title: