0000-0003-0683-2900; Tennakoon,
   Gayashan/0000-0003-3258-5771; Megeney, Lynn/0000-0002-6824-8569
FU Canadian Institutes of Health Research; Ontario Graduate Scholarship in
   Science and Technology fellowship
FX This work was supported by the Canadian Institutes of Health Research
   (to P.G.B. & L.A.M.) and an Ontario Graduate Scholarship in Science and
   Technology fellowship (to J.J.W.). The authors declare that they have no
   conflicts of interest with the contents of this article.
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NR 15
TC 10
Z9 10
U1 0
U2 4
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD DEC 21
PY 2018
VL 293
IS 51
BP 19761
EP 19770
DI 10.1074/jbc.RA118.003758
PG 10
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA HF5SW
UT WOS:000454294900021
PM 30389785
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Cohen, T
   Ravid, L
   Altman, N
   Madar-Shapiro, L
   Fein, A
   Weil, M
   Horowitz, M
AF Cohen, T
   Ravid, L
   Altman, N
   Madar-Shapiro, L
   Fein, A
   Weil, M
   Horowitz, M
TI Conservation of expression and alternative splicing in the prosaposin
   gene
SO MOLECULAR BRAIN RESEARCH
LA English
DT Article
DE prosaposin; saposins; alternative splicing
ID SPHINGOLIPID ACTIVATOR PROTEINS; CO-BETA-GLUCOSIDASE; MESSENGER-RNA;
   SULFATIDE ACTIVATOR; METACHROMATIC LEUKODYSTROPHY; TARGETED DISRUPTION;
   REPRODUCTIVE-SYSTEM; GLYCOSYLATION SITE; VARIANT FORM; CELL-DEATH
AB Prosaposin is the precursor of four lysosomal activator molecules known as saposins A, B, C and D. It is also secreted and was proposed to be a neurotrophic factor. The neurotrophic function was attributed to the amino terminus of saposin C. In man, mouse and rat prosaposin is transcribed to two major isoforms differing in the inclusion of 9 bps of exon 8 within the saposin B domain. In the present study, we show that there is evolutionary conservation of the prosaposin structure and alternative splicing in chick and zebrafish as well. Moreover, there is conservation in prosaposin expression as tested immunohistochemically in the mouse and chick developing brain. We developed a sensitive assay to quantitate the prosaposin alternatively spliced forms. Our results indicate that, in mouse brain, skeletal and cardiac muscle the exon 8-containing RNA is most abundant, while it is almost absent from visceral and smooth muscle-containing organs. We observed temporal and differential expression of the alternatively spliced prosaposin mRNAs in mouse and chick brain as well as during development. The elevation in the abundance of exon 8-containing prosaposin RNA during mouse and chick brain development may suggest a role for the exon 8-containing prosaposin form in this process. (C) 2004 Elsevier B.V. All rights reserved.
C1 Tel Aviv Univ, Fac Life Sci, Dept Cell Res & Immunol, IL-69978 Tel Aviv, Israel.
   Tel Aviv Univ, Sackler Sch Med, Dept Cell & Dev Biol, IL-69978 Tel Aviv, Israel.
C3 Tel Aviv University; Tel Aviv University; Sackler Faculty of Medicine
RP Tel Aviv Univ, Fac Life Sci, Dept Cell Res & Immunol, IL-69978 Tel Aviv, Israel.
EM horwitzm@post.tau.ac.il
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NR 67
TC 14
Z9 17
U1 0
U2 5
PU ELSEVIER SCIENCE BV
PI AMSTERDAM
PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
SN 0169-328X
J9 MOL BRAIN RES
JI Mol. Brain Res.
PD OCT 22
PY 2004
VL 129
IS 1-2
BP 8
EP 19
DI 10.1016/j.molbrainres.2004.06.027
PG 12
WC Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 863UL
UT WOS:000224588800002
PM 15469878
DA 2025-04-10
ER

PT J
AU Eddy, AC
   Chapman, H
   Brown, DT
   George, EM
AF Eddy, Adrian C.
   Chapman, Heather
   Brown, David T.
   George, Eric M.
TI Differential regulation of sFlt-1 splicing by U2AF65 and JMJD6 in
   placental-derived and endothelial cells
SO BIOSCIENCE REPORTS
LA English
DT Article
ID CONTAINING PROTEIN 6; TYROSINE KINASE-1; PREECLAMPSIA; HYPERTENSION
AB Despite years of study, the gestational disorder preeclampsia (PE) remains poorly understood. One proposed mechanism of PE development is increased soluble VEGF receptor-1 (sFlt-1), ultimately causing angiogenic imbalance and endothelial dysfunction. The soluble protein is an alternative splice variant of FLT1, which also encodes for the full-length receptor Flt-1. The mechanism of the alternative splicing, and the reason for its inappropriate increase in preeclampsia, is not well understood. U2 auxiliary factor 65 (U2AF65) and jumonji C domain-containing protein 6 (JMJD6) have been implicated in the splicing of sFlt-1. Using siRNA knockdown and plasmid overexpression in immortalized placental trophoblasts (BeWo) and primary endothelial cells (HUVECs), we examined the role these proteins play in production of sFlt-1. Our results showed that U2AF65 has little, if any, effect on sFlt-1 splicing, and JMJD6 may enhance sFlt-1 splicing, but is not necessary for splicing to occur. Utilizing a hypoxic environment to mimic conditions of the preeclamptic placenta, as well as S examining placentae in the reduced uterine perfusion pressure (RUPP) model of PE, which exhibits increased circulating sFlt-1, we found increased expression of JMJD6 in both hypoxic cells and placental tissue. Additionally, we observed a potential role for U2AF65 and JMJD6 to regulate the extracellular matrix enzyme heparanase, which may be involved in the release of sFlt-1 protein from the extracellular matrix. It will be important to study the role of these proteins in different tissues in the future, as changes in expression had differential effects on sFlt-1 splicing in the different cell types studied here.
C1 [Eddy, Adrian C.; Chapman, Heather; George, Eric M.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA.
   [Brown, David T.; George, Eric M.] Univ Mississippi, Med Ctr, Dept Cell & Mol Biol, Jackson, MS 39216 USA.
C3 University of Mississippi Medical Center; University of Mississippi;
   University of Mississippi; University of Mississippi Medical Center
RP George, EM (corresponding author), Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA.; George, EM (corresponding author), Univ Mississippi, Med Ctr, Dept Cell & Mol Biol, Jackson, MS 39216 USA.
EM egeorge@umc.edu
RI George, Eric/ABE-2767-2020
OI Eddy, Adrian/0000-0002-9945-2810
FU NIH [P01HL51971, P20GM104357, R00HL116774, R01HL 137791]; AHA GRNT
   [31460000, 19PRE34430044]; American Heart Association (AHA)
   [19PRE34430044] Funding Source: American Heart Association (AHA)
FX This work was supported by the following grants NIH [grant numbers
   P01HL51971, P20GM104357, R00HL116774 and R01HL 137791]; and AHA GRNT
   [grant numbers 31460000 and 19PRE34430044].
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NR 23
TC 8
Z9 9
U1 0
U2 3
PU PORTLAND PRESS LTD
PI LONDON
PA 5TH FLR, 90 HIGH HOLBORN, LONDON WC1V 6LJ, ENGLAND
SN 0144-8463
EI 1573-4935
J9 BIOSCIENCE REP
JI Biosci. Rep.
PD FEB 25
PY 2020
VL 40
AR BSR20193252
DI 10.1042/BSR20193252
PN 2
PG 13
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA KT3DW
UT WOS:000518896800001
PM 32039444
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Soliman, D
   Hamming, KSC
   Matemisz, LC
   Light, PE
AF Soliman, Daniel
   Hamming, Kevin S. C.
   Matemisz, Laura C.
   Light, Peter E.
TI Reactive oxygen species directly modify sodium-calcium exchanger
   activity in a splice variant-dependent manner
SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
LA English
DT Article
DE Sodium/calcium exchanger; NCX1; Splice variant; Reactive oxygen species;
   H2O2; Patch-clamp
ID FREE-RADICAL GENERATION; NA+/CA2+ EXCHANGER; NA+-CA2+ EXCHANGER;
   MOLECULAR DETERMINANTS; OXIDATIVE STRESS; NA+/H+ EXCHANGER; CA-2+
   OVERLOAD; ISCHEMIA; OVEREXPRESSION; NCX1
AB The sodium-calcium exchanger isoform 1 (NCX1) operating in calcium-efflux mode plays an important role in maintaining calcium homeostasis in the heart Paradoxically, activity of NCX1 in calcium-influx mode contributes to the pathological intracellular calcium overload during cardiac ischemia-reperfusion injury Reactive oxygen species (ROS) also contribute to myocardial dysfunction in ischemia-reperfusion and are reported to alter NCX1 activity However, the molecular mechanism(s) by which ROS modifies NCX1 activity have not been elucidated. Therefore, the effects of the ROS. H2O2, on recombinant NCX1 splice variants were studied using the patch-clamp technique. H2O2 irreversibly increased calcium-influx mode activity in the cardiac NCX1.1 splice variant, without affecting calcium-efflux mode activity. In direct contrast, H2O2 inhibited the calcium-influx mode of the vascular NCX1 3 splice variant indicating that these disparate effects of H2O2 may be dependent on the exon complement of the alternative splicing region. Using NCX1 splice variants with various exon compositions, the mutually exclusive exons A and B were found to below the differential effects of H2O2 oil NCX1 function. As NCX1 inhibition is a potential therapeutic strategy for ischemia-reperfusion injury, the effects of the NCX1 inhibitor KB-R7943 were examined KB-R7943 was similar to 7-fold less potent at inhibiting NCX1 activity after H2O2 modification. In summary. this study provides insights into the molecular regulation of NCX1 by ROS and indicates that ROS may elicit differential effects in various tissues depending on the exon composition of the splice variant expressed These results also highlight that the potency of NCX1 inhibitors may be impaired under conditions of oxidative stress (C) 2009 Elsevier Inc. All rights reserved
C1 [Soliman, Daniel; Hamming, Kevin S. C.; Matemisz, Laura C.; Light, Peter E.] Univ Alberta, Dept Pharmacol, Fac Med & Dent, Edmonton, AB T6G 2H7, Canada.
C3 University of Alberta
RP Light, PE (corresponding author), Univ Alberta, Dept Pharmacol, Alberta Diabet Inst, 6-126A HRIF E, Edmonton, AB T6G 2E1, Canada.
FU Canadian Institutes of Health Research [MOP 37945]; Alberta Heritage
   Foundation; CIHR Strategic Training Initiative; AHFMR
FX We thank Dr. J.R. Dyck (University of Alberta) for generously providing
   neonatal cardiac myocytes. This work was supported by an operating grant
   from the Canadian Institutes of Health Research (CIHR, MOP 37945) to PEL
   DS is supported by an Alberta Heritage Foundation for Medical Research
   (AHFMR) trainee award. KSCH received support from the CIHR Strategic
   Training Initiative for the study of membrane proteins. PEL received
   salary support as an AHFMR Senior Scholar.
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NR 45
TC 20
Z9 20
U1 0
U2 3
PU ELSEVIER SCI LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND
SN 0022-2828
EI 1095-8584
J9 J MOL CELL CARDIOL
JI J. Mol. Cell. Cardiol.
PD NOV
PY 2009
VL 47
IS 5
BP 595
EP 602
DI 10.1016/j.yjmcc.2009.05.011
PG 8
WC Cardiac & Cardiovascular Systems; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Cell Biology
GA 510RG
UT WOS:000271108000006
PM 19481548
DA 2025-04-10
ER

PT J
AU Gabellini, N
AF Gabellini, N
TI A polymorphic GT repeat from the human cardiac
   Na<SUP>+</SUP>Ca<SUP>2+</SUP> exchanger intron 2 activates splicing
SO EUROPEAN JOURNAL OF BIOCHEMISTRY
LA English
DT Article
DE human polymorphism; intronic splicing enhancer; Na+Ca2+ exchanger
ID FUNCTIONAL EXPRESSION; NA+-CA-2+ EXCHANGER; MOLECULAR-CLONING;
   ALTERNATIVE EXON; GENE; TRANSCRIPTS; PROTEINS; ISOFORMS; SEQUENCE;
   ENHANCER
AB The sequence analysis of the human intron 2 from the Na+/Ca2+ exchanger 1 (NCX1) gene has revealed a GT repeat of variable length (10-16). The 5' sequence of intron 2 exhibited significant homology (65-70%) with other minisatellite sequences. DNA segments at the 5' end of intron 2 were inserted in the NCX1 cDNA (3.7 kb) to reconstruct the exon 2/intron 2 junction. Transient expression of these constructs in HEK293 cells generated shortened mRNAs (approximate to 2.5 kb). RT-PCR and ribonuclease protection analysis of the 3' end of the short transcripts indicated a splicing event at the intron 2/exon 2 junction (5' site) and in the vector sequence downstream of the NCX1 insert (3' site). Molecular dissection of the 5'-intron 2 sequence showed that the GT repeat was required for splicing activation, whereas the remainder of the 5'-intron 2 segment was completely inactive. The results indicate that the GT repeat is a strong intronic splicing enhancer that could be involved in the regulation of NCX1 expression, possibly mediating tissue-specific alternative splicing of the mutually exclusive exons 3 and 4, and/or exon-2 circularization.
C1 Univ Padua, Dept Biol Chem, I-35121 Padua, Italy.
C3 University of Padua
RP Univ Padua, Dept Biol Chem, Via G Colombo 3, I-35121 Padua, Italy.
EM nadiagab@civ.bio.unipd.it
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NR 37
TC 48
Z9 56
U1 0
U2 1
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0014-2956
J9 EUR J BIOCHEM
JI Eur. J. Biochem.
PD FEB
PY 2001
VL 268
IS 4
BP 1076
EP 1083
DI 10.1046/j.1432-1327.2001.01974.x
PG 8
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 406WH
UT WOS:000167238800022
PM 11179974
OA Bronze
DA 2025-04-10
ER

PT J
AU Sheng, JJ
   Jin, JP
AF Sheng, Juan-Juan
   Jin, Jian-Ping
TI Gene regulation, alternative splicing, and posttranslational
   modification of troponin subunits in cardiac development and adaptation:
   a focused review
SO FRONTIERS IN PHYSIOLOGY
LA English
DT Review
DE isoforms; cardiac muscle; myofilament proteins; posttranslational
   modification; cardiomyopathy
ID PROTEIN-KINASE-C; FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; NH2-TERMINAL
   VARIABLE REGION; AMINO-ACID-SEQUENCE; MYOFILAMENT CALCIUM SENSITIVITY;
   TRANSGENIC MOUSE MODEL; N-TERMINAL TRUNCATION; METAL-BINDING CLUSTER; T
   ISOFORM EXPRESSION; SKELETAL-MUSCLE
AB Troponin plays a central role in regulating the contraction and relaxation of vertebrate striated muscles. This review focuses on the isoform gene regulation, alternative RNA splicing, and posttranslational modifications of troponin subunits in cardiac development and adaptation. Transcriptional and posttranscriptional regulations such as phosphorylation and proteolysis modifications, and structure-function relationships of troponin subunit proteins are summarized. The physiological and pathophysiological significances are discussed for impacts on cardiac muscle contractility, heart function, and adaptations in health and diseases.
C1 [Sheng, Juan-Juan; Jin, Jian-Ping] Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA.
C3 Wayne State University
RP Jin, JP (corresponding author), Wayne State Univ, Sch Med, Dept Physiol, 540 E Canfield, Detroit, MI 48201 USA.
EM jjin@med.wayne.edu
RI Jin, Jian-Ping/AAD-1149-2020
OI Jin, JP/0000-0001-9932-1063
FU National Institutes of Health [AR048816, HL098945]; Office of Vice
   President for Research Wayne State University; China Scholarship Council
FX We would like to thank the current and past members of our laboratory
   who have made invaluable contributions to our troponin research
   discussed in this review. This work was supported by grants from the
   National Institutes of Health (AR048816 and HL098945) and a
   Multidisciplinary Incubator Grant from the Office of Vice President for
   Research Wayne State University to Jian-Ping Jin. Juan-Juan Sheng is
   recipient of a graduate fellowship from the China Scholarship Council.
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NR 200
TC 43
Z9 53
U1 0
U2 6
PU FRONTIERS MEDIA SA
PI LAUSANNE
PA AVENUE DU TRIBUNAL FEDERAL 34, LAUSANNE, CH-1015, SWITZERLAND
SN 1664-042X
J9 FRONT PHYSIOL
JI Front. Physiol.
PD APR 30
PY 2014
VL 5
AR 165
DI 10.3389/fphys.2014.00165
PG 16
WC Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Physiology
GA AX6OQ
UT WOS:000347041800001
PM 24817852
OA gold, Green Published
DA 2025-04-10
ER

PT J
AU Jin, JP
AF Jin, JP
TI Alternative RNA splicing-generated cardiac troponin T isoform switching:
   A non-heart-restricted genetic programming synchronized in developing
   cardiac and skeletal muscles
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
ID COMPLETE NUCLEOTIDE-SEQUENCE; ADULT ISOFORMS; MOLECULAR-BASIS; RABBIT
   HEART; I GENE; PURIFICATION; CONTRACTION; EXPRESSION; EXONS
AB An alternative RNA splicing-generated cardiac troponin T (cTnT) isoform switching has been found during both avian and mammalian heart development. The present study demonstrates that the mouse cTnT isoform switching is similar to 10 days earlier than that in rat during perinatal heart development. The mouse cTnT isoform switching is also similar to 10 days earlier than the transcriptionally regulated troponin I (TnI) isoform switching, a transition that showed similar timing during mouse and rat heart development. In addition, synchronized cTnT and TnI switches are observed during both rat and chicken heart development. More interestingly, the expression of cTnT in both mouse and rat neonatal skeletal muscles showed an isoform transition pattern synchronized with the cTnT isoform switching in the neonatal heart of the corresponding species. The results suggest that the alternative RNA splicing-generated cTnT isoform switching during development is (a) not a direct response to the functional changes in perinatal myocardium and (b) not a restricted regulation in the heart, bur is controlled by a species-specific programming that is synchronized in developing cardiac and skeletal muscles. (C) 1996 Academic Press, Inc.
RP Jin, JP (corresponding author), UNIV CALGARY,FAC MED,DEPT MED BIOCHEM,CALGARY,AB T2N 4N1,CANADA.
RI Jin, Jian-Ping/AAD-1149-2020
OI Jin, JP/0000-0001-9932-1063
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NR 24
TC 60
Z9 64
U1 0
U2 4
PU ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495
SN 0006-291X
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD AUG 23
PY 1996
VL 225
IS 3
BP 883
EP 889
DI 10.1006/bbrc.1996.1267
PG 7
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA VE458
UT WOS:A1996VE45800031
PM 8780706
DA 2025-04-10
ER

PT J
AU Brotman, SM
   Raulerson, CK
   Vadlamudi, S
   Currin, KW
   Shen, QJ
   Parsons, VA
   Iyengar, AK
   Roman, TS
   Furey, TS
   Kuusisto, J
   Collins, FS
   Boehnke, M
   Laakso, M
   Pajukanta, P
   Mohlke, KL
AF Brotman, Sarah M.
   Raulerson, Chelsea K.
   Vadlamudi, Swarooparani
   Currin, Kevin W.
   Shen, Qiujin
   Parsons, Victoria A.
   Iyengar, Apoorva K.
   Roman, Tamara S.
   Furey, Terrence S.
   Kuusisto, Johanna
   Collins, Francis S.
   Boehnke, Michael
   Laakso, Markku
   Pajukanta, Paivi
   Mohlke, Karen L.
TI Subcutaneous adipose tissue splice quantitative trait loci reveal
   differences in isoform usage associated with cardiometabolic traits
SO AMERICAN JOURNAL OF HUMAN GENETICS
LA English
DT Article
ID GENE-EXPRESSION; GENOME-WIDE; VARIANTS; QUANTIFICATION; PROVIDES;
   DISEASE
AB Alternate splicing events can create isoforms that alter gene function, and genetic variants associated with alternate gene isoforms may reveal molecular mechanisms of disease. We used subcutaneous adipose tissue of 426 Finnish men from the METSIM study and iden-tified splice junction quantitative trait loci (sQTLs) for 6,077 splice junctions (FDR < 1%). In the same individuals, we detected expres-sion QTLs (eQTLs) for 59,443 exons and 15,397 genes (FDR 1%). We identified 595 genes with an sQTL and exon eQTL but no gene eQTL, which could indicate potential isoform differences. Of the significant sQTL signals, 2,114 (39.8%) included at least one proxy variant (linkage disequilibrium r(2) > 0.8) located within an intron spanned by the splice junction. We identified 203 sQTLs that colocal-ized with 141 genome-wide association study (GWAS) signals for cardiometabolic traits, including 25 signals for lipid traits, 24 signals for body mass index (BMI), and 12 signals for waist-hip ratio adjusted for BMI. Among all 141 GWAS signals colocalized with an sQTL, we detected 26 that also colocalized with an exon eQTL for an exon skipped by the sQTL splice junction. At a GWAS signal for high-density lipoprotein cholesterol colocalized with an NR1H3 sQTL splice junction, we show that the alternative splice product encodes an NR1H3 transcription factor that lacks a DNA binding domain and fails to activate transcription. Together, these results detect splicing events and candidate mechanisms that may contribute to gene function at GWAS loci.
C1 [Brotman, Sarah M.; Raulerson, Chelsea K.; Vadlamudi, Swarooparani; Currin, Kevin W.; Shen, Qiujin; Parsons, Victoria A.; Iyengar, Apoorva K.; Roman, Tamara S.; Furey, Terrence S.; Mohlke, Karen L.] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.
   [Furey, Terrence S.] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA.
   [Kuusisto, Johanna; Laakso, Markku] Univ Eastern Finland, Kuopio Univ Hosp, Inst Clin Med, Kuopio 70210, Finland.
   [Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA.
   [Boehnke, Michael] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA.
   [Laakso, Markku] Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA.
   [Pajukanta, Paivi] Univ Calif Los Angeles, David Geffen Sch Med, Inst Precis Hlth, Los Angeles, CA 90095 USA.
   [Pajukanta, Paivi] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA.
C3 University of North Carolina; University of North Carolina Chapel Hill;
   University of North Carolina; University of North Carolina Chapel Hill;
   University of Eastern Finland; University of Eastern Finland Hospital;
   Kuopio University Hospital; National Institutes of Health (NIH) - USA;
   NIH National Human Genome Research Institute (NHGRI); University of
   Michigan System; University of Michigan; University of Michigan System;
   University of Michigan; University of California System; University of
   California Los Angeles; University of California Los Angeles Medical
   Center; David Geffen School of Medicine at UCLA; University of
   California System; University of California Los Angeles; University of
   California Los Angeles Medical Center; David Geffen School of Medicine
   at UCLA
RP Mohlke, KL (corresponding author), Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA.
EM mohlke@med.unc.edu
RI Kuusisto, Johanna/AGM-7927-2022; Brotman, Sarah/AAI-3710-2021
OI Shen, Qiujin/0000-0003-2103-4253; Raulerson,
   Chelsea/0000-0001-5888-5196; Brotman, Sarah/0000-0002-7566-8895
FU NIH [T32GM067553, T32GM007092, F31HL154730, F31HL146121, R25GM055336,
   R01DK093757, R01DK072193, U01DK105561, U01DK062370, 1-ZIA-HG000024,
   P01HL028041]; Academy of Finland; Finnish Heart Foundation; Finnish
   Diabetes Foundation; Finnish Funding Agency for Technology and
   Innovation (TEKES) [1510/31/06]; Commission of the European Community
   [HEALTH-F2-2007201681]; Common Fund of the Office of theDirector of the
   National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS;
   National Institute of Diabetes and Digestive and Kidney Diseases
   [R01DK093757, R01DK062370, U01DK062370] Funding Source: NIH RePORTER
FX This study was supported by NIH grants R01DK093757, R01DK072193,
   U01DK105561, U01DK062370, 1-ZIA-HG000024, and P01HL028041; the Academy
   of Finland; the Finnish Heart Foundation; the Finnish Diabetes
   Foundation; Finnish Funding Agency for Technology and Innovation (TEKES)
   contract 1510/31/06; and the Commission of the European Community
   HEALTH-F2-2007201681. Individuals were supported by NIH T32GM067553
   (C.K.R., K.W.C.), T32GM007092 (S.M.B., V.A.P.), F31HL154730 (S.M.B.),
   F31HL146121 (K.W.C.), and R25GM055336 (K.W.C). The Genotype-Tissue
   Expression (GTEx) Project was supported by the Common Fund of the Office
   of theDirector of the National Institutes of Health, and by NCI, NHGRI,
   NHLBI, NIDA, NIMH, and NINDS. GTEx data usedfor the analyses described
   inthismanuscriptwere obtained from the GTEx Portal. RNA Binding Protein
   eCLIP data from the ENCODEConsortiumwere generatedby theGeneYeo
   laboratory at UCSD. We thank Anne H. Moxley for assistance plotting
   variants relative to gene models. We thank Jason L. Stein and Nil
   Aygu<spacing diaeresis> n for their advice on sQTL analyses and
   interpretation.
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NR 61
TC 13
Z9 13
U1 1
U2 11
PU CELL PRESS
PI CAMBRIDGE
PA 50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA
SN 0002-9297
EI 1537-6605
J9 AM J HUM GENET
JI Am. J. Hum. Genet.
PD JAN 6
PY 2022
VL 109
IS 1
BP 66
EP 80
DI 10.1016/j.ajhg.2021.11.019
EA JAN 2022
PG 15
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA YP2YV
UT WOS:000748493200006
PM 34995504
OA Green Published, Bronze
DA 2025-04-10
ER

PT J
AU Yang, HJ
   Liu, WJ
   Song, S
   Bai, LN
   Nie, Y
   Bai, YP
   Zhang, GG
AF Yang, Huijun
   Liu, Weijing
   Song, Shen
   Bai, Lina
   Nie, Yu
   Bai, Yongping
   Zhang, Guogang
TI Proteogenomics Integrating Reveal a Complex Network, Alternative
   Splicing, Hub Genes Regulating Heart Maturation
SO GENES
LA English
DT Article
DE heart maturation; gene network; alternative splicing; hub gens; OgdhL
ID CARDIOMYOCYTE
AB Heart maturation is an essentially biological process for neonatal heart transition to adult heart, thus illustrating the mechanism of heart maturation may be helpful to explore postnatal heart development and cardiac cardiomyopathy. This study combined proteomic analysis based on isobaric tags for relative and absolute quantitation (iTRAQ) and transcriptome analysis based on RNA sequencing to detect the proteins and genes associated with heart maturation in mice. The proteogenomics integrating analysis identified 254 genes/proteins as commonly differentially expressed between neonatal and adult hearts. Functional and pathway analysis demonstrated that these identified genes/proteins contribute to heart maturation mainly by regulating mRNA processing and energy metabolism. Genome-wide alternative splicing (AS) analysis showed that some important sarcomere and energy-associated genes undergo different AS events. Through the Cytoscape plug-in CytoHubba, a total of 23 hub genes were found and further confirmed by RT-qPCR. Next, we verified that the most up-regulated hub gene, Ogdhl, plays an essential role in heart maturation by detecting energy metabolism phenotype changes in the Ogdhl-interfering cardiomyocytes. Together, we revealed a complex gene network, AS genes and patterns, and candidate hub genes controlling heart maturation by proteome and transcriptome combination analysis.
C1 [Yang, Huijun; Zhang, Guogang] Cent South Univ, Xiangya Hosp, Dept Cardiovasc Med, Changsha 410008, Peoples R China.
   [Liu, Weijing; Song, Shen; Bai, Lina; Nie, Yu] Chinese Acad Med Sci & Peking Union Med Coll, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100037, Peoples R China.
   [Bai, Yongping] Cent South Univ, Natl Clin Res Ctr Geriatr Disorders, Xiangya Hosp, Dept Geriatr Med, Changsha 410008, Peoples R China.
C3 Central South University; Chinese Academy of Medical Sciences - Peking
   Union Medical College; Peking Union Medical College; Fu Wai Hospital -
   CAMS; Central South University
RP Zhang, GG (corresponding author), Cent South Univ, Xiangya Hosp, Dept Cardiovasc Med, Changsha 410008, Peoples R China.
EM y_huijun@126.com; liuwjsx001@163.com; songs_193@163.com;
   bailina0520@163.com; nieyuniverse@126.com; baiyongping@csu.edu.cn;
   zhangguogang@csu.edu.cn
RI yongping, Bai/HHZ-4785-2022; YANG, June/AHC-4229-2022
OI NIE, Yu/0000-0002-8744-0046; Song, Shen/0000-0001-9126-7840; Yang,
   Huijun/0000-0001-5166-5721
FU National Key Research and Development Project of China [2019YFA0801500];
   National Natural Science Foundation of China [81873479, 81873509,
   31801068]; Project of Innovation-driven Plan in Central South University
   [2020CX017]
FX This work was funded by the National Key Research and Development
   Project of China (grant number 2019YFA0801500), the National Natural
   Science Foundation of China (grant number 81873479, 81873509, and
   31801068), and he APC was funded by Project of Innovation-driven Plan in
   Central South University (No. 2020CX017).
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NR 32
TC 1
Z9 1
U1 0
U2 9
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2073-4425
J9 GENES-BASEL
JI Genes
PD FEB
PY 2022
VL 13
IS 2
AR 250
DI 10.3390/genes13020250
PG 15
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA E4QL9
UT WOS:000975403800001
PM 35205300
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Fu, K
   Mende, Y
   Bhetwal, BP
   Baker, S
   Perrino, BA
   Wirth, B
   Fisher, SA
AF Fu, Kang
   Mende, Ylva
   Bhetwal, Bhupal P.
   Baker, Salah
   Perrino, Brian A.
   Wirth, Brunhilde
   Fisher, Steven A.
TI Tra2β Protein Is Required for Tissue-specific Splicing of a Smooth
   Muscle Myosin Phosphatase Targeting Subunit Alternative Exon
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID PRE-MESSENGER-RNA; LIGHT-CHAIN PHOSPHATASE; SIGNALING PATHWAYS;
   PORTAL-VEIN; IN-SITU; EXPRESSION; ISOFORM; RAT; HYPERTENSION; MECHANISMS
AB Alternative splicing of the smooth muscle myosin phosphatase targeting subunit (Mypt1) exon 23 (E23) is tissue-specific and developmentally regulated and, thus, an attractive model for the study of smooth muscle phenotypic specification. We have proposed that Tra2 beta functions as a tissue-specific activator of Mypt1 E23 splicing on the basis of concordant expression patterns and Tra2 beta activation of Mypt1 E23 mini-gene splicing in vitro. In this study we examined the relationship between Tra2 beta and Mypt1 E23 splicing in vivo in the mouse. Tra2 beta was 2- to 5-fold more abundant in phasic smooth muscle tissues, such as the portal vein, small intestine, and small mesenteric artery, in which Mypt1 E23 is predominately included as compared with the tonic smooth muscle tissues, such as the aorta and inferior vena cava, in which Mypt1 E23 is predominately skipped. Tra2 beta was up-regulated in the small intestine postnatally, concordant with a switch to Mypt1 E23 splicing. Targeting of Tra2 beta in smooth muscle cells using SM22 alpha-Cre caused a substantial reduction in Mypt1 E23 inclusion specifically in the intestinal smooth muscle of heterozygotes, indicating sensitivity to Tra2 beta gene dosage. The switch to the Mypt1 E23 skipped isoform coding for the C-terminal leucine zipper motif caused increased sensitivity of the muscle to the relaxant effects of 8-Br-cyclic guanosine monophosphate (cGMP). We conclude that Tra2 beta is necessary for the tissue-specific splicing of Mypt1 E23 in the phasic intestinal smooth muscle. Tra2 beta, by regulating the splicing of Mypt1 E23, sets the sensitivity of smooth muscle to cGMP-mediated relaxation.
C1 [Fu, Kang; Fisher, Steven A.] Case Western Reserve Univ, Dept Med Cardiol, Cleveland, OH 44106 USA.
   [Fisher, Steven A.] Case Western Reserve Univ, Dept Physiol & Biophys, Cleveland, OH 44106 USA.
   [Mende, Ylva; Wirth, Brunhilde] Univ Cologne, Inst Genet, Inst Human Genet, D-50931 Cologne, Germany.
   [Mende, Ylva; Wirth, Brunhilde] Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany.
   [Bhetwal, Bhupal P.; Baker, Salah; Perrino, Brian A.] Univ Nevada, Sch Med, Ctr Biomed Res Excellence, Dept Physiol & Cell Biol, Reno, NV 89557 USA.
C3 University System of Ohio; Case Western Reserve University; University
   System of Ohio; Case Western Reserve University; University of Cologne;
   University of Cologne; Nevada System of Higher Education (NSHE);
   University of Nevada Reno
RP Fisher, SA (corresponding author), Univ Maryland, Sch Med, S-003C HSF-2,20 Penn St, Baltimore, MD 21201 USA.
EM SFisher1@medicine.umaryland.edu
RI Wirth, Brunhilde/H-3192-2019
OI Wirth, Brunhilde/0000-0003-4051-5191; BAKER, SAL/0000-0002-1514-6876
FU National Institutes of Health [RO1 HL-66171, GM103513, CMMC D7]
FX This work was supported, in whole or in part, by National Institutes of
   Health Grants RO1 HL-66171 (to S. A. F.), GM103513 (to B. A. P.), and
   CMMC D7 (to B. W.).
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NR 49
TC 16
Z9 18
U1 0
U2 3
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
EI 1083-351X
J9 J BIOL CHEM
JI J. Biol. Chem.
PD MAY 11
PY 2012
VL 287
IS 20
BP 16575
EP 16585
DI 10.1074/jbc.M111.325761
PG 11
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 942GB
UT WOS:000304030900047
PM 22437831
OA hybrid, Green Published
DA 2025-04-10
ER

PT J
AU Khoo, B
   Roca, X
   Chew, SL
   Krainer, AR
AF Khoo, Bernard
   Roca, Xavier
   Chew, Shern L.
   Krainer, Adrian R.
TI Antisense oligonucleotide-induced alternative splicing of the
   APOB mRNA generates a novel isoform of APOB
SO BMC MOLECULAR BIOLOGY
LA English
DT Article
ID TRUNCATED APOLIPOPROTEIN-B; NONSENSE-MEDIATED DECAY; FAMILIAL
   HYPOBETALIPOPROTEINEMIA; SECONDARY STRUCTURE; MAMMALIAN-CELLS;
   GENE-EXPRESSION; IN-VIVO; IDENTIFICATION; PROTEIN; ENHANCERS
AB Background: Apolipoprotein B (APOB) is an integral part of the LDL, VLDL, IDL, Lp(a) and chylomicron lipoprotein particles. The APOB pre-mRNA consists of 29 constitutively-spliced exons. APOB exists as two natural isoforms: the full-length APOB100 isoform, assembled into LDL, VLDL, IDL and Lp(a) and secreted by the liver in humans; and the C-terminally truncated APOB48, assembled into chylomicrons and secreted by the intestine in humans. Down-regulation of APOB100 is a potential therapy to lower circulating LDL and cholesterol levels.
   Results: We investigated the ability of 2' O-methyl RNA antisense oligonucleotides (ASOs) to induce the skipping of exon 27 in endogenous APOB mRNA in HepG2 cells. These ASOs are directed towards the 5' and 3' splice-sites of exon 27, the branch-point sequence (BPS) of intron 26-27 and several predicted exonic splicing enhancers within exon 27. ASOs targeting either the 5' or 3' splice-site, in combination with the BPS, are the most effective. The splicing of other alternatively spliced genes are not influenced by these ASOs, suggesting that the effects seen are not due to non-specific changes in alternative splicing. The skip 27 mRNA is translated into a truncated isoform, APOB87(SKIP27).
   Conclusion: The induction of APOB87(SKIP27) expression in vivo should lead to decreased LDL and cholesterol levels, by analogy to patients with hypobetalipoproteinemia. As intestinal APOB mRNA editing and APOB48 expression rely on sequences within exon 26, exon 27 skipping should not affect APOB48 expression unlike other methods of down-regulating APOB100 expression which also down-regulate APOB48.
C1 Univ London Queen Mary Coll, William Harvey Res Inst, London EC1M 6BQ, England.
   Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA.
C3 University of London; Queen Mary University London; Cold Spring Harbor
   Laboratory
RP Khoo, B (corresponding author), Univ London Queen Mary Coll, William Harvey Res Inst, Charterhouse Sq, London EC1M 6BQ, England.
EM b.khoo@qmul.ac.uk; roca@cshl.edu; s.l.chew@qmul.ac.uk; krainer@cshl.edu
RI Khoo, Bernard/B-1247-2009; Roca Castella, Francesc Xavier/C-5838-2011
OI Khoo, Bernard/0000-0002-4223-9736; Roca Castella, Francesc
   Xavier/0000-0003-3853-5273; Krainer, Adrian/0000-0001-9024-9501
FU Medical Research Council [G0802469] Funding Source: Medline; NIGMS NIH
   HHS [R37 GM042699, R01 GM042699, GM42699] Funding Source: Medline;
   Wellcome Trust [071426/Z/03/Z] Funding Source: Medline
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NR 58
TC 43
Z9 49
U1 0
U2 6
PU BIOMED CENTRAL LTD
PI LONDON
PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND
SN 1471-2199
J9 BMC MOL BIOL
JI BMC Mol. Biol.
PD JAN 17
PY 2007
VL 8
AR 3
DI 10.1186/1471-2199-8-3
PG 13
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 134CB
UT WOS:000244059100001
PM 17233885
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU Maroney, SA
   Ferrel, JP
   Collins, ML
   Mast, AE
AF Maroney, S. A.
   Ferrel, J. P.
   Collins, M. L.
   Mast, A. E.
TI Tissue factor pathway inhibitor-γ is an active alternatively spliced
   form of tissue factor pathway inhibitor present in mice but not in
   humans
SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS
LA English
DT Article
DE alternative splicing; coagulation; tissue factor; TFPI
ID COAGULATION INHIBITOR; HUMAN PLATELETS; HEMOSTASIS; SURFACE; EXPRESSION;
   THROMBOSIS; SEPSIS; ENDOTHELIUM; SYNTHESIZE; BINDING
AB Background: Tissue factor pathway inhibitor (TFPI) is a potent inhibitor of tissue factor procoagulant activity produced as two alternatively spliced isoforms, TFPI alpha and TFPI beta, which differ in domain structure and mechanism for cell surface association. 3' Rapid amplification of cDNA ends was used to search for new TFPI isoforms. TFPI gamma, a new alternatively spliced form of TFPI, was identified and characterized. Methods: The tissue expression, cell surface association and anticoagulant activity of TFPI gamma were characterized and compared to those of TFPI alpha and TFPI beta through studies of mouse and human tissues and expression of recombinant proteins in Chinese hamster ovary (CHO) cells. Results: TFPI gamma is produced by alternative splicing using the same 5'-splice donor site as TFPI beta and a 3'-splice acceptor site 276 nucleotides beyond the stop codon of TFPI beta in exon 8. The resulting protein has the first two Kunitz domains connected to an 18 amino acid C-terminal region specific to TFPI gamma. TFPI gamma mRNA is differentially produced in mouse tissues but is not encoded within the human TFPI gene. When expressed in CHO cells, TFPI gamma is secreted into conditioned media and effectively inhibits tissue factor procoagulant activity. Conclusions: TFPI gamma is a third alternatively spliced form of TFPI that is widely expressed in mouse tissues but not made by human tissues. It contains the first two Kunitz domains and is a secreted, rather than a cell surface-associated, protein. It is a functional anticoagulant and may partially explain the resistance of mice to coagulopathy in tissue factor-mediated models of disease.
C1 [Maroney, S. A.; Ferrel, J. P.; Collins, M. L.; Mast, A. E.] Blood Ctr Wisconsin, Blood Res Inst, Milwaukee, WI 53201 USA.
   [Mast, A. E.] Med Coll Wisconsin, Dept Cell Biol Neurobiol & Anat, Milwaukee, WI 53226 USA.
C3 Versiti Blood Center of Wisconsin; Medical College of Wisconsin
RP Mast, AE (corresponding author), Blood Ctr Wisconsin, Blood Res Inst, POB 2178, Milwaukee, WI 53201 USA.
EM alan.mast@bcw.edu
FU NHLBI NIH HHS [R01 HL068835] Funding Source: Medline
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NR 35
TC 26
Z9 27
U1 0
U2 2
PU WILEY-BLACKWELL
PI MALDEN
PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA
SN 1538-7933
J9 J THROMB HAEMOST
JI J. Thromb. Haemost.
PD AUG
PY 2008
VL 6
IS 8
BP 1344
EP 1351
DI 10.1111/j.1538-7836.2008.03033.x
PG 8
WC Hematology; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Hematology; Cardiovascular System & Cardiology
GA 327VQ
UT WOS:000257757000015
PM 18503630
OA Green Accepted, Bronze
DA 2025-04-10
ER

PT J
AU Nikonova, E
   Kao, SY
   Ravichandran, K
   Wittner, A
   Spletter, ML
AF Nikonova, Elena
   Kao, Shao-Yen
   Ravichandran, Keshika
   Wittner, Anja
   Spletter, Maria L.
TI Conserved functions of RNA-binding proteins in muscle
SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
LA English
DT Article
DE Alternative splicing; Muscle; Development; RNA-binding proteins;
   Drosophila
ID PRE-MESSENGER-RNA; MYOSIN HEAVY-CHAIN; SPINAL MUSCULAR-ATROPHY;
   MYOTONIC-DYSTROPHY TYPE-1; PERIPHERAL NERVOUS-SYSTEM; SPLICING REGULATOR
   RBFOX2; INDIRECT FLIGHT-MUSCLE; CARDIAC TROPONIN-T; SKELETAL-MUSCLE;
   DROSOPHILA MODEL
AB Animals require different types of muscle for survival, for example for circulation, motility, reproduction and digestion. Much emphasis in the muscle field has been placed on understanding how transcriptional regulation generates diverse types of muscle during development. Recent work indicates that alternative splicing and RNA regulation are as critical to muscle development, and altered function of RNA-binding proteins causes muscle disease. Although hundreds of genes predicted to bind RNA are expressed in muscles, many fewer have been functionally characterized. We present a cross-species view summarizing what is known about RNA-binding protein function in muscle, from worms and flies to zebrafish, mice and humans. In particular, we focus on alternative splicing regulated by the CELF, MBNL and RBFOX families of proteins. We discuss the systemic nature of diseases associated with loss of RNA-binding proteins in muscle, focusing on mis-regulation of CELF and MBNL in myotonic dystrophy. These examples illustrate the conservation of RNA-binding protein function and the marked utility of genetic model systems in understanding mechanisms of RNA regulation.
C1 [Nikonova, Elena; Kao, Shao-Yen; Ravichandran, Keshika; Wittner, Anja; Spletter, Maria L.] Ludwig Maximilians Univ Munchen, Dept Physiol Chem, Biomed Ctr, Grosshaderner Str 9, D-82152 Martinsried Planegg, Germany.
   [Spletter, Maria L.] Ludwig Maximilians Univ Munchen, Dept Chem, CIPSM, Munich, Germany.
C3 University of Munich; University of Munich
RP Spletter, ML (corresponding author), Ludwig Maximilians Univ Munchen, Dept Physiol Chem, Biomed Ctr, Grosshaderner Str 9, D-82152 Martinsried Planegg, Germany.
EM maria.spletter@bmc.med.lmu.de
RI Spletter, Maria/T-5917-2018
OI Spletter, Maria/0000-0002-2068-3350; Nikonova, Elena/0009-0003-2153-8790
FU International Max Planck Research School, Germany; Frederich-Bauer
   Stiftung, Germany [06/17]; Center for Integrated Protein Science Munich
   (CIPSM) at the Department of Chemistry, Ludwig-Maximilians-University,
   Germany; Deutsche Forschungs Gemeinschaft, Germany [SP 1662/3-1]
FX We thank the Bloomington and VDRC stock centers for fly stocks. We are
   grateful to Andreas Ladumer and Frank Schnorrer for generous support and
   to Sandra Esser for excellent technical assistance. We thank interns
   Kelley Manbeck and Sophie Gottke for helping screen UAS-RNAi line
   phenotypes. We acknowledge the Core Facility Bioimaging at the LMU
   Biomedical Center (Martinsried, DE) for help with confocal imaging. Our
   work was supported by the International Max Planck Research School,
   Germany (EN), the Frederich-Bauer Stiftung, Germany (MLS, Nr. 06/17),
   the Center for Integrated Protein Science Munich (CIPSM) at the
   Department of Chemistry, Ludwig-Maximilians-University, Germany (MIS)
   and the Deutsche Forschungs Gemeinschaft, Germany (MIS, SP 1662/3-1).
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NR 425
TC 18
Z9 19
U1 1
U2 9
PU PERGAMON-ELSEVIER SCIENCE LTD
PI OXFORD
PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
SN 1357-2725
EI 1878-5875
J9 INT J BIOCHEM CELL B
JI Int. J. Biochem. Cell Biol.
PD MAY
PY 2019
VL 110
BP 29
EP 49
DI 10.1016/j.biocel.2019.02.008
PG 21
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA HZ3AT
UT WOS:000468720600004
PM 30818081
DA 2025-04-10
ER

PT J
AU Guo, MX
   Zhou, CL
   Xu, GF
   Tang, L
   Ruan, YC
   Yu, Y
   Lin, XH
   Wu, DD
   Chen, H
   Yu, P
   Jin, LY
   Wang, YY
   Wu, YM
   Ullah, K
   Rahman, TU
   Liu, XM
   Sheng, JZ
   Chan, HC
   Huang, HF
AF Guo, Mengxi
   Zhou, Chengliang
   Xu, Gufeng
   Tang, Lin
   Ruan, Yechun
   Yu, Ying
   Lin, Xianhua
   Wu, Dandan
   Chen, Hao
   Yu, Priscilla
   Jin, Luyang
   Wang, Yinyu
   Wu, Yimei
   Ullah, Kamran
   Rahman, Tanzil Ur
   Liu, Xinmei
   Sheng, Jianzhong
   Chan, Hsiao-Chang
   Huang, Hefeng
TI An alternative splicing variant of mineralocorticoid receptor discovered
   in preeclampsia tissues and its effect on endothelial dysfunction
SO SCIENCE CHINA-LIFE SCIENCES
LA English
DT Article
DE preeclampsia; mineralocorticoid receptor; alternative splicing variant;
   offspring; endothelial dysfunction
ID BLOOD-PRESSURE; HYPERTENSIVE DISORDERS; CARDIOVASCULAR RISK; PREGNANCY;
   HEALTH; CELL
AB The pathophysiology of preeclampsia (PE) remains unclear. PE spiral artery remodeling dysfunction and PE offspring cardiovascular future development has been a worldwide concern. We collected placental and umbilical artery samples from nor-motensive and PE pregnancies. Mineralocorticoid receptor (MR) and its alternative splicing variant (ASV) expression and their biological effects on PE were examined. An MR ASV was found to be highly expressed in all PE samples and slightly expressed in about half of the normotensive samples (umbilical artery, ~57.58%; placenta, ~36.84%). The MR ASV expression was positively associated with blood pressure in both groups. The MR ASV protein changed the aldosterone-induced expression pattern of MR target genes related to ion exchanges and cell signaling pathways. The MR ASV can also impair the proliferation, migration, and tube formation ability of endothelial cells. These findings indicate that MR ASV in PE placenta plays a pathogenic role in PE pathophysiology, especially in endothelial dysfunction, and the existence of the MR ASV in PE umbilical artery provides a new direction in the study of PE offspring with increased risk of cardiovascular diseases.
C1 [Guo, Mengxi; Zhou, Chengliang; Xu, Gufeng; Yu, Ying; Jin, Luyang; Huang, Hefeng] Zhejiang Univ, Sch Med, Womens Hosp, Hangzhou 310058, Peoples R China.
   [Guo, Mengxi; Zhou, Chengliang; Tang, Lin; Lin, Xianhua; Wu, Dandan; Wang, Yinyu; Wu, Yimei; Liu, Xinmei; Huang, Hefeng] Shanghai Jiao Tong Univ, Sch Med, Int Peace Maternal & Child Hlth Hosp, Shanghai 200030, Peoples R China.
   [Ruan, Yechun; Chen, Hao; Yu, Priscilla; Chan, Hsiao-Chang] Chinese Univ Hong Kong, Sch Biomed Sci, Epithelial Cell Biol Res Ctr, Fac Med, Hong Kong, Peoples R China.
   [Guo, Mengxi; Zhou, Chengliang; Jin, Luyang; Ullah, Kamran; Rahman, Tanzil Ur; Sheng, Jianzhong; Huang, Hefeng] Zhejiang Univ, Minist Educ, Key Lab Reprod Genet, Hangzhou 310058, Peoples R China.
   [Ullah, Kamran; Rahman, Tanzil Ur; Sheng, Jianzhong] Zhejiang Univ, Sch Med, Dept Pathol & Pathophysiol, Hangzhou 310058, Peoples R China.
   [Huang, Hefeng] Shanghai Key Lab Embryo Original Dis, Shanghai 20030, Peoples R China.
C3 Zhejiang University; Shanghai Jiao Tong University; Chinese University
   of Hong Kong; Zhejiang University; Zhejiang University
RP Huang, HF (corresponding author), Zhejiang Univ, Sch Med, Womens Hosp, Hangzhou 310058, Peoples R China.; Huang, HF (corresponding author), Shanghai Jiao Tong Univ, Sch Med, Int Peace Maternal & Child Hlth Hosp, Shanghai 200030, Peoples R China.; Chan, HC (corresponding author), Chinese Univ Hong Kong, Sch Biomed Sci, Epithelial Cell Biol Res Ctr, Fac Med, Hong Kong, Peoples R China.; Huang, HF (corresponding author), Zhejiang Univ, Minist Educ, Key Lab Reprod Genet, Hangzhou 310058, Peoples R China.; Huang, HF (corresponding author), Shanghai Key Lab Embryo Original Dis, Shanghai 20030, Peoples R China.
EM hsiaocchan@cuhk.edu.hk; hhf57@zju.edu.cn
RI yu, ying/J-6700-2012; Ullah, Kamran/KXQ-5465-2024; Chen,
   Hao/AAH-4124-2020; Huang, He-Feng/AAN-7985-2020; XU, GUFENG/T-7316-2019;
   Chen, Hao/D-3425-2012; Ruan, Ye Chun/T-5919-2017
OI Chen, Hao/0000-0001-8319-8101; Xu, Gufeng/0000-0003-0641-6325; Ruan, Ye
   Chun/0000-0002-4266-6789
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NR 34
TC 4
Z9 4
U1 1
U2 10
PU SCIENCE PRESS
PI BEIJING
PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA
SN 1674-7305
EI 1869-1889
J9 SCI CHINA LIFE SCI
JI Sci. China-Life Sci.
PD MAR
PY 2020
VL 63
IS 3
BP 388
EP 400
DI 10.1007/s11427-018-9535-9
PG 13
WC Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Life Sciences & Biomedicine - Other Topics
GA KU1DB
UT WOS:000519449200007
PM 31197761
OA Bronze
DA 2025-04-10
ER

PT J
AU Hashimoto, K
   Ishida, E
   Matsumoto, S
   Shibusawa, N
   Okada, S
   Monden, T
   Satoh, T
   Yamada, M
   Mori, M
AF Hashimoto, Koshi
   Ishida, Emi
   Matsumoto, Shunichi
   Shibusawa, Nobuyuki
   Okada, Shuichi
   Monden, Tsuyoshi
   Satoh, Tetsurou
   Yamada, Masanobu
   Mori, Masatomo
TI A liver X receptor (LXR)-β alternative splicing variant (LXRBSV) acts as
   an RNA co-activator of LXR-β
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE LXR-beta; Alternative splicing variant; RNA co-activator
ID CENTRAL-NERVOUS-SYSTEM; THYROID-HORMONE; GENE-EXPRESSION; NONCODING RNA;
   CHOLESTEROL HOMEOSTASIS; ALPHA; DEGENERATION; GENOME
AB We report the isolation and functional characterization of a novel transcriptional co-activator, termed LXRBSV. LXRBSV is an alternative splicing variant of liver X receptor (LXR)-beta LXRBSV has an intronic sequence between exons 2 and 3 in the mouse LXR-beta gene. The LXRBSV gene is expressed in various tissues including the liver and brain. We sub-cloned LXRBSV into pSG5, a mammalian expression vector, and LXRBSV in pSG5 augmented human Sterol Response Element Binding Protein (SREBP)-1c promoter activity in HepG2 cells in a ligand (TO901317) dependent manner. The transactivation mediated by LXRBSV is selective for LXR-beta. The LXRBSV protein was deduced to be 64 amino acids in length; however, a GAL4-LXRBSV fusion protein was not able to induce transactivation. Serial deletion constructs of LXRBSV demonstrated that the intronic sequence inserted in LXRBSV is required for its transactivation activity. An ATG mutant of LXRBSV was able to induce transactivation as wild type. Furthermore, LXRBSV functions in the presence of cycloheximide. Taken together, we have concluded that LXRBSV acts as an RNA transcript not as a protein. In the current study, we have demonstrated for the first time that an alternative splicing variant of a nuclear receptor acts as an RNA co-activator. (C) 2009 Elsevier Inc. All rights reserved.
C1 [Hashimoto, Koshi; Ishida, Emi; Matsumoto, Shunichi; Shibusawa, Nobuyuki; Okada, Shuichi; Satoh, Tetsurou; Yamada, Masanobu; Mori, Masatomo] Gunma Univ, Grad Sch Med, Dept Med & Mol Sci, Gunma 3718511, Japan.
   [Monden, Tsuyoshi] Dokkyo Med Coll, Dept Endocrinol & Metab, Mibu, Tochigi, Japan.
C3 Gunma University; Dokkyo Medical University
RP Hashimoto, K (corresponding author), Gunma Univ, Grad Sch Med, Dept Med & Mol Sci, 3-39-15 Showa Machi, Gunma 3718511, Japan.
EM khashi@med.gunma-u.ac.jp
RI Hashimoto, Koshi/AAL-7339-2020
FU Kowa Life Foundation
FX This study was supported by a grant from Kowa Life Foundation (to K.H.).
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NR 24
TC 24
Z9 25
U1 0
U2 5
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD DEC 25
PY 2009
VL 390
IS 4
BP 1260
EP 1265
DI 10.1016/j.bbrc.2009.10.132
PG 6
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA 531GB
UT WOS:000272650800034
PM 19878653
DA 2025-04-10
ER

PT J
AU Song, HK
   Hong, SE
   Kim, T
   Kim, DH
AF Song, Hong Ki
   Hong, Seong-Eui
   Kim, Taeyong
   Kim, Do Han
TI Deep RNA Sequencing Reveals Novel Cardiac Transcriptomic Signatures for
   Physiological and Pathological Hypertrophy
SO PLOS ONE
LA English
DT Article
ID MUSCLE LIM PROTEIN-1; GENE-EXPRESSION; MICROARRAY ANALYSIS; SPLICE
   VARIANTS; MESSENGER-RNA; C-MYC; LOCALIZATION; SKELETAL; ISOFORM;
   IDENTIFICATION
AB Although both physiological hypertrophy (PHH) and pathological hypertrophy (PAH) of the heart have similar morphological appearances, only PAH leads to fatal heart failure. In the present study, we used RNA sequencing (RNA-Seq) to determine the transcriptomic signatures for both PHH and PAH. Approximately 13-20 million reads were obtained for both models, among which PAH showed more differentially expressed genes (DEGs) (2,041) than PHH (245). The expression of 417 genes was barely detectable in the normal heart but was suddenly activated in PAH. Among them, Foxm1 and Plk1 are of particular interest, since Ingenuity Pathway Analysis (IPA) using DEGs and upstream motif analysis showed that they are essential hub proteins that regulate the expression of downstream proteins associated with PAH. Meanwhile, 52 genes related to collagen, chemokines, and actin showed opposite expression patterns between PHH and PAH. MAZ-binding motifs were enriched in the upstream region of the participating genes. Alternative splicing (AS) of exon variants was also examined using RNA-Seq data for PAH and PHH. We found 317 and 196 exon inclusions and exon exclusions, respectively, for PAH, and 242 and 172 exon inclusions and exclusions, respectively for PHH. The AS pattern was mostly related to gains or losses of domains, changes in activity, and localization of the encoded proteins. The splicing variants of 8 genes (i.e., Fhl1, Rcan1, Ndrg2, Synpo, Ttll1, Cxxc5, Egfl7, and Tmpo) were experimentally confirmed. Multilateral pathway analysis showed that the patterns of quantitative (DEG) and qualitative (AS) changes differ depending on the type of pathway in PAH and PHH. One of the most significant changes in PHH is the severe downregulation of autoimmune pathways accompanied by significant AS. These findings revealed the unique transcriptomic signatures of PAH and PHH and also provided a more comprehensive understanding at both the quantitative and qualitative levels.
C1 [Song, Hong Ki] Gwangju Inst Sci & Technol, Sch Life Sci, Kwangju, South Korea.
   Gwangju Inst Sci & Technol, Syst Biol Res Ctr, Kwangju, South Korea.
C3 Gwangju Institute of Science & Technology (GIST); Gwangju Institute of
   Science & Technology (GIST)
RP Song, HK (corresponding author), Gwangju Inst Sci & Technol, Sch Life Sci, Kwangju, South Korea.
EM dhkim@gist.ac.kr
OI Kim, Taeyong/0000-0002-4147-3635
FU Korea MEST NRF [20110002144]; 2011 GIST Systems Biology Infrastructure
   Establishment Grant
FX This work was supported by the Korea MEST NRF grant (20110002144) and
   the 2011 GIST Systems Biology Infrastructure Establishment Grant (2011).
   The funders had no role in study design, data collection and analysis,
   decision to publish, or preparation of the manuscript.
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NR 64
TC 89
Z9 101
U1 0
U2 16
PU PUBLIC LIBRARY SCIENCE
PI SAN FRANCISCO
PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
SN 1932-6203
J9 PLOS ONE
JI PLoS One
PD APR 16
PY 2012
VL 7
IS 4
AR e35552
DI 10.1371/journal.pone.0035552
PG 13
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 959VO
UT WOS:000305345000075
PM 22523601
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Cohen, N
   Rimessi, P
   Gualandi, F
   Ferlini, A
   Muntoni, F
AF Cohen, N
   Rimessi, P
   Gualandi, F
   Ferlini, A
   Muntoni, F
TI In vivo study of an aberrant dystrophin exon inclusion in X-linked
   dilated cardiomyopathy
SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
LA English
DT Article
DE dystrophin; X-linked dilated cardiomyopathy; splicing; myoblasts;
   cardiomyocytes
ID SPLICE-SITE SELECTION; RNA-BINDING; GENE CAUSES; EXPRESSION; DEFINITION;
   MODULATION; MUTATION; FAMILY; INTRON
AB We previously identified a dystrophin intron 11 rearrangement in one family with X-linked dilated cardiomyopathy, causing incorporation of an aberrant exon in a tissue-specific manner. In this study we analyzed the role of different intron 11 genomic regions in the regulation of splicing by using mini-genes based approach, in C2C 12 (skeletal muscle) myoblasts and myotubes, H9C2 cardiomyocytes, and HeLa cells. We show that inclusion of the aberrant exon is favored in H9C2 and differentiated C2C12 myotubes. These data suggest that the aberrant exon undergoes a differentiation-specific splicing. Unexpectedly, length of intron has a favorable effect in inclusion of the aberrant exon in the cardiac cells, suggesting that cardiac cells might be more prone to steric hindrance of trans-acting factors, involved in the inclusion of the aberrant exon. Furthermore, the cultured cell system used can serve as a suitable model to study human alternative splicing. (C) 2004 Elsevier Inc. All rights reserved.
C1 Univ London Imperial Coll Sci & Technol, Hammersmith Hosp, Dept Paediat, Dubowitz Neuromusc Unit, London W12 0NN, England.
   Univ Ferrara, Sez Genet Med, Dipartimento Med Sperimentale & Diagnost, Ferrara, Italy.
C3 Imperial College London; University of Ferrara
RP Univ London Imperial Coll Sci & Technol, Hammersmith Hosp, Dept Paediat, Dubowitz Neuromusc Unit, Du Cane Rd, London W12 0NN, England.
EM f.muntoni@ic.ac.uk
RI Gualandi, Francesca/K-7513-2016; FERLINI, ALESSANDRA/K-7532-2016
OI Gualandi, Francesca/0000-0001-9551-057X; FERLINI,
   ALESSANDRA/0000-0001-8385-9870
FU Telethon [GGP02311] Funding Source: Medline
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NR 17
TC 4
Z9 4
U1 0
U2 0
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0006-291X
EI 1090-2104
J9 BIOCHEM BIOPH RES CO
JI Biochem. Biophys. Res. Commun.
PD MAY 14
PY 2004
VL 317
IS 4
BP 1215
EP 1220
DI 10.1016/j.bbrc.2004.03.175
PG 6
WC Biochemistry & Molecular Biology; Biophysics
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Biophysics
GA 817JX
UT WOS:000221174900037
PM 15094399
DA 2025-04-10
ER

PT J
AU Feng, HZ
   Jin, JP
AF Feng, Han-Zhong
   Jin, J. -P.
TI Coexistence of cardiac troponin T variants reduces heart efficiency
SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
LA English
DT Article
DE cardiac function; muscle contraction; cardiomyopathy; heart failure
ID N-TERMINAL TRUNCATION; FUNCTIONAL ADAPTATION; PROTEIN ISOFORMS;
   SKELETAL; MODULATION; EXPRESSION; ISCHEMIA; MUTATION; MICE
AB Feng HZ, Jin JP. Coexistence of cardiac troponin T variants reduces heart efficiency. Am J Physiol Heart Circ Physiol 299: H97-H105, 2010. First published April 23, 2010; doi:10.1152/ajpheart.01105.2009.-Corresponding to the synchronized contraction of the myocardium and rhythmic pumping function of the heart, a single form of cardiac troponin T (cTnT) is present in the adult cardiac muscle of humans and most other vertebrate species. Alternative splicing variants of cTnT are found in failing human hearts and animal dilated cardiomyopathies. Biochemical analyses have shown that these cTnT variants are functional and produce shifted myofilament Ca2+ sensitivity. We proposed a hypothesis that the coexistence of two or more functionally distinct TnT variants in the adult ventricular muscle that is normally activated as a syncytium may decrease heart function and cause cardiomyopathy (Huang et al., Am J Physiol Cell Physiol 294: C213-C222, 2008). In the present study, we studied transgenic mouse hearts expressing one or two cTnT variants in addition to normal adult cTnT to investigate whether desynchronized myofilament activation decreases ventricular efficiency. The function of ex vivo working hearts was examined in the absence of systemic neurohumoral influence. The results showed that the transgenic mouse hearts produced lower maximum left ventricular pressure, slower contractile and relaxation velocities, and decreased stroke volume compared with wild-type controls. Ventricular pumping efficiency, calculated by the ejection integral versus total systolic integral and cardiac work versus oxygen consumption, was significantly lower in transgenic mouse hearts and corresponded to the number of cTnT variants present. The results indicated a pathogenic mechanism in which the coexistence of functionally different cTnT variants in cardiac muscle reduces myocardial efficiency due to desynchronized thin filament activation.
C1 [Feng, Han-Zhong; Jin, J. -P.] Wayne State Univ, Sch Med, Dept Physiol, Detroit, MI 48201 USA.
C3 Wayne State University
RP Jin, JP (corresponding author), Wayne State Univ, Sch Med, Dept Physiol, 540 E Canfield, Detroit, MI 48201 USA.
EM jjin@med.wayne.edu
RI Jin, Jian-Ping/AAD-1149-2020
OI Jin, JP/0000-0001-9932-1063
FU National Institutes of Health [HL-078773, AR-048816]
FX This work was supported by National Institutes of Health Grants
   HL-078773 and AR-048816 (to J.-P. Jin).
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NR 33
TC 24
Z9 28
U1 0
U2 5
PU AMER PHYSIOLOGICAL SOC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA
SN 0363-6135
EI 1522-1539
J9 AM J PHYSIOL-HEART C
JI Am. J. Physiol.-Heart Circul. Physiol.
PD JUL
PY 2010
VL 299
IS 1
BP H97
EP H105
DI 10.1152/ajpheart.01105.2009
PG 9
WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Physiology
GA 612HT
UT WOS:000278888400015
PM 20418479
OA Green Published
DA 2025-04-10
ER

PT J
AU Shi, DL
AF Shi, De-Li
TI RNA-Binding Proteins in Cardiomyopathies
SO JOURNAL OF CARDIOVASCULAR DEVELOPMENT AND DISEASE
LA English
DT Review
DE cardiomyopathy; RNA-binding protein; post-transcriptional regulation;
   RBM20; RBM24; RBPMS; RBFOX; IGF2BP2; YTHDC1
ID CONGENITAL HEART-DISEASE; EMERGING ROLES; RBM24; EXPRESSION; GENE;
   ZEBRAFISH; REGULATOR; RBFOX2; MUTATIONS; PROMOTE
AB The post-transcriptional regulation of gene expression plays an important role in heart development and disease. Cardiac-specific alternative splicing, mediated by RNA-binding proteins, orchestrates the isoform switching of proteins that are essential for cardiomyocyte organization and contraction. Dysfunctions of RNA-binding proteins impair heart development and cause the main types of cardiomyopathies, which represent a heterogenous group of abnormalities that severely affect heart structure and function. In particular, mutations of RBM20 and RBFOX2 are associated with dilated cardiomyopathy, hypertrophic cardiomyopathy, or hypoplastic left heart syndrome. Functional analyses in different animal models also suggest possible roles for other RNA-binding proteins in cardiomyopathies because of their involvement in organizing cardiac gene programming. Recent studies have provided significant insights into the causal relationship between RNA-binding proteins and cardiovascular diseases. They also show the potential of correcting pathogenic mutations in RNA-binding proteins to rescue cardiomyopathy or promote cardiac regeneration. Therefore, RNA-binding proteins have emerged as promising targets for therapeutic interventions for cardiovascular dysfunction. The challenge remains to decipher how they coordinately regulate the temporal and spatial expression of target genes to ensure heart function and homeostasis. This review discusses recent advances in understanding the implications of several well-characterized RNA-binding proteins in cardiomyopathies, with the aim of identifying research gaps to promote further investigation in this field.
C1 [Shi, De-Li] Guangdong Med Univ, Affiliated Hosp, Dept Med Res, Zhanjiang 524001, Peoples R China.
   [Shi, De-Li] Sorbonne Univ, Inst Biol Paris Seine IBPS, CNRS, UMR7622,Lab Dev Biol, F-75005 Paris, France.
C3 Guangdong Medical University; Sorbonne Universite; Centre National de la
   Recherche Scientifique (CNRS); CNRS - National Institute for Biology
   (INSB)
RP Shi, DL (corresponding author), Guangdong Med Univ, Affiliated Hosp, Dept Med Res, Zhanjiang 524001, Peoples R China.
EM de-li.shi@upmc.fr
RI Shi, De-Li/AAG-1807-2021
OI Shi, Deli/0000-0002-6104-9137
FU National Natural Science Foundation of China
FX No Statement Available
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NR 111
TC 4
Z9 4
U1 0
U2 2
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2308-3425
J9 J CARDIOVASC DEV DIS
JI J. Cardiovasc. Dev. Dis.
PD MAR
PY 2024
VL 11
IS 3
AR 88
DI 10.3390/jcdd11030088
PG 14
WC Cardiac & Cardiovascular Systems
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA MI0B3
UT WOS:001192865300001
PM 38535111
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Abudureyimu, S
   He, CH
   Xie, W
   Chen, Z
   Airikenjiang, H
   Abulaiti, D
   Cao, Y
   Qiu, HT
   Gao, Y
AF Abudureyimu, Shajidan
   He, Chunhui
   Xie, Wei
   Chen, Zhuo
   Airikenjiang, Halisha
   Abulaiti, Dilihumaer
   Cao, Yan
   Qiu, Haitang
   Gao, Ying
TI FOXO3a functions as a transcriptional and co-transcriptional splicing
   regulator in vascular endothelial cell lines
SO GENE
LA English
DT Article
DE Coronary heart disease; FOXO3a; Targeted regulation; Alternative
   splicing
ID CORONARY-ARTERY-DISEASE; EXPRESSION; APOPTOSIS; PATHOPHYSIOLOGY; INSULIN
AB Recent studies have indicated a connection between Forkhead box O3a protein and coronary artery disease, yet the exact role of FOXO3a in the regulation of metabolic processes and apoptosis in vascular endothelial cells is still unknown. Therefore, we investigated the role of FOXO3a on target genes in a human vascular endothelial cell line. Through the utilization of high-throughput sequencing technology, we analyzed gene expression profiles and alternative splicing patterns in human vascular endothelial cells with FOXO3a over expression. This study identified 419 DEGs between FOXO3a-OE HUVEC model and control cells. KEGG analysis indicated that the upregulated genes were mainly enriched in inflammation-related signaling pathways, and the downregulated genes were enriched in lipid metabolism-related pathways.
C1 [Abudureyimu, Shajidan; Airikenjiang, Halisha; Abulaiti, Dilihumaer; Qiu, Haitang; Gao, Ying] Xinjiang Med Univ, Dept Comprehens Internal Med, Affiliated Hosp 1, Urumqi 830011, Xinjiang, Peoples R China.
   [He, Chunhui] Chinese Acad Med Sci & Peking Union Med Coll, Fuwai Hosp, China Heart Failure Ctr, Natl Ctr Cardiovasc Dis,State Key Lab Cardiovasc D, Beijing 100010, Peoples R China.
   [Xie, Wei] Xinjiang Prod & Construct Corps Hosp, Dept Cardiol, Urumqi 830011, Xinjiang, Peoples R China.
   [Chen, Zhuo] Xinjiang Med Univ, Clin Med Coll 2, Urumqi 830011, Xinjiang, Peoples R China.
   [Cao, Yan] Xinjiang Med Univ, Dept Hepatobiliary & Pancreat Surg, Affiliated Canc Hosp, Urumqi 830000, Xinjiang, Peoples R China.
C3 Xinjiang Medical University; Chinese Academy of Medical Sciences -
   Peking Union Medical College; Fu Wai Hospital - CAMS; Peking Union
   Medical College; Xinjiang Medical University; Xinjiang Medical
   University
RP Gao, Y (corresponding author), Xinjiang Med Univ, Dept Comprehens Internal Med, Affiliated Hosp 1, Urumqi 830011, Xinjiang, Peoples R China.
EM gaoydct@163.com
RI qiu, haitang/AAN-9585-2020; he, chunhui/KXR-8968-2024
OI Qiu, Haitang/0009-0001-0731-0939; chen, zhuo/0000-0001-8121-3099
FU Xinjiang Uygur Autonomous Region Tianshan Talent Program
   [2022TSYCLJ0023]
FX <B>Funding</B> This work was supported by Xinjiang Uygur Autonomous
   Region Tianshan Talent Program (2022TSYCLJ0023) .
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NR 51
TC 1
Z9 1
U1 2
U2 10
PU ELSEVIER
PI AMSTERDAM
PA RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS
SN 0378-1119
EI 1879-0038
J9 GENE
JI Gene
PD APR 30
PY 2024
VL 904
AR 148221
DI 10.1016/j.gene.2024.148221
EA FEB 2024
PG 9
WC Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Genetics & Heredity
GA JX0J0
UT WOS:001176338300001
PM 38286271
DA 2025-04-10
ER

PT J
AU Kao, SY
   Nikonova, E
   Chaabane, S
   Sabani, A
   Martitz, A
   Wittner, A
   Heemken, J
   Straub, T
   Spletter, ML
AF Kao, Shao-Yen
   Nikonova, Elena
   Chaabane, Sabrina
   Sabani, Albiona
   Martitz, Alexandra
   Wittner, Anja
   Heemken, Jakob
   Straub, Tobias
   Spletter, Maria L.
TI A Candidate RNAi Screen Reveals Diverse RNA-Binding Protein Phenotypes
   in Drosophila Flight Muscle
SO CELLS
LA English
DT Article
DE RNA binding proteins; SF1; Hrb87F; Bru1; Drosophila; flight muscle;
   RNAi; splicing
ID SPLICING FACTOR SF1; MECHANICAL-PROPERTIES; SOMATIC MUSCULATURE;
   MYOBLAST FUSION; DOMAINS; EXPRESSION; MYOFIBRIL; IDENTITY; MODELS; ROLES
AB The proper regulation of RNA processing is critical for muscle development and the fine-tuning of contractile ability among muscle fiber-types. RNA binding proteins (RBPs) regulate the diverse steps in RNA processing, including alternative splicing, which generates fiber-type specific isoforms of structural proteins that confer contractile sarcomeres with distinct biomechanical properties. Alternative splicing is disrupted in muscle diseases such as myotonic dystrophy and dilated cardiomyopathy and is altered after intense exercise as well as with aging. It is therefore important to understand splicing and RBP function, but currently, only a small fraction of the hundreds of annotated RBPs expressed in muscle have been characterized. Here, we demonstrate the utility of Drosophila as a genetic model system to investigate basic developmental mechanisms of RBP function in myogenesis. We find that RBPs exhibit dynamic temporal and fiber-type specific expression patterns in mRNA-Seq data and display muscle-specific phenotypes. We performed knockdown with 105 RNAi hairpins targeting 35 RBPs and report associated lethality, flight, myofiber and sarcomere defects, including flight muscle phenotypes for Doa, Rm62, mub, mbl, sbr, and clu. Knockdown phenotypes of spliceosome components, as highlighted by phenotypes for A-complex components SF1 and Hrb87F (hnRNPA1), revealed level- and temporal-dependent myofibril defects. We further show that splicing mediated by SF1 and Hrb87F is necessary for Z-disc stability and proper myofibril development, and strong knockdown of either gene results in impaired localization of kettin to the Z-disc. Our results expand the number of RBPs with a described phenotype in muscle and underscore the diversity in myofibril and transcriptomic phenotypes associated with splicing defects. Drosophila is thus a powerful model to gain disease-relevant insight into cellular and molecular phenotypes observed when expression levels of splicing factors, spliceosome components and splicing dynamics are altered.
C1 [Kao, Shao-Yen; Nikonova, Elena; Chaabane, Sabrina; Wittner, Anja; Heemken, Jakob; Spletter, Maria L.] Ludwig Maximilians Univ Munchen, Biomed Ctr, Dept Physiol Chem, Grosshaderner Str 9, D-82152 Martinsried, Germany.
   [Sabani, Albiona] Univ Wisconsin, Dept Biol, 1117 W Johnson St, Madison, WI 53706 USA.
   [Martitz, Alexandra] Tech Univ Munich, Else Kroner Fresenius Ctr, Mol Nutr Med, D-85354 Freising Weihenstephan, Germany.
   [Straub, Tobias] Ludwig Maximilians Univ Munchen, Biomed Ctr, Bioinformat Core Facil, Grosshaderner Str 9, D-82152 Martinsried, Germany.
C3 University of Munich; University of Wisconsin System; University of
   Wisconsin Madison; Technical University of Munich; University of Munich
RP Spletter, ML (corresponding author), Ludwig Maximilians Univ Munchen, Biomed Ctr, Dept Physiol Chem, Grosshaderner Str 9, D-82152 Martinsried, Germany.
EM shao-yen.kao@bmc.med.lmu.de; elena.nikonova@bmc.med.lmu.de;
   sabrina.chaabane@tum.de; sabani2@wisc.edu;
   alexandra.martitz@ndcls.ox.ac.uk; wittner@genzentrum.lmu.de;
   Jakob.Heemken@campus.lmu.de; tstraub@bmc.med.lmu.de;
   maria.spletter@bmc.med.lmu.de
RI Spletter, Maria/T-5917-2018; Straub, Tobias/B-2023-2009
OI Spletter, Maria/0000-0002-2068-3350; Straub, Tobias/0000-0002-0547-0453;
   Nikonova, Elena/0009-0003-2153-8790
FU Deutsche Forschungsgemeinschaft [417912216]; Center for Integrated
   Protein Science Munich (CIPSM; Maximilians-Universitaet Muenchen (MLS;
   International Max Planck Research School (EN)
FX Funding This research was funded by the Deutsche Forschungsgemeinschaft
   (MLS, 417912216), the Center for Integrated Protein Science Munich
   (CIPSM) at the Ludwig-Maximilians-Universitaet Muenchen (MLS), the
   Deutsche Gesellschaft fuer Muskelkranke e.V. (MLS), and the
   International Max Planck Research School (EN).
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NR 135
TC 7
Z9 7
U1 0
U2 8
PU MDPI
PI BASEL
PA ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND
EI 2073-4409
J9 CELLS-BASEL
JI Cells
PD OCT
PY 2021
VL 10
IS 10
AR 2505
DI 10.3390/cells10102505
PG 31
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA WV3BA
UT WOS:000717110400001
PM 34685485
OA Green Published, gold
DA 2025-04-10
ER

PT J
AU Brand, K
   Dugi, KA
   Brunzell, JD
   Nevin, DN
   SantamarinaFojo, S
AF Brand, K
   Dugi, KA
   Brunzell, JD
   Nevin, DN
   SantamarinaFojo, S
TI A novel A->G mutation in intron I of the hepatic lipase gene leads to
   alternative splicing resulting in enzyme deficiency
SO JOURNAL OF LIPID RESEARCH
LA English
DT Article
DE expression studies; hepatic lipase deficiency; premature
   atherosclerosis; splicing defect
ID HUMAN LIPOPROTEIN-LIPASE; HIGH-DENSITY LIPOPROTEIN; MESSENGER-RNA;
   TRIGLYCERIDE LIPASE; PLASMA-LIPOPROTEINS; ENDOTHELIAL LIPASE; BASE
   SUBSTITUTION; APOLIPOPROTEIN-B; CDNA SEQUENCE; GLOBIN GENE
AB We have identified the underlying molecular defect in a patient with hepatic lipase (HL) deficiency presenting with hypertriglyceridemia and premature cardiovascular disease. DNA sequencing of polymerase chain reaction (PCR) amplified DNA and digestion with BsrI established homozygosity for an A --> G mutation in intron I of the patient's hepatic lipase gene. This mutation introduces an additional AG motif within a potential branch lariat signal located 13 bp upstream of the native 3' splice site. Two minigene constructs (normal and mutant) consisting of exons 1 and 2 as well as 192 bp of intron I of HL were generated by the overlap PCR extension method and transfected in human 293 cells, Sequence analysis of reverse transcribed, amplified cDNA generated from total RNA isolated from transfected cells demonstrated the presence of abnormally spliced products containing 13 and 78 additional bases as well as the accumulation of unspliced mRNA. No normally spliced mRNA was identified. Thus, the A --> G mutation disrupts normal splicing of intron I and generates a new AG site that is utilized as an alternative 3' splice signal leading to the most prominent RT-PCR product in vitro. Translation of these alternatively spliced products leads to premature termination resulting in the synthesis of a truncated, non-functional enzyme. The absence of normal HL protein in post heparin plasma of this patient was confirmed by Western blotting. DNA restriction analysis demonstrated that all four of the proband's children, who exhibit HL activity levels between those of the HL-deficient father and the mother with normal HL activity, are heterozygotes for the splice site mutation. Thus, our studies establish the functional significance of a novel mutation in the HL gene of a patient presenting with HL deficiency.
C1 NHLBI, MOLEC DIS BRANCH, NIH, BETHESDA, MD 20892 USA.
   UNIV WASHINGTON, DEPT MED, DIV METAB ENDOCRINOL & NUTR, SEATTLE, WA 98195 USA.
C3 National Institutes of Health (NIH) - USA; NIH National Heart Lung &
   Blood Institute (NHLBI); University of Washington; University of
   Washington Seattle
FU NCRR NIH HHS [RR37] Funding Source: Medline; NIDDK NIH HHS [DK 02456]
   Funding Source: Medline
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NR 57
TC 49
Z9 50
U1 0
U2 0
PU LIPID RESEARCH INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998
SN 0022-2275
J9 J LIPID RES
JI J. Lipid Res.
PD JUN
PY 1996
VL 37
IS 6
BP 1213
EP 1223
PG 11
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA UU476
UT WOS:A1996UU47600006
PM 8808756
DA 2025-04-10
ER

PT J
AU Donner, K
   Nowak, KJ
   Aro, M
   Pelin, K
   Wallgren-Pettersson, C
AF Donner, Kati
   Nowak, Kristen J.
   Aro, Mimmi
   Pelin, Katarina
   Wallgren-Pettersson, Carina
TI Developmental and muscle-type-specific expression of mouse nebulin exons
   127 and 128
SO GENOMICS
LA English
DT Article
DE nebulin; alternative splicing; transcripts; mouse muscle development
ID CONGENITAL NEMALINE MYOPATHY; SKELETAL-MUSCLE; STRIATED-MUSCLE;
   THIN-FILAMENTS; ACTIN GENE; MUTATIONS; IDENTIFICATION; SEQUENCE; MICE
AB The human nebutin gene includes 183 exons and four regions of alternative splicing. The mouse nebulin gene, with 166 exons, has a similar organization. Here we describe the expression patterns of one of the alternatively spliced regions of nebulin: exons 127 and 128 in the mouse gene, corresponding to human nebulin exons 143 and 144. Expression was elucidated by quantifying the differentially spliced transcripts in mice of different ages. In most of the muscles studied, transcripts expressing exon 127 were more prominent in muscles from younger mice, while older mice showed higher quantities of the transcript expressing exon 128. Some muscles, e.g., diaphragm and masseter, almost exclusively expressed only one of the two transcripts, whereas others, e.g., soleus and cardiac muscle, expressed equal quantities of both transcripts. The expression patterns did not correlate with fiber-type composition. We speculate that these exons harbor a regulatory function utilized during muscle maturation. (c) 2006 Elsevier Inc. All rights reserved.
C1 Univ Helsinki, Folkhalsan Inst Genet, Biomedicum Helsinki, FIN-00014 Helsinki, Finland.
   Univ Helsinki, Dept Med Genet, Biomedicum Helsinki, FIN-00014 Helsinki, Finland.
   Univ Western Australia, Med Res Ctr, Western Australian Inst Med Res, Nedlands, WA 6009, Australia.
   Univ Helsinki, Dept Biol & Environm Sci, Biomedicum Helsinki, FIN-00014 Helsinki, Finland.
C3 University of Helsinki; University of Helsinki; University of Western
   Australia; University of Helsinki
RP Donner, K (corresponding author), Univ Helsinki, Folkhalsan Inst Genet, Biomedicum Helsinki, FIN-00014 Helsinki, Finland.
EM kati.donner@helsinki.fi
RI Donner, Kati/HJI-0750-2023
OI Donner, Kati/0000-0001-9190-4336; Pelin, Katarina/0000-0002-7040-7266
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NR 29
TC 17
Z9 18
U1 0
U2 5
PU ACADEMIC PRESS INC ELSEVIER SCIENCE
PI SAN DIEGO
PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA
SN 0888-7543
J9 GENOMICS
JI Genomics
PD OCT
PY 2006
VL 88
IS 4
BP 489
EP 495
DI 10.1016/j.ygeno.2006.06.008
PG 7
WC Biotechnology & Applied Microbiology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Genetics & Heredity
GA 093WX
UT WOS:000241202100011
PM 16860535
DA 2025-04-10
ER

PT J
AU Bär, C
   Chatterjee, S
   Thum, T
AF Bar, Christian
   Chatterjee, Shambhabi
   Thum, Thomas
TI Long Noncoding RNAs in Cardiovascular Pathology, Diagnosis, and Therapy
SO CIRCULATION
LA English
DT Article
DE biomarkers; cardiovascular diseases; cardiovascular physiological
   phenomena; diagnosis; RNA, long noncoding; therapeutics
ID CIRCULAR RNA; CARDIAC-HYPERTROPHY; BIRTH-DEFECTS; HEART; IDENTIFICATION;
   TRANSCRIPTION; GENE; MICRORNA; LANDSCAPE; ROLES
AB Vast parts of mammalian genomes encode for transcripts that are not further translated into proteins. The purpose of the majority of such noncoding ribonucleic acids (RNAs) remained paradoxical for a long time. However, a growing body of evidence demonstrates that long noncoding RNAs are dynamically expressed in different cell types, diseases, or developmental stages to execute a wide variety of regulatory roles at virtually every step of gene expression and translation. Indeed, long noncoding RNAs influence gene expression via epigenetic modulations, through regulating alternative splicing, or by acting as molecular sponges. The abundance of long noncoding RNAs in the cardiovascular system indicates that they may be part of a complex regulatory network governing physiology and pathology of the heart. In this review, we discuss the multifaceted functions of long noncoding RNAs and highlight the current literature with an emphasis on cardiac development and disease. Furthermore, as the enormous spectrum of long noncoding RNAs potentially opens up new avenues for diagnosis and prevention of heart failure, we ultimately evaluate the futuristic prospects of long noncoding RNAs as biomarkers, and therapeutic targets for the treatment of cardiovascular disorders, as well.
C1 [Bar, Christian; Chatterjee, Shambhabi; Thum, Thomas] Hannover Med Sch, Inst Mol & Translat Therapeut Strategies, OE8886,Carl Neuberg Str 1, D-30625 Hannover, Germany.
C3 Hannover Medical School
RP Thum, T (corresponding author), Hannover Med Sch, Inst Mol & Translat Therapeut Strategies, OE8886,Carl Neuberg Str 1, D-30625 Hannover, Germany.
EM thum.thomas@mh-hannover.de
RI Thum, Thomas/ABD-3487-2022; Bär, Christian/AAC-5914-2019; Chatterjee,
   Shambhabi/AAX-9332-2021
OI Bar, Christian/0000-0001-9276-9383; Chatterjee,
   Shambhabi/0000-0001-5978-3562
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NR 111
TC 192
Z9 203
U1 1
U2 41
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA
SN 0009-7322
EI 1524-4539
J9 CIRCULATION
JI Circulation
PD NOV 8
PY 2016
VL 134
IS 19
BP 1484
EP 1499
DI 10.1161/CIRCULATIONAHA.116.023686
PG 16
WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology
GA EB4OB
UT WOS:000387350100014
PM 27821419
DA 2025-04-10
ER

PT J
AU Fouani, Y
   Kirchhof, L
   Stanicek, L
   Luxán, G
   Heumüller, AW
   Knau, A
   Fischer, A
   Devraj, K
   John, D
   Neumann, P
   Bindereif, A
   Boon, RA
   Liebner, S
   Wittig, I
   Mogler, C
   Karimova, M
   Dimmeler, S
   Jaé, N
AF Fouani, Youssef
   Kirchhof, Luisa
   Stanicek, Laura
   Luxan, Guillermo
   Heumueller, Andreas W.
   Knau, Andrea
   Fischer, Ariane
   Devraj, Kavi
   John, David
   Neumann, Philipp
   Bindereif, Albrecht
   Boon, Reinier A.
   Liebner, Stefan
   Wittig, Ilka
   Mogler, Carolin
   Karimova, Madina
   Dimmeler, Stefanie
   Jae, Nicolas
TI The splicing-regulatory lncRNA NTRAS sustains vascular integrity
SO EMBO REPORTS
LA English
DT Article
DE alternative splicing; long non-coding RNA; tight junctions; vascular
   integrity
ID MOLECULAR-MECHANISMS; TIGHT JUNCTIONS; HNRNP-L; PERMEABILITY
AB Vascular integrity is essential for organ homeostasis to prevent edema formation and infiltration of inflammatory cells. Long non-coding RNAs (lncRNAs) are important regulators of gene expression and often expressed in a cell type-specific manner. By screening for endothelial-enriched lncRNAs, we identified the undescribed lncRNA NTRAS to control endothelial cell functions. Silencing of NTRAS induces endothelial cell dysfunction in vitro and increases vascular permeability and lethality in mice. Biochemical analysis revealed that NTRAS, through its CA-dinucleotide repeat motif, sequesters the splicing regulator hnRNPL to control alternative splicing of tight junction protein 1 (TJP1; also named zona occludens 1, ZO-1) pre-mRNA. Deletion of the hnRNPL binding motif in mice (Ntras( increment CA/ increment CA)) significantly repressed TJP1 exon 20 usage, favoring expression of the TJP1 alpha- isoform, which augments permeability of the endothelial monolayer. Ntras( increment CA/ increment CA) mice further showed reduced retinal vessel growth and increased vascular permeability and myocarditis. In summary, this study demonstrates that NTRAS is an essential gatekeeper of vascular integrity.
C1 [Fouani, Youssef; Kirchhof, Luisa; Stanicek, Laura; Luxan, Guillermo; Heumueller, Andreas W.; Knau, Andrea; Fischer, Ariane; John, David; Neumann, Philipp; Boon, Reinier A.; Dimmeler, Stefanie; Jae, Nicolas] Goethe Univ, Ctr Mol Med, Inst Cardiovasc Regenerat, Frankfurt, Germany.
   [Fouani, Youssef; Kirchhof, Luisa; Heumueller, Andreas W.] Goethe Univ, Fac Biol Sci, Frankfurt, Germany.
   [Fouani, Youssef; Kirchhof, Luisa; Luxan, Guillermo; Heumueller, Andreas W.; Boon, Reinier A.; Dimmeler, Stefanie; Jae, Nicolas] German Ctr Cardiovasc Res DZHK, Frankfurt, Germany.
   [Stanicek, Laura; Boon, Reinier A.] Vrije Univ Amsterdam Med Ctr, Dept Physiol, Amsterdam Cardiovasc Sci, Amsterdam, Netherlands.
   [Devraj, Kavi; Liebner, Stefan] Goethe Univ, Univ Hosp, Inst Neurol Edinger Inst, Frankfurt, Germany.
   [Bindereif, Albrecht] Univ Giessen, Inst Biochem, Giessen, Germany.
   [Wittig, Ilka] Goethe Univ, Inst Cardiovasc Physiol, Funct Prote, Frankfurt, Germany.
   [Mogler, Carolin] Tech Univ Munich, Inst Pathol, Munich, Germany.
   [Karimova, Madina] Georg Speyer Haus, Inst Tumor Biol & Expt Therapy, Frankfurt, Germany.
C3 Goethe University Frankfurt; Goethe University Frankfurt; German Centre
   for Cardiovascular Research; Vrije Universiteit Amsterdam; VU UNIVERSITY
   MEDICAL CENTER; Goethe University Frankfurt; Goethe University Frankfurt
   Hospital; Justus Liebig University Giessen; Goethe University Frankfurt;
   Technical University of Munich; Octapharma
RP Jaé, N (corresponding author), Goethe Univ, Ctr Mol Med, Inst Cardiovasc Regenerat, Frankfurt, Germany.; Jaé, N (corresponding author), German Ctr Cardiovasc Res DZHK, Frankfurt, Germany.
EM jae@med.uni-frankfurt.de
RI Dimmeler, Stefanie/D-3108-2011; Liebner, Stefan/JQJ-2908-2023; Boon,
   Reinier/E-8423-2011; Mogler, Carolin/HZM-1973-2023; Devraj,
   Kavi/I-4701-2019
OI Devraj, Kavi/0000-0002-5005-3413; Luxan, Guillermo/0000-0001-8350-8659;
   Boon, Reinier/0000-0001-7944-9748; Kirchhof, Luisa/0000-0002-4613-1511
FU ERC (Advanced Grant Angiolnc); DFG [TRR 267, SFB1366, FOR2325,
   390649896, BtRAIN 675619]; DZHK [81X2200133]; State of Hesse
FX We thank Aditi Patel for assistance in generating the NtrasDCA/DCA mice,
   Silke Schreiner for support with the in vitro splicing assays, Marion
   Muhly-Reinholz for help with microscopy, and Jana Meisterknecht for
   assistance in sample preparation for mass spectrometry. This study was
   supported by the ERC (Advanced Grant Angiolnc to S.D.), the DFG (TRR 267
   to S.D., N.J., and I.W.; SFB1366 to C.M. and S.D.; FOR2325 to S.L.), the
   CPI (390649896 to S.L), the EU HORIZON 2020 ITN (BtRAIN 675619 to S.L.),
   the DZHK (81X2200133 to S.L.), and the State of Hesse with a LOEWE-Grant
   to the CePTER-Consortium (www.unifrankfurt.de/67689811; to S.L.). Open
   Access funding enabled and organized by Projekt DEAL.
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NR 37
TC 3
Z9 4
U1 0
U2 2
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1469-221X
EI 1469-3178
J9 EMBO REP
JI EMBO Rep.
PD JUN 7
PY 2022
VL 23
IS 6
AR e54157
DI 10.15252/embr.202154157
EA MAY 2022
PG 13
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 1W4WX
UT WOS:000792101100001
PM 35527520
OA Green Published, hybrid
DA 2025-04-10
ER

PT J
AU More, DA
   Kumar, A
AF More, Dhanashree Anil
   Kumar, Arun
TI SRSF3: Newly discovered functions and roles in human health and diseases
SO EUROPEAN JOURNAL OF CELL BIOLOGY
LA English
DT Review
DE Splicing factors; SR proteins; SRSF; SRSF3; Cancer; Disease
ID RICH SPLICING FACTOR-3; MESSENGER-RNA; SR PROTEINS; ALTERNATIVE
   POLYADENYLATION; TRANSCRIPTION TERMINATION; INCREASED EXPRESSION;
   DOWN-REGULATION; OVARIAN-CANCER; RS DOMAIN; SRP20
AB The serine/arginine rich proteins (SR proteins) are members of a family of RNA binding proteins involved in regulating various features of RNA metabolism, including pre-mRNA constitutive and alternative splicing. In humans, a total of 12 SR splicing factors (SRSFs) namely SRSF1-SRSF12 have been reported. SRSF3, the smallest member of the SR family and the focus of this review, regulates critical steps in mRNA metabolism and has been shown to have mRNA-independent functions as well. Recent studies on SRSF3 have uncovered its role in a wide array of complex biological processes. We have also reviewed the involvement of SRSF3 in disease conditions like cancer, ageing, neurological and cardiac disorders. Finally, we have discussed in detail the autoregulation of SRSF3 and its implications in cancer and commented on the potential of SRSF3 as a therapeutic target, especially in the context of cancer.
C1 [More, Dhanashree Anil; Kumar, Arun] Indian Inst Sci, Dept Mol Reprod Dev & Genet, Bangalore 560012, Karnataka, India.
C3 Indian Institute of Science (IISC) - Bangalore
RP Kumar, A (corresponding author), Indian Inst Sci, Dept Mol Reprod Dev & Genet, Bangalore 560012, Karnataka, India.
EM arunk@iisc.ac.in
FU DBT [BT/PR10272/BRB/10/1266/2013, BT/PR8670/AGR/36/757/2013]; DST-FIST
   [SR/FST/LS11-036/2014(C)]; UGC-SAP [F.4.13/2018/DRSIII (SAP-II)];
   DBT-IISc Partnership Program Phase-II [BT/PR27952INF/22/212/2018]
FX Financially support in AK laboratory from DBT
   (Grant#BT/PR10272/BRB/10/1266/2013 and BT/PR8670/AGR/36/757/2013),
   DST-FIST [SR/FST/LS11-036/2014(C)], UGC-SAP [F.4.13/2018/DRSIII
   (SAP-II)] and DBT-IISc Partnership Program Phase-II
   (BT/PR27952INF/22/212/2018) is gratefully acknowledged.
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NR 102
TC 28
Z9 29
U1 0
U2 13
PU ELSEVIER GMBH
PI MUNICH
PA HACKERBRUCKE 6, 80335 MUNICH, GERMANY
SN 0171-9335
EI 1618-1298
J9 EUR J CELL BIOL
JI Eur. J. Cell Biol.
PD AUG
PY 2020
VL 99
IS 6
AR 151099
DI 10.1016/j.ejcb.2020.151099
PG 9
WC Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cell Biology
GA NB7CG
UT WOS:000560670800004
PM 32800280
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Haenold, R
   Wassef, R
   Hansel, A
   Heinemann, SH
   Hoshi, T
AF Haenold, Ronny
   Wassef, Ramez
   Hansel, Alfred
   Heinemann, Stefan H.
   Hoshi, Toshinori
TI Identification of a new functional splice variant of the enzyme
   methionine sulphoxide reductase A (MSRA) expressed in rat vascular
   smooth muscle cells
SO FREE RADICAL RESEARCH
LA English
DT Article
DE oxidative stress; vasculature; MSRA; protein oxidation; alternative
   splicing
ID OXIDATIVE STRESS; LIFE-SPAN; PEPTIDE; APOPTOSIS; MITOCHONDRIAL;
   LOCALIZATION; RESISTANCE; OVEREXPRESSION; GENERATION; PROTECTION
AB Reactive oxygen species contribute to ageing of the vascular system and development of cardiovascular disease. Methionine-S-sulphoxide, an oxidized form of methionine, is repaired by the enzyme methionine sulphoxide reductase A (MSRA). The enzyme, targeted to mitochondria or the cytosol by alternative splicing, is vital for oxidative stress resistance. This study was designed to examine the endogenous expression and intracellular localization of MSRA in rat aortic vascular smooth muscle cells (VSMCs). We detected robust MSRA immunoreactivity exclusively in mitochondria. Sequence analysis of msrA transcripts revealed the presence of a novel mitochondrial splice variant, msrA2a, in cultured rat VSMCs as well as in aortic tissue preparations. The enzymatic activity of a recombinant MSRA2a protein was confirmed by the reduction of methionine sulphoxide in a model substrate peptide. We conclude that multiple MSRA variants participate in the repair of oxidized proteins in VSMC mitochondria, but that other protective mechanisms may exist in the cytoplasmic compartment.
C1 [Haenold, Ronny; Wassef, Ramez; Hoshi, Toshinori] Univ Penn, Dept Physiol, Philadelphia, PA 19104 USA.
   [Hansel, Alfred; Heinemann, Stefan H.] Univ Jena, Dept Biophys, Ctr Mol Biomed, D-07747 Jena, Germany.
C3 University of Pennsylvania; Friedrich Schiller University of Jena
RP Hoshi, T (corresponding author), Univ Penn, Dept Physiol, 3700 Hamilton Walk,Richards D100, Philadelphia, PA 19104 USA.
EM hoshi@hoshi.org
RI Haenold, Ronny/ABH-1579-2020
OI Heinemann, Stefan H./0000-0002-4144-0251
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NR 47
TC 8
Z9 9
U1 0
U2 0
PU TAYLOR & FRANCIS LTD
PI ABINGDON
PA 2-4 PARK SQUARE, MILTON PARK, ABINGDON OR14 4RN, OXON, ENGLAND
SN 1071-5762
EI 1029-2470
J9 FREE RADICAL RES
JI Free Radic. Res.
PD NOV
PY 2007
VL 41
IS 11
BP 1233
EP 1245
DI 10.1080/10715760701642096
PG 13
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 249SM
UT WOS:000252250000005
PM 17907003
DA 2025-04-10
ER

PT J
AU Chutkow, WA
   Makielski, JC
   Nelson, DJ
   Burant, CF
   Fan, Z
AF Chutkow, WA
   Makielski, JC
   Nelson, DJ
   Burant, CF
   Fan, Z
TI Alternative splicing of sur2 exon 17 regulates nucleotide
   sensitivity of the ATP-sensitive potassium channel
SO JOURNAL OF BIOLOGICAL CHEMISTRY
LA English
DT Article
ID TRANSMEMBRANE CONDUCTANCE REGULATOR; PIG VENTRICULAR MYOCYTES; HEART
   CELL-MEMBRANE; PANCREATIC B-CELLS; K+ CHANNEL; SULFONYLUREA RECEPTOR;
   SKELETAL-MUSCLE; SMOOTH-MUSCLE; FUNCTIONAL SIMILARITIES; DISTINCT
   FUNCTIONS
AB ATP-sensitive potassium channels (K-ATP) are implicated in a diverse array of physiological functions. Previous work has shown that alternative usage of exons 14, 39, and 40 of the muscle-specific K-ATP channel regulatory subunit,, sur2, occurs in tissue-specific patterns. Here, we show that exon 17 of the first nucleotide binding fold of sur2 is also alternatively spliced. RNase protection demonstrates that SUR2(Delta 17) predominates in skeletal muscle and gut and is also expressed in bladder, fat, heart, lung, liver, and kidney. Polymerase chain reaction and restriction digest analysis of sur2 cDNA demonstrate the existence of at least five sur2 splice variants as follows: SUR2(39), SUR2(40), SUR2(Delta 17/39), SUR2(Delta 17/40), and SUR2(Delta 14/39). Electrophysiological recordings of excised, inside-out patches from COS cells cotransfected with Kir6.2 and the sur2 variants demonstrated that exon 17 splicing alters KATP sensitivity to ATP block, by a;fold hom;approximate to 40 to approximate to 90 mu M for exon 17 and Delta 17, respectively. Single channel kinetic analysis of SUR2(39) and SUR2(Delta 17/39) demonstrated that both exhibited characteristic K-ATP kinetics but that SUR2(Delta 17/39) exhibited longer mean burst durations and shorter mean interburst dwell times. In sum, alternative splicing of sur2 enhances the observed diversity of K-ATP and may contribute to tissue-specific modulation of ATP sensitivity.
C1 Univ Chicago, Dept Med, Chicago, IL 60637 USA.
   Univ Chicago, Dept Pharmacol & Physiol Sci, Chicago, IL 60637 USA.
   Univ Wisconsin, Dept Med, Madison, WI 53792 USA.
C3 University of Chicago; University of Chicago; University of Wisconsin
   System; University of Wisconsin Madison
RP Burant, CF (corresponding author), Warner Lambert Parke Davis, Parke Davis Pharmaceut Res, 2800 Plymouth Rd, Ann Arbor, MI 48105 USA.
RI Burant, Charles/GPC-5690-2022
OI Burant, Charles/0000-0001-9189-5003
FU NHLBI NIH HHS [R01-HL57414, R29 HL58133-01] Funding Source: Medline;
   NIDDK NIH HHS [DK-K08-02170] Funding Source: Medline
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NR 54
TC 82
Z9 95
U1 0
U2 0
PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PI BETHESDA
PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
SN 0021-9258
J9 J BIOL CHEM
JI J. Biol. Chem.
PD MAY 7
PY 1999
VL 274
IS 19
BP 13656
EP 13665
DI 10.1074/jbc.274.19.13656
PG 10
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 194NL
UT WOS:000080200400100
PM 10224138
OA hybrid
DA 2025-04-10
ER

PT J
AU Salomonis, N
   Schlieve, CR
   Pereira, L
   Wahlquist, C
   Colas, A
   Zambon, AC
   Vranizan, K
   Spindler, MJ
   Pico, AR
   Cline, MS
   Clark, TA
   Williams, A
   Blume, JE
   Samal, E
   Mercola, M
   Merrill, BJ
   Conklin, BR
AF Salomonis, Nathan
   Schlieve, Christopher R.
   Pereira, Laura
   Wahlquist, Christine
   Colas, Alexandre
   Zambon, Alexander C.
   Vranizan, Karen
   Spindler, Matthew J.
   Pico, Alexander R.
   Cline, Melissa S.
   Clark, Tyson A.
   Williams, Alan
   Blume, John E.
   Samal, Eva
   Mercola, Mark
   Merrill, Bradley J.
   Conklin, Bruce R.
TI Alternative splicing regulates mouse embryonic stem cell pluripotency
   and differentiation
SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
   AMERICA
LA English
DT Article
DE AltAnalyze; microRNA; splice isoforms; Atp2a2; Tcf7l1
ID SELF-RENEWAL; TRANSCRIPTIONAL REPRESSION; BETA-CATENIN; PROTEIN 4.1R;
   HEART; TCF3; CARDIOMYOPATHY; MXI1-SR-ALPHA; MECHANISMS; CHECKPOINT
AB Two major goals of regenerative medicine are to reproducibly transform adult somatic cells into a pluripotent state and to control their differentiation into specific cell fates. Progress toward these goals would be greatly helped by obtaining a complete picture of the RNA isoforms produced by these cells due to alternative splicing (AS) and alternative promoter selection (APS). To investigate the roles of AS and APS, reciprocal exon-exon junctions were interrogated on a genome-wide scale in differentiating mouse embryonic stem (ES) cells with a prototype Affymetrix microarray. Using a recently released open-source software package named AltAnalyze, we identified 144 genes for 170 putative isoform variants, the majority (67%) of which were predicted to alter protein sequence and domain composition. Verified alternative exons were largely associated with pathways of Wnt signaling and cell-cycle control, and most were conserved between mouse and human. To examine the functional impact of AS, we characterized isoforms for two genes. As predicted by AltAnalyze, we found that alternative isoforms of the gene Serca2 were targeted by distinct microRNAs (miRNA-200b, miRNA-214), suggesting a critical role for AS in cardiac development. Analysis of the Wnt transcription factor Tcf3, using selective knockdown of an ES cell-enriched and characterized isoform, revealed several distinct targets for transcriptional repression (Stmn2, Ccnd2, Atf3, Klf4, Nodal, and Jun) as well as distinct differentiation outcomes in ES cells. The findings herein illustrate a critical role for AS in the specification of ES cells with differentiation, and highlight the utility of global functional analyses of AS.
C1 [Salomonis, Nathan; Schlieve, Christopher R.; Spindler, Matthew J.; Pico, Alexander R.; Samal, Eva; Conklin, Bruce R.] Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA.
   [Salomonis, Nathan; Spindler, Matthew J.; Conklin, Bruce R.] Univ Calif San Francisco, Pharmaceut Sci & Pharmacogenom Grad Program, San Francisco, CA 94143 USA.
   [Pereira, Laura; Merrill, Bradley J.] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA.
   [Wahlquist, Christine; Colas, Alexandre; Mercola, Mark] Sanford Burnham Inst Med Res, La Jolla, CA 92037 USA.
   [Zambon, Alexander C.] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA.
   [Vranizan, Karen] Univ Calif Berkeley, Funct Genom Lab, Berkeley, CA 94720 USA.
   [Cline, Melissa S.; Clark, Tyson A.; Williams, Alan; Blume, John E.] Affymetrix Inc, Santa Clara, CA 95051 USA.
   [Conklin, Bruce R.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA.
   [Conklin, Bruce R.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA.
C3 University of California System; University of California San Francisco;
   The J David Gladstone Institutes; University of California System;
   University of California San Francisco; University of Illinois System;
   University of Illinois Chicago; University of Illinois Chicago Hospital;
   Sanford Burnham Prebys Medical Discovery Institute; University of
   California System; University of California San Diego; University of
   California System; University of California Berkeley; Affymetrix;
   University of California System; University of California San Francisco;
   University of California System; University of California San Francisco
RP Salomonis, N (corresponding author), Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA.
EM nsalomonis@gladstone.ucsf.edu; bconklin@gladstone.ucsf.edu
RI Cline, Melissa/AER-3138-2022; Pico, Alexander/HCH-4305-2022; Schlieve,
   Christopher/I-6167-2019; Conklin, Bruce/E-4738-2019
OI Conklin, Bruce/0000-0003-1463-6061; Schlieve,
   Christopher/0000-0002-8355-4046; Clark, Tyson/0000-0002-7779-3227; Pico,
   Alexander/0000-0001-5706-2163; Blume, John/0000-0003-3026-953X
FU National Institutes of Health [GM080223, HG003053, HL66621, HL057181,
   HL092851, R01CA128571, R37HL059502, R33HL088266]; California Institute
   for Regenerative Medicine [RC1-000132-1]
FX We thank Gary Howard and Stephen Ordway, Drs. Chuck Sugnet, Jernej Ule,
   and Kathryn Ivey for data analysis advice, and Jo Dee Fish and Chris
   Barker from the Gladstone Histology and Genomic Cores. This work was
   supported by National Institutes of Health Grants GM080223, HG003053,
   HL66621 (to B. R. C. and N.S.), HL057181, HL092851 (to E. S.),
   R01CA128571 (to B.J.M.), R37HL059502, R33HL088266 and California
   Institute for Regenerative Medicine RC1-000132-1 (to M. M.).
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NR 49
TC 172
Z9 208
U1 1
U2 23
PU NATL ACAD SCIENCES
PI WASHINGTON
PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA
SN 0027-8424
J9 P NATL ACAD SCI USA
JI Proc. Natl. Acad. Sci. U. S. A.
PD JUN 8
PY 2010
VL 107
IS 23
BP 10514
EP 10519
DI 10.1073/pnas.0912260107
PG 6
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA 608AH
UT WOS:000278549300035
PM 20498046
OA Green Published
DA 2025-04-10
ER

PT J
AU Periasamy, M
   Kalyanasundaram, A
AF Periasamy, Muthu
   Kalyanasundaram, Anuradra
TI SERCA pump isoforms: Their role in calcium transport and disease
SO MUSCLE & NERVE
LA English
DT Review
DE calcium; endoplasmic reticulum; phospholamban; sarcolipin; sarcoplasmic
   reticulum; SERCA
ID SARCOPLASMIC-RETICULUM CA2+-ATPASE; TRANSIENT KINETIC ANALYSES; FAILING
   HUMAN MYOCARDIUM; MYOSIN HEAVY-CHAIN; SLOW-TWITCH MUSCLE; CA2+ ATPASE
   SERCA; THYROID-HORMONE; SKELETAL-MUSCLE; HEART-FAILURE; GENE-EXPRESSION
AB The sarcoendoplasmic reticulum (SR) calcium transport ATPase (SERCA) is a pump that transports calcium ions from the cytoplasm into the SR. It is present in both animal and plant cells, although knowledge of SERCA in the latter is scant. The pump shares the catalytic properties of ion-motive ATPases of the P-type family, but has distinctive regulation properties. The SERCA pump is encoded by a family of three genes, SERCA 1, 2, and 3, that are highly conserved but localized on different chromosomes. The SERCA isoform diversity is dramatically enhanced by alternative splicing of the transcripts, occurring mainly at the COOH-terminal. At present, more than 10 different SERCA isoforms have been detected at the protein level, These isoforms exhibit both tissue and developmental speck ficity, suggesting that they contribute to unique physiological properties of the tissue in which they are expressed. The function of the SERCA pump is modulated by the endogenous molecules phospholamban (PLB) and sarcolipin (SLN), expressed in cardiac and skeletal muscles. The mechanism of action of PLB on SERCA is well characterized, whereas that of SLN is only beginning to be understood. Because the SERCA pump plays a major role in muscle contraction, a number of investigations have focused on understanding its role in cardiac and skeletal muscle disease. These studies document that SERCA pump expression and activity are decreased in aging and in a variety of pathophysiological conditions including heart failure. Recently, SERCA pump gene transfer was shown to be effective in restoring contractile function in failing heart muscle, thus emphasizing its importance in muscle physiology and its potential use as a therapeutic agent.
C1 Ohio State Univ, Coll Med, Dept Physiol & Cell Biol, Columbus, OH 43210 USA.
C3 University System of Ohio; Ohio State University
RP Periasamy, M (corresponding author), Ohio State Univ, Coll Med, Dept Physiol & Cell Biol, 394 Hamilton Hall,1645 Neil Ave, Columbus, OH 43210 USA.
EM Periasamy.1@osu.edu
OI Periasamy, Muthu/0000-0001-8834-5975
FU NHLBI NIH HHS [R0-1 HL 64140] Funding Source: Medline
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NR 109
TC 416
Z9 536
U1 2
U2 77
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 0148-639X
EI 1097-4598
J9 MUSCLE NERVE
JI Muscle Nerve
PD APR
PY 2007
VL 35
IS 4
BP 430
EP 442
DI 10.1002/mus.20745
PG 13
WC Clinical Neurology; Neurosciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology
GA 152MJ
UT WOS:000245365800003
PM 17286271
DA 2025-04-10
ER

PT J
AU Yu, GS
   Lu, YC
   Gulick, T
AF Yu, GS
   Lu, YC
   Gulick, T
TI Expression of novel isoforms of carnitine palmitoyltransferase I (CPT-1)
   generated by alternative splicing of the CPT-Iβ gene
SO BIOCHEMICAL JOURNAL
LA English
DT Article
ID MALONYL-COA SENSITIVITY; RAT-LIVER; CHROMOSOMAL LOCALIZATION; SINGLE
   POLYPEPTIDE; CARDIAC MYOCYTES; ENZYME-SYSTEM; CDNA; HEART; CLONING;
   ACETYLTRANSFERASE
AB Carnitine palmitoyltransferase I (CPT-I) catalyses the rate-determining step in mitochondrial fatty acid beta-oxidation. The enzyme has two cognate structural genes that are preferentially expressed in liver (alpha) or fat and muscle (beta). We hypothesized the existence of additional isoforms in heart to account for unique kinetic characteristics of enzyme activity in this tissue. Hybridization and PCR screening of a human cardiac cDNA library revealed the expression of two novel CPT-I isoforms generated by alternative splicing of the CPT-I beta transcript, in addition to the beta and alpha cDNA species previously described. Ribonuclease protection and reverse transcriptase-mediated PCR assays confirmed the presence of mRNA species of each splicing variant in heart, skeletal muscle and liver, with differing relative concentrations in the tissues. The novel splicing variants omit exons or utilize a cryptic splice donor site within an exon. Deduced polypeptide sequences of the novel enzymes include omissions in the region of putative membrane-spanning and malonyl-CoA regulatory domains compared with the previously described CPT-Is, implying that the encoded enzymes will exhibit unique features with respect to outer mitochondrial membrane topology and response to physiological and pharmacological inhibitors.
C1 Massachusetts Gen Hosp, Diabet Unit, Charlestown, MA 02129 USA.
   Massachusetts Gen Hosp, Med Serv, Charlestown, MA 02129 USA.
   Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA.
C3 Harvard University; Harvard University Medical Affiliates; Massachusetts
   General Hospital; Harvard University; Harvard University Medical
   Affiliates; Massachusetts General Hospital; Harvard University; Harvard
   Medical School
RP Gulick, T (corresponding author), Massachusetts Gen Hosp, Diabet Unit, MGH E,CNY 149 3610,149 13th St, Charlestown, MA 02129 USA.
EM gulick@helix.mgh.harvard.edu
FU NIDDK NIH HHS [P30-DK40561, K02-DK02461] Funding Source: Medline
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NR 37
TC 26
Z9 26
U1 0
U2 1
PU PORTLAND PRESS
PI LONDON
PA 59 PORTLAND PLACE, LONDON, ENGLAND W1N 3AJ
SN 0264-6021
J9 BIOCHEM J
JI Biochem. J.
PD AUG 15
PY 1998
VL 334
BP 225
EP 231
DI 10.1042/bj3340225
PN 1
PG 7
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA 113NM
UT WOS:000075558200031
PM 9693124
OA Green Published
DA 2025-04-10
ER

PT J
AU Lipscombe, D
   Andrade, A
AF Lipscombe, Diane
   Andrade, Arturo
TI Calcium Channel CaVα1 Splice Isoforms - Tissue
   Specificity and Drug Action
SO CURRENT MOLECULAR PHARMACOLOGY
LA English
DT Article
DE Alternative splicing; Cacna1 genes; dihydropyridines; morphine; splicing
   factors; voltage-gated calcium channels; ziconotide
ID LAMINA-I PROJECTION; CA2+ CHANNEL; N-TYPE; DIHYDROPYRIDINE RECEPTOR;
   ALPHA(1C) SUBUNIT; DEPENDENT INHIBITION; FUNCTIONAL DIVERSITY;
   DNA-METHYLATION; OMEGA-CONOTOXIN; BINDING DOMAINS
AB Voltage-gated calcium ion channels are essential for numerous biological functions of excitable cells and there is wide spread appreciation of their importance as drug targets in the treatment of many disorders including those of cardiovascular and nervous systems. Each Cacna1 gene has the potential to generate a number of structurally, functionally, and in some cases pharmacologically unique Ca-V alpha 1 subunits through alternative pre-mRNA splicing and the use of alternate promoters. Analyses of rapidly emerging deep sequencing data for a range of human tissue transcriptomes contain information to quantify tissue-specific and alternative exon usage patterns for Cacna1 genes. Cell-specific actions of nuclear DNA and RNA binding proteins control the use of alternate promoters and the selection of alternate exons during pre-mRNA splicing, and they determine the spectrum of protein isoforms expressed within different types of cells. Amino acid compositions within discrete protein domains can differ substantially among Ca-V isoforms expressed in different tissues, and such differences may be greater than those that exist across CaV channel homologs of closely related species. Here we highlight examples of CaV isoforms that have unique expression patterns and that exhibit different pharmacological sensitivities. Knowledge of expression patterns of CaV isoforms in different human tissues, cell populations, ages, and disease states should inform strategies aimed at developing the next generation of CaV channel inhibitors and agonists with improved tissue-specificity.
C1 [Lipscombe, Diane; Andrade, Arturo] Brown Univ, Dept Neurosci, Providence, RI 02912 USA.
C3 Brown University
RP Lipscombe, D (corresponding author), Brown Univ, Dept Neurosci, Providence, RI 02912 USA.
EM Diane_Lipscombe@brown.edu
FU NIH [RO1NS055251, K99MH099405]
FX NIH grants RO1NS055251 (DL) and K99MH099405 (AA).
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NR 123
TC 30
Z9 36
U1 0
U2 6
PU BENTHAM SCIENCE PUBL LTD
PI SHARJAH
PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB
   EMIRATES
SN 1874-4672
EI 1874-4702
J9 CURR MOL PHARMACOL
JI Curr. Molec. Pharmacol.
PY 2015
VL 8
IS 1
BP 22
EP 31
DI 10.2174/1874467208666150507103215
PG 10
WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy
GA V1S0T
UT WOS:000217183400005
PM 25966698
OA Green Accepted
DA 2025-04-10
ER

PT J
AU Seno, MMG
   Gwadry, FG
   Hu, PZ
   Scherer, SW
AF Seno, Mohammad M. Ghahramani
   Gwadry, Fuad G.
   Hu, Pingzhao
   Scherer, Stephen W.
TI Neuregulin 1-alpha regulates phosphorylation, acetylation, and
   alternative splicing in lymphoblastoid cells
SO GENOME
LA English
DT Article
DE NRG1-alpha; transcriptome; phosphorylation; acetylation; alternative
   splicing; schizophrenia
ID SIGNALING PATHWAYS; APOLIPOPHORIN-III; GENE; SCHIZOPHRENIA; EXPRESSION;
   DYSREGULATION; INTRON; MIR-33; HDL
AB Neuregulins (NRGs) are signaling molecules involved in various cellular and developmental processes. Abnormal expression and (or) genomic variations of some of these molecules, such as NRG1, have been associated with disease conditions such as cancer and schizophrenia. To gain a comprehensive molecular insight into possible pathways/networks regulated by NRG1-alpha, we performed a global expression profiling analysis on lymphoblastoid cell lines exposed to NRG1-alpha. Our data show that this signaling molecule mainly regulates coordinated expression of genes involved in three processes: phosphorylation, acetylation, and alternative splicing. These processes have fundamental roles in proper development and function of various tissues including the central nervous system (CNS)-a fact that may explain conditions associated with NRG1 dysregulations such as schizophrenia. The data also suggest NRG1-alpha regulates genes (FBXO41) and miRNAs (miR-33) involved in cholesterol metabolism. Moreover, RPN2, a gene already shown to be dysregulated in breast cancer cells, is also differentially regulated by NRG1-alpha treatment.
C1 [Seno, Mohammad M. Ghahramani; Gwadry, Fuad G.; Hu, Pingzhao; Scherer, Stephen W.] Hosp Sick Children, Program Genet & Genome Biol, Ctr Appl Genom, Toronto, ON M5G 1L7, Canada.
   [Seno, Mohammad M. Ghahramani] Ferdowsi Univ Mashhad, Sch Vet Med, Dept Basic Sci, Mashhad, Iran.
   [Seno, Mohammad M. Ghahramani] Shiraz Univ, Sch Vet Med, Dept Pathobiol, Shiraz, Iran.
   [Scherer, Stephen W.] Univ Toronto, McLaughlin Ctr, Toronto, ON M5S 1A8, Canada.
   [Scherer, Stephen W.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.
C3 University of Toronto; Hospital for Sick Children (SickKids); Ferdowsi
   University Mashhad; Shiraz University; University of Toronto; University
   of Toronto
RP Seno, MMG (corresponding author), Hosp Sick Children, Program Genet & Genome Biol, Ctr Appl Genom, Toronto, ON M5G 1L7, Canada.
EM mgseno@yahoo.com
RI Scherer, Stephen/B-3785-2013
OI Scherer, Stephen W./0000-0002-8326-1999; Hu,
   Pingzhao/0000-0002-9546-2245; Ghahramani Seno, Mohammad
   M./0000-0001-7376-2004
FU Centre for Applied Genomics; NeuroDevNet; University of Toronto
   McLaughlin Centre, Genome Canada; Government of Ontario; Canadian
   Institutes of Health Research (CIHR); Hospital for Sick Children
   Foundation; Autism Speaks, USA
FX We appreciate the helpful advice we received from Yoshitatsu Sei (Blood
   Genomics Laboratory, GCAP, National Institute of Mental Health,
   Bethesda) on the use of NRG1 for LCLs treatment and acknowledge Sylvia
   Lamoureux for her technical assistance. We also appreciate the help of
   Janet Buchanan in editing the manuscript. This work was supported by The
   Centre for Applied Genomics, NeuroDevNet, the University of Toronto
   McLaughlin Centre, Genome Canada, the Government of Ontario, the
   Canadian Institutes of Health Research (CIHR), and The Hospital for Sick
   Children Foundation. M. M. G. S. was supported by a fellowship from
   Autism Speaks, USA. S. W. S. holds the GlaxoSmithKline-CIHR Chair in
   Genome Sciences at the University of Toronto and The Hospital for Sick
   Children.
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NR 53
TC 5
Z9 5
U1 0
U2 9
PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS
PI OTTAWA
PA 65 AURIGA DR, SUITE 203, OTTAWA, ON K2E 7W6, CANADA
SN 0831-2796
EI 1480-3321
J9 GENOME
JI Genome
PD OCT
PY 2013
VL 56
IS 10
SI SI
BP 619
EP 625
DI 10.1139/gen-2013-0068
PG 7
WC Biotechnology & Applied Microbiology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biotechnology & Applied Microbiology; Genetics & Heredity
GA 258EI
UT WOS:000327441600015
PM 24237343
DA 2025-04-10
ER

PT J
AU Charton, K
   Suel, L
   Henriques, SF
   Moussu, JP
   Bovolenta, M
   Taillepierre, M
   Becker, C
   Lipson, K
   Richard, I
AF Charton, Karine
   Suel, Laurence
   Henriques, Sara F.
   Moussu, Jean-Paul
   Bovolenta, Matteo
   Taillepierre, Miguel
   Becker, Celine
   Lipson, Karelia
   Richard, Isabelle
TI Exploiting the CRISPR/Cas9 system to study alternative splicing in
   vivo: application to titin
SO HUMAN MOLECULAR GENETICS
LA English
DT Article
ID MUSCLE-SPECIFIC CALPAIN; ZINC-FINGER TARGETER; ONE-STEP GENERATION;
   C-TERMINAL TITIN; SKELETAL-MUSCLE; MUSCULAR-DYSTROPHY; M-BAND;
   HUMAN-TRANSCRIPTOME; MYOTONIC-DYSTROPHY; FINE-STRUCTURE
AB The giant protein titin is the third most abundant protein in striated muscle. Mutations in its gene are responsible for diseases affecting the cardiac and/or the skeletal muscle. Titin has been reported to be expressed in multiple isoforms with considerable variability in the I-band, ensuring the modulation of the passive mechanical properties of the sarcomere. In the M-line, only the penultimate Mex5 exon coding for the specific is7 domain has been reported to be subjected to alternative splicing. Using the CRISPR-Cas9 editing technology, we generated a mouse model where we stably prevent the expression of alternative spliced variant(s) carrying the corresponding domain. Interestingly, the suppression of the domain induces a phenotype mostly in tissues usually expressing the isoform that has been suppressed, indicating that it fulfills (a) specific function(s) in these tissues allowing a perfect adaptation of the M-line to physiological demands of different muscles.
C1 [Charton, Karine; Suel, Laurence; Henriques, Sara F.; Richard, Isabelle] INSERM, INTEGRARE Res Unit Evry, U951, F-75654 Paris 13, France.
   [Charton, Karine; Suel, Laurence; Henriques, Sara F.; Richard, Isabelle] Genethon, 1 Bis Rue Int, F-91000 Evry, France.
   [Henriques, Sara F.] Univ Evry Val DEssone, Evry, France.
   [Moussu, Jean-Paul; Taillepierre, Miguel; Becker, Celine; Lipson, Karelia] CNRS, SEAT SErvice Animaux Transgen, TAAM Phenomin UPS44, Batiment G7,Rue Guy Moquet, F-94800 Villejuif, France.
   [Bovolenta, Matteo] Univ Ferrara, Dept Life Sci & Biotechnol, Ferrara, Italy.
C3 Institut National de la Sante et de la Recherche Medicale (Inserm);
   Universite Paris Saclay; Centre National de la Recherche Scientifique
   (CNRS); CNRS - National Institute for Biology (INSB); University of
   Ferrara
RP Richard, I (corresponding author), Genethon, 1 Bis Rue Int, F-91000 Evry, France.
EM richard@genethon.fr
RI charton, karine/AAU-4926-2021; Richard, isabelle/J-8298-2013
OI Bovolenta, Matteo/0000-0002-9937-009X
FU Association Francaise contre les Myopathies; Fondation Leducq
FX The study was supported by the Association Francaise contre les
   Myopathies and a grant from the Fondation Leducq.
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   Young C. S., 2016, CELL STEM C IN PRESS
NR 67
TC 18
Z9 19
U1 0
U2 7
PU OXFORD UNIV PRESS
PI OXFORD
PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND
SN 0964-6906
EI 1460-2083
J9 HUM MOL GENET
JI Hum. Mol. Genet.
PD OCT 15
PY 2016
VL 25
IS 20
BP 4518
EP 4532
DI 10.1093/hmg/ddw280
PG 15
WC Biochemistry & Molecular Biology; Genetics & Heredity
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Genetics & Heredity
GA EN1ZM
UT WOS:000395809100013
PM 28173117
OA Bronze
DA 2025-04-10
ER

PT J
AU Staudacher, K
   Baldea, I
   Kisselbach, J
   Staudacher, I
   Rahm, AK
   Schweizer, PA
   Becker, R
   Katus, HA
   Thomas, D
AF Staudacher, Kathrin
   Baldea, Ioana
   Kisselbach, Jana
   Staudacher, Ingo
   Rahm, Ann-Kathrin
   Schweizer, Patrick A.
   Becker, Ruediger
   Katus, Hugo A.
   Thomas, Dierk
TI Alternative splicing determines mRNA translation initiation and function
   of human K2P10.1 K<SUP>+</SUP> channels
SO JOURNAL OF PHYSIOLOGY-LONDON
LA English
DT Article
ID POTASSIUM LEAK; PROTEIN; MECHANISMS; EXPRESSION; TREK-2; BRAIN
AB Potassium-selective ion channels regulate cardiac and neuronal excitability by stabilizing the resting membrane potential and by modulating shape and frequency of action potentials. The delicate control of membrane voltage requires structural and functional diversity of K+ channel subunits expressed in a given cell. Here we reveal a previously unrecognized biological mechanism. Tissue-specific mRNA splicing regulates alternative translation initiation (ATI) of human K(2P)10.1 K+ background channels via recombination of 5' nucleotide motifs. ATI-dependent expression of full-length protein or truncated subunits initiated from two downstream start codons determines macroscopic current amplitudes and biophysical properties of hK(2P)10.1 channels. The interaction between hK(2P)10.1 mRNA splicing, translation and function increases K+ channel complexity and is expected to contribute to electrophysiological plasticity of excitable cells.
C1 [Staudacher, Kathrin; Baldea, Ioana; Kisselbach, Jana; Staudacher, Ingo; Rahm, Ann-Kathrin; Schweizer, Patrick A.; Becker, Ruediger; Katus, Hugo A.; Thomas, Dierk] Med Univ Hosp Heidelberg, Dept Cardiol, D-69120 Heidelberg, Germany.
C3 Ruprecht Karls University Heidelberg
RP Thomas, D (corresponding author), Med Univ Hosp Heidelberg, Dept Cardiol, Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
EM dthomas@ix.urz.uni-heidelberg.de
RI Thomas, Dierk/V-3940-2017; Rahm, Ann-Kathrin/AAC-7262-2021
FU German Research Foundation; ADUMED-Foundation; German Heart
   Foundation/German Foundation of Heart Research; Max Planck Society
FX We thank E. Ficker and B. Thomas for helpful suggestions and critical
   readings of the manuscript, and S. Bauer, R. Bloehs, J. Gutermann and B.
   Menrath for technical assistance. This work was supported by grants from
   the German Research Foundation (FRONTIERS programme to D. T.), the
   ADUMED-Foundation (to D. T.), the German Heart Foundation/German
   Foundation of Heart Research (to D. T.), and the Max Planck Society
   (TANDEM program to P.A.S.).
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NR 21
TC 33
Z9 34
U1 0
U2 1
PU WILEY-BLACKWELL
PI MALDEN
PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA
SN 0022-3751
J9 J PHYSIOL-LONDON
JI J. Physiol.-London
PD AUG 1
PY 2011
VL 589
IS 15
BP 3709
EP 3720
DI 10.1113/jphysiol.2011.210666
PG 12
WC Neurosciences; Physiology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Neurosciences & Neurology; Physiology
GA 798XT
UT WOS:000293246200006
PM 21669980
OA Green Published
DA 2025-04-10
ER

PT J
AU Nakagaki-Silva, EE
   Gooding, C
   Llorian, M
   Jacob, AG
   Richards, F
   Buckroyd, A
   Sinha, S
   Smith, CWJ
AF Nakagaki-Silva, Erick E.
   Gooding, Clare
   Llorian, Miriam
   Jacob, Aishwarya G.
   Richards, Frederick
   Buckroyd, Adrian
   Sinha, Sanjay
   Smith, Christopher W. J.
TI Identification of RBPMS as a mammalian smooth muscle master splicing
   regulator via proximity of its gene with super-enhancers
SO ELIFE
LA English
DT Article
ID RNA-BINDING PROTEIN; CELLS; RECOGNITION; EXPRESSION; MYOCARDIN; MOTIFS;
   DOMAIN; REPRESSION; INSIGHTS; DATABASE
AB Alternative splicing (AS) programs are primarily controlled by regulatory RNA-binding proteins (RBPs). It has been proposed that a small number of master splicing regulators might control cell-specific splicing networks and that these RBPs could be identified by proximity of their genes to transcriptional super-enhancers. Using this approach we identified RBPMS as a critical splicing regulator in differentiated vascular smooth muscle cells (SMCs). RBPMS is highly down-regulated during phenotypic switching of SMCs from a contractile to a motile and proliferative phenotype and is responsible for 20% of the AS changes during this transition. RBPMS directly regulates AS of numerous components of the actin cytoskeleton and focal adhesion machineries whose activity is critical for SMC function in both phenotypes. RBPMS also regulates splicing of other splicing, post-transcriptional and transcription regulators including the key SMC transcription factor Myocardin, thereby matching many of the criteria of a master regulator of AS in SMCs.
C1 [Nakagaki-Silva, Erick E.; Gooding, Clare; Llorian, Miriam; Jacob, Aishwarya G.; Richards, Frederick; Buckroyd, Adrian; Sinha, Sanjay; Smith, Christopher W. J.] Univ Cambridge, Dept Biochem, Cambridge, England.
   [Llorian, Miriam] Francis Crick Inst, London, England.
   [Jacob, Aishwarya G.; Sinha, Sanjay] Univ Cambridge, Cambridge Stem Cell Inst, Anne McLaren Lab, Cambridge, England.
C3 University of Cambridge; Francis Crick Institute; University of
   Cambridge
RP Smith, CWJ (corresponding author), Univ Cambridge, Dept Biochem, Cambridge, England.
EM cwjs1@cam.ac.uk
RI Sinha, Sanjay/AAF-1692-2021
OI Smith, Chris/0000-0002-2753-3398; Gooding, Clare/0000-0001-9656-4924;
   Richards, Frederick/0000-0003-3800-3162; Jacob, Aishwarya
   Griselda/0000-0002-0570-0829; NAKAGAKI SILVA, ERICK
   EIDY/0000-0002-6878-4409
FU British Heart Foundation [PG/16/28/32123, FS/11/85/29129,
   FS/18/46/33663]; Wellcome [092900/Z/10/Z, 209368/Z/17/Z]; Conselho
   Nacional de Desenvolvimento Cientifico e Tecnologico [206813/2014-7];
   Wellcome Trust [209368/Z/17/Z, 092900/Z/10/Z] Funding Source: Wellcome
   Trust
FX British Heart Foundation PG/16/28/32123 Sanjay Sinha Christopher WJ
   SmithBritish Heart Foundation FS/11/85/29129 Adrian Buckroyd Christopher
   WJ SmithBritish Heart Foundation FS/18/46/33663 Sanjay SinhaWellcome
   092900/Z/10/Z Christopher WJ SmithWellcome 209368/Z/17/Z Christopher WJ
   SmithConselho Nacional de Desenvolvimento Cientifico e Tecnologico
   206813/2014-7 Erick E Nakagaki-SilvaThe funders had no role in study
   design, data collection and interpretation, or the decision to submit
   the work for publication.
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NR 81
TC 27
Z9 31
U1 0
U2 4
PU ELIFE SCIENCES PUBLICATIONS LTD
PI CAMBRIDGE
PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND
SN 2050-084X
J9 ELIFE
JI eLife
PD JUL 8
PY 2019
VL 8
AR e46327
DI 10.7554/eLife.46327
PG 33
WC Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Life Sciences & Biomedicine - Other Topics
GA IH5KW
UT WOS:000474533900001
PM 31283468
OA gold, Green Submitted, Green Published
DA 2025-04-10
ER

PT J
AU Benoff, S
   Chu, CC
   Marmar, JL
   Sokol, RZ
   Goodwin, LO
   Hurley, IR
AF Benoff, Susan
   Chu, Charles C.
   Marmar, Joel L.
   Sokol, Rebecca Z.
   Goodwin, Leslie O.
   Hurley, Ian R.
TI Voltage-dependent calcium channels in mammalian spermatozoa revisited
SO FRONTIERS IN BIOSCIENCE-LANDMARK
LA English
DT Review
DE testis; sperm; calcium channels; Isoforms; alternative splicing;
   infertility; contraception; environmental exposure; toxic exposure;
   review
ID SPERM ACROSOME REACTION; MALE GERM-CELLS; VASCULAR SMOOTH-MUSCLE; RAT
   PHEOCHROMOCYTOMA CELLS; STATIONARY NIGHT BLINDNESS; ALPHA(1E) CA2+
   CHANNEL; GATED ION CHANNELS; PRE-MESSENGER-RNA; T-TYPE; MOUSE SPERM
AB The last few years have seen an explosion in the number of voltage- dependent ion channel sequences detected in sperm and testes. The complex structural paradigm of these channels is now known to include a pore- forming alpha(1) subunit( s) whose electrophysiological properties are modulated by an intracellular beta subunit, a disulfide- linked complex of a membrane- spanning delta subunit with an extracellular alpha(2) subunit, and a transmembrane gamma subunit. Many of these are alternatively spliced. Furthermore, the known number of genes coding each subtype has expanded significantly ( 10 alpha1, 4 beta, 4 alpha(2)delta, 8 gamma). Recently, the CatSper gene family has been characterized based on similarity to the voltage- dependent calcium channel alpha1 subunit. From among this multiplicity, a wide cross- section is active in sperm, including many splice variants. For example, expression of the various alpha1 subunits appears strictly localized in discrete domains of mature sperm, and seems to control distinct physiological roles such as cellular signaling pathways. These include alpha1 alternative splicing variants that are regulated by ions passed by channels in developing sperm. Various combinations of ion channel sequence variants have been studies in research models and in a variety of human diseases, including male infertility. For example, rats that are genetically resistant to testes damage by lead seem to respond to lead ions by increasing alpha1 alternative splicing. In contrast, in varicocele- associated male infertility, the outcome from surgical correction correlates with suppression of alpha1 alternative splicing, Ion channel blockers remain attractive model contraceptive drugs because of their ability to modulate cholesterol levels. However, the large number of sperm ion channel variants shared with other cell types make ion channels less attractive targets for male contraceptive development than a few years ago. In this review, the genetics, structure and function of voltage-dependent calcium channels and related CatSper molecules will be discussed, and several practical clinical applications associated with these channels will be reported.
C1 Feinstein Inst Med Res, Fertil Res Labs, Ctr Oncol & Cell Biol, N Shore Long Isl Jewish Hlth Syst, Manhasset, NY 11030 USA.
   N Shore Univ Hosp, Dept Obstet & Gynecol, Manhasset, NY 11030 USA.
   NYU, Sch Med, Dept Obstet & Gynecol, New York, NY USA.
   NYU, Sch Med, Dept Cell Biol, New York, NY USA.
   Feinstein Inst Med Res, Ctr Immunol & Inflammat, Lab Gene Activat, Manhasset, NY USA.
   N Shore Univ Hosp, Dept Med, Manhasset, NY 11030 USA.
   NYU, Sch Med, Dept Med, New York, NY USA.
   Long Isl Univ, Dept Biol Sci, Brookville, NY USA.
   Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Div Urol, Camden, NJ 08103 USA.
   Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA.
   Univ So Calif, Dept Med, Los Angeles, CA 90089 USA.
   Feinstein Inst Med Res, Core Res Facil, Manhasset, NY 11030 USA.
C3 Northwell Health; Northwell Health; North Shore University Hospital; New
   York University; New York University; Northwell Health; Northwell
   Health; North Shore University Hospital; New York University; Long
   Island University; Long Island University Post; Rutgers University
   System; Rutgers University New Brunswick; Rutgers University Biomedical
   & Health Sciences; University of Southern California; University of
   Southern California; Northwell Health
RP Benoff, S (corresponding author), Feinstein Inst Med Res, Fertil Res Labs, Ctr Oncol & Cell Biol, N Shore Long Isl Jewish Hlth Syst, 350 Community Dr,Room 125, Manhasset, NY 11030 USA.
EM sbenoff@nshs.edu
FU NIEHS NIH HHS [ES06100, ES10496] Funding Source: Medline
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NR 303
TC 15
Z9 19
U1 0
U2 11
PU FRONTIERS IN BIOSCIENCE INC
PI IRVINE
PA 16471 SCIENTIFIC WAY, IRVINE, CA 92618 USA
SN 1093-9946
EI 1093-4715
J9 FRONT BIOSCI-LANDMRK
JI Front. Biosci.
PD JAN 1
PY 2007
VL 12
BP 1420
EP 1449
DI 10.2741/2158
PG 30
WC Biochemistry & Molecular Biology; Cell Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology; Cell Biology
GA 129QS
UT WOS:000243745000115
PM 17127392
OA Bronze
DA 2025-04-10
ER

PT J
AU van der Veer, EP
   de Bruin, RG
   Kraaijeveld, AO
   de Vries, MR
   Bot, I
   Pera, T
   Segers, FM
   Trompet, S
   van Gils, JM
   Roeten, MK
   Beckers, CM
   van Santbrink, PJ
   Janssen, A
   van Solingen, C
   Swildens, J
   de Boer, HC
   Peters, EA
   Bijkerk, R
   Rousch, M
   Doop, M
   Kuiper, J
   Schalij, MJ
   van der Wal, AC
   Richard, S
   van Berkel, TJC
   Pickering, JG
   Hiemstra, PS
   Goumans, MJ
   Rabelink, TJ
   de Vries, AAF
   Quax, PHA
   Jukema, JW
   Biessen, EAL
   van Zonneveld, AJ
AF van der Veer, Eric P.
   de Bruin, Ruben G.
   Kraaijeveld, Adriaan O.
   de Vries, Margreet R.
   Bot, Ilze
   Pera, Tonio
   Segers, Filip M.
   Trompet, Stella
   van Gils, Janine M.
   Roeten, Marko K.
   Beckers, Cora M.
   van Santbrink, Peter J.
   Janssen, Anique
   van Solingen, Coen
   Swildens, Jim
   de Boer, Hetty C.
   Peters, Erna A.
   Bijkerk, Roel
   Rousch, Mat
   Doop, Merijn
   Kuiper, Johan
   Schalij, Martin Jan
   van der Wal, Allard C.
   Richard, Stephane
   van Berkel, Theo J. C.
   Pickering, J. Geoffrey
   Hiemstra, Pieter S.
   Goumans, Marie Jose
   Rabelink, Ton J.
   de Vries, Antoine A. F.
   Quax, Paul H. A.
   Jukema, J. Wouter
   Biessen, Erik A. L.
   van Zonneveld, Anton Jan
TI Quaking, an RNA-Binding Protein, Is a Critical Regulator of Vascular
   Smooth Muscle Cell Phenotype
SO CIRCULATION RESEARCH
LA English
DT Article
DE alternative splicing; differentiation; myocardin; Qk; restenosis;
   RNA-binding protein Quaking; vascular injury; vascular smooth muscle
   cells
ID SERUM RESPONSE FACTOR; NEOINTIMAL HYPERPLASIA; GENE-EXPRESSION;
   TRANSGENIC MICE; PAR-CLIP; MYOCARDIN; ATHEROSCLEROSIS; DIFFERENTIATION;
   PROLIFERATION; DISEASE
AB Rationale: RNA-binding proteins are critical post-transcriptional regulators of RNA and can influence pre-mRNA splicing, RNA localization, and stability. The RNA-binding protein Quaking (QKI) is essential for embryonic blood vessel development. However, the role of QKI in the adult vasculature, and in particular in vascular smooth muscle cells (VSMCs), is currently unknown.
   Objective: We sought to determine the role of QKI in regulating adult VSMC function and plasticity.
   Methods and Results: We identified that QKI is highly expressed by neointimal VSMCs of human coronary restenotic lesions, but not in healthy vessels. In a mouse model of vascular injury, we observed reduced neointima hyperplasia in Quaking viable mice, which have decreased QKI expression. Concordantly, abrogation of QKI attenuated fibroproliferative properties of VSMCs, while potently inducing contractile apparatus protein expression, rendering noncontractile VSMCs with the capacity to contract. We identified that QKI localizes to the spliceosome, where it interacts with the myocardin pre-mRNA and regulates the splicing of alternative exon 2a. This post-transcriptional event impacts the Myocd_v3/Myocd_v1 mRNA balance and can be modulated by mutating the quaking response element in exon 2a of myocardin. Furthermore, we identified that arterial damage triggers myocardin alternative splicing and is tightly coupled with changes in the expression levels of distinct QKI isoforms.
   Conclusions: We propose that QKI is a central regulator of VSMC phenotypic plasticity and that intervention in QKI activity can ameliorate pathogenic, fibroproliferative responses to vascular injury.
C1 [van der Veer, Eric P.; de Bruin, Ruben G.; de Vries, Margreet R.; Trompet, Stella; van Gils, Janine M.; Roeten, Marko K.; Beckers, Cora M.; van Solingen, Coen; de Boer, Hetty C.; Peters, Erna A.; Bijkerk, Roel; Rabelink, Ton J.; Quax, Paul H. A.; Jukema, J. Wouter; van Zonneveld, Anton Jan] Leiden Univ, Med Ctr, Einthoven Lab Expt Vasc Med, NL-2333 ZA Leiden, Netherlands.
   [van der Veer, Eric P.; de Bruin, Ruben G.; van Gils, Janine M.; Roeten, Marko K.; van Solingen, Coen; de Boer, Hetty C.; Bijkerk, Roel; Rabelink, Ton J.; van Zonneveld, Anton Jan] Leiden Univ, Med Ctr, Dept Nephrol, NL-2333 ZA Leiden, Netherlands.
   [Kraaijeveld, Adriaan O.; Trompet, Stella; Swildens, Jim; Schalij, Martin Jan; de Vries, Antoine A. F.; Jukema, J. Wouter] Leiden Univ, Med Ctr, Dept Cardiol, NL-2333 ZA Leiden, Netherlands.
   [de Vries, Margreet R.; Bot, Ilze; Peters, Erna A.; Quax, Paul H. A.] Leiden Univ, Med Ctr, Dept Surg, NL-2333 ZA Leiden, Netherlands.
   [Pera, Tonio; Hiemstra, Pieter S.] Leiden Univ, Med Ctr, Dept Pulmonol, NL-2333 ZA Leiden, Netherlands.
   [Goumans, Marie Jose] Leiden Univ, Med Ctr, Dept Mol & Cellular Biol, NL-2333 ZA Leiden, Netherlands.
   [Bot, Ilze; Segers, Filip M.; van Santbrink, Peter J.; Doop, Merijn; Kuiper, Johan; van Berkel, Theo J. C.; Biessen, Erik A. L.] Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Biopharmaceut, NL-2333 ZA Leiden, Netherlands.
   [van der Wal, Allard C.] Univ Amsterdam, Acad Med Ctr, Dept Pathol, NL-1105 AZ Amsterdam, Netherlands.
   [Richard, Stephane] McGill Univ, Lady Davis Inst Med Res, Dept Oncol & Med, Montreal, PQ, Canada.
   [Pickering, J. Geoffrey] Univ Western Ontario, Robarts Res Inst, Dept Med Biochem & Med Biophys, London, ON, Canada.
   [Jukema, J. Wouter] Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands.
   [Segers, Filip M.; Beckers, Cora M.; Janssen, Anique; Rousch, Mat; Biessen, Erik A. L.] Acad Univ Hosp Maastricht, Cardiovasc Res Inst Maastricht, Dept Pathol, Maastricht, Netherlands.
C3 Leiden University - Excl LUMC; Leiden University; Leiden University
   Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University;
   Leiden University Medical Center (LUMC); Leiden University; Leiden
   University Medical Center (LUMC); Leiden University - Excl LUMC; Leiden
   University; Leiden University Medical Center (LUMC); Leiden University -
   Excl LUMC; Leiden University - Excl LUMC; Leiden University; Leiden
   University Medical Center (LUMC); Leiden University; Leiden University
   Medical Center (LUMC); Leiden University - Excl LUMC; Leiden University
   - Excl LUMC; Leiden University; Vrije Universiteit Amsterdam; University
   of Amsterdam; Academic Medical Center Amsterdam; Lady Davis Institute;
   McGill University; Western University (University of Western Ontario);
   University Western Ontario Hospital; Maastricht University; Maastricht
   University Medical Centre (MUMC)
RP van der Veer, EP (corresponding author), Leiden Univ, Med Ctr, Dept Nephrol, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands.
EM e.p.van_der_veer@lumc.nl
RI Trompet, Stella/JZS-9375-2024; De Vries, Margreet/Z-5653-2019; Van
   Berkel, Theo/ABD-7677-2021; RICHARD, Stéphane/O-1005-2017; Goumans,
   Marie/U-1455-2019; van der Zande, Patrick/GPT-3511-2022; Bijkerk,
   Roel/AAC-6977-2020; Quax, Paul/W-8520-2019; de Vries,
   Antoine/ABG-5787-2021; Rabelink, Ton/A-5316-2008; Hiemstra,
   Pieter/K-8587-2018; Jukema, J. Wouter/ABD-6503-2021; van Zonneveld,
   Anton Jan/D-8060-2018; Pickering, J. Geoffrey/G-3341-2011
OI Rabelink, Ton/0000-0001-6780-5186; de Vries,
   Margreet/0000-0002-3648-9130; Biessen, Erik/0000-0002-6454-8548;
   Hiemstra, Pieter/0000-0002-0238-5982; Jukema, J.
   Wouter/0000-0002-3246-8359; Quax, Paul/0000-0002-6853-5760; Swildens,
   Jim/0000-0001-7793-8580; Trompet, Stella/0000-0001-5006-0528; van
   Solingen, Coen/0000-0002-5817-2003; van Zonneveld, Anton
   Jan/0000-0002-1676-7738; Pickering, J. Geoffrey/0000-0001-6474-3274;
   Bot, Ilze/0000-0002-1242-1959; van der Wal, Allard/0000-0001-5590-3758;
   van Gils, Janine/0000-0003-2429-7462; Goumans, Marie
   Jose/0000-0001-9344-6746
FU Netherlands Heart Foundation [M93.001, 2001-D0-32, 2003T201];
   Netherlands Institute of Regenerative Medicine; Dutch Kidney Foundation
   [NSN C 09.2329]; European Community [LSHM-CT-2003-503254]
FX This work was supported by the Netherlands Heart Foundation (grant
   M93.001 to A.O. Kraaijeveld and E.A.L. Biessen). J.W. Jukema and E.A.L.
   Biessen are (Clinical) Established Investigators of the Netherlands
   Heart Foundation (grants 2001-D0-32 and 2003T201, respectively). R.G. de
   Bruin and J.M. van Gils were supported by research grants from the
   Netherlands Institute of Regenerative Medicine and the Dutch Kidney
   Foundation (NSN C 09.2329), respectively. T.J.C. van Berkel and E.A.L.
   Biessen belong to the European Vascular Genomics Network
   (http://www.evgn.org), a Network of Excellence supported by the European
   Community's Sixth Framework Program for Research Priority 1 (Life
   Sciences, Genomics, and Biotechnology for Health; contract
   LSHM-CT-2003-503254).
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NR 44
TC 80
Z9 83
U1 0
U2 14
PU LIPPINCOTT WILLIAMS & WILKINS
PI PHILADELPHIA
PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA
SN 0009-7330
EI 1524-4571
J9 CIRC RES
JI Circ.Res.
PD OCT 12
PY 2013
VL 113
IS 9
BP 1065
EP 1075
DI 10.1161/CIRCRESAHA.113.301302
PG 11
WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular
   Disease
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Cardiovascular System & Cardiology; Hematology
GA 286QM
UT WOS:000329483800010
PM 23963726
OA Bronze
DA 2025-04-10
ER

PT J
AU Poore, CP
   Yang, JL
   Wei, SH
   Fhu, CK
   Bichler, Z
   Wang, JJ
   Soong, TW
   Liao, P
AF Poore, Charlene Priscilla
   Yang, Jialei
   Wei, Shunhui
   Fhu, Chee Kong
   Bichler, Zoe
   Wang, Juejin
   Soong, Tuck Wah
   Liao, Ping
TI Enhanced isradipine sensitivity in vascular smooth muscle cells due to
   hypoxia-induced Cav1.2 splicing and RbFox1/Fox2
   downregulation
SO FEBS JOURNAL
LA English
DT Article
DE alternative splicing; Ca(v)1.2; hypoxia; isradipine; RbFox
ID CALCIUM-CHANNEL; CA2+ CHANNEL; DEPENDENT INHIBITION; EXPRESSION;
   ARTERIES; ANTAGONIST; NIMODIPINE
AB Calcium influx via the L-type voltage-gated Ca(v)1.2 calcium channel in smooth muscle cells regulates vascular contraction. Calcium channel blockers (CCBs) are widely used to treat hypertension by inhibiting Ca(v)1.2 channels. Using the vascular smooth muscle cell line, A7r5 and primary culture of cerebral vascular smooth muscle cells, we found that the expression and function of Ca(v)1.2 channels are downregulated during hypoxia. Furthermore, hypoxia induces structural changes in Ca(v)1.2 channels via alternative splicing. The expression of exon 9* is upregulated, whereas exon 33 is downregulated. Such structural alterations of Ca(v)1.2 channels are caused by the decreased expression of RNA-binding proteins RNA-binding protein fox-1 homolog 1 and 2 (RbFox1 and RbFox2). Overexpression of RbFox1 and RbFox2 prevents hypoxia-induced exon 9* inclusion and exon 33 exclusion. Importantly, such structural alterations of the Ca(v)1.2 channel partly contribute to the enhanced sensitivity of Cav1.2 to isradipine (a CCB) under hypoxia. Overexpression of RbFox1 and RbFox2 successfully reduces isradipine sensitivity in hypoxic smooth muscle cells. Our results suggest a new strategy to manage ischemic diseases such as stroke and myocardial infarction.
C1 [Poore, Charlene Priscilla; Wei, Shunhui; Fhu, Chee Kong; Liao, Ping] Natl Neurosci Inst, Calcium Signaling Lab, Singapore 308433, Singapore.
   [Yang, Jialei] Guangxi Med Univ, Sch Publ Hlth, Nanning, Peoples R China.
   [Bichler, Zoe] Jackson Lab, Ctr Biometr Anal, Neurobehav Phenotyping Core, Bar Harbor, ME USA.
   [Wang, Juejin] Nanjing Med Univ, Dept Physiol, Nanjing, Peoples R China.
   [Soong, Tuck Wah] Natl Univ Singapore, Dept Physiol, Singapore, Singapore.
C3 National Neuroscience Institute (NNI); Guangxi Medical University;
   Jackson Laboratory; Nanjing Medical University; National University of
   Singapore
RP Liao, P (corresponding author), Natl Neurosci Inst, Calcium Signaling Lab, Singapore 308433, Singapore.
EM ping_liao@nni.com.sg
RI Juejin, Wang/JAX-4081-2023; Liao, Ping/ABF-7940-2021
OI Liao, Ping/0000-0002-6205-4042
FU National Medical Research Council [NMRC/CIRG/1469/2017,
   NMRC/OFIRG/0070/2018, MOH-000522-00]; Singapore Ministry of Health's
   National Medical Research Council
FX This work was supported by grants NMRC/CIRG/1469/2017,
   NMRC/OFIRG/0070/2018, and MOH-000522-00 from the Singapore Ministry of
   Health's National Medical Research Council.
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NR 49
TC 1
Z9 1
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U2 6
PU WILEY
PI HOBOKEN
PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA
SN 1742-464X
EI 1742-4658
J9 FEBS J
JI FEBS J.
PD OCT
PY 2024
VL 291
IS 19
BP 4265
EP 4285
DI 10.1111/febs.17159
EA MAY 2024
PG 21
WC Biochemistry & Molecular Biology
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Biochemistry & Molecular Biology
GA I1Z5C
UT WOS:001230686500001
PM 38794806
OA hybrid
DA 2025-04-10
ER

PT J
AU Li, JJ
   Jiang, HY
   Mu, YW
   Wei, ZX
   Ma, AKZ
   Sun, MH
   Zhao, JJ
   Zhu, CQ
   Chen, XH
AF Li, Junjie
   Jiang, Hanyang
   Mu, Yawei
   Wei, Zixuan
   Ma, Ankangzhi
   Sun, Menghan
   Zhao, Jingjing
   Zhu, Cuiqing
   Chen, Xianhua
TI SRSF10 regulates proliferation of neural progenitor cells and affects
   neurogenesis in developing mouse neocortex
SO ISCIENCE
LA English
DT Article
ID CEREBRAL-CORTEX; PROTEINS; NSSR1; NASP; DIFFERENTIATION; CHAPERONE;
   PROMOTES; BEHAVIOR; BINDING; SRP38
AB Alternative pre-mRNA splicing plays critical roles in brain development. SRSF10 is a splicing factor highly expressed in central nervous system and plays important roles in maintaining normal brain functions. However, its role in neural development is unclear. In this study, by conditional depleting SRSF10 in neural progenitor cells (NPCs) in vivo and in vitro, we found that dysfunction of SRSF10 leads to developmental defects of the brain, which manifest as abnormal ventricle enlargement and cortical thinning anatomically, as well as decreased NPCs proliferation and weakened cortical neurogenesis histologically. Furthermore, we proved that the function of SRSF10 on NPCs proliferation involved the regulation of PI3K-AKT-mTOR-CCND2 pathway and the alternative splicing of Nasp, a gene encoding isoforms of cell cycle regulators. These findings highlight the necessity of SRSF10 in the formation of a structurally and functionally normal brain.
C1 [Li, Junjie; Jiang, Hanyang; Mu, Yawei; Wei, Zixuan; Ma, Ankangzhi; Sun, Menghan; Zhu, Cuiqing; Chen, Xianhua] Fudan Univ, State Key Lab Med Neurobiol, Shanghai, Peoples R China.
   [Li, Junjie; Jiang, Hanyang; Mu, Yawei; Wei, Zixuan; Ma, Ankangzhi; Sun, Menghan; Zhu, Cuiqing; Chen, Xianhua] Fudan Univ, Inst Brain Sci, MOE Frontiers Ctr Brain Sci, Shanghai, Peoples R China.
   [Zhao, Jingjing] Nanjing Med Univ, Affiliated Wuxi Peoples Hosp, Ctr Clin Res, Wuxi 214023, Peoples R China.
C3 Fudan University; Fudan University; Nanjing Medical University
RP Chen, XH (corresponding author), Fudan Univ, State Key Lab Med Neurobiol, Shanghai, Peoples R China.
EM xhchen@fudan.edu.cn
RI Chen, Xianhua/HLW-2251-2023
OI Chen, Xianhua/0000-0002-6394-8726
FU National Natural Science Foundation of China [31771112, 31571037,
   81901259]; Natural Science Foundation of Shanghai [23ZR1412700];
   Shanghai Municipal Science and Technology Major Project [2018SHZDZX01];
   ZJ Lab; Shanghai Center for Brain Science and Brain -Inspired
   Technology; Top Talent Support Program for young and middle- aged people
   of Wuxi Health Committee [HB2020015]
FX We thank Dr. Y. Xie for providing constructive suggestions for this
   work. We thank Dr. J. Wang for critically reading the manuscript. This
   work was supported by the National Natural Science Foundation of China
   (grant numbers 31771112, 31571037, 81901259) , Natural Science
   Foundation of Shanghai (23ZR1412700) , Shanghai Municipal Science and
   Technology Major Project (No. 2018SHZDZX01) , ZJ Lab, Shanghai Center
   for Brain Science and Brain -Inspired Technology, and Top Talent Support
   Program for young and middle- aged people of Wuxi Health Committee
   (HB2020015) .
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NR 62
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J9 ISCIENCE
JI iScience
PD JUL 21
PY 2023
VL 26
IS 7
AR 107042
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EA JUN 2023
PG 27
WC Multidisciplinary Sciences
WE Science Citation Index Expanded (SCI-EXPANDED)
SC Science & Technology - Other Topics
GA Q8GC8
UT WOS:001059842000001
PM 37360696
OA Green Published, gold
DA 2025-04-10
ER

EF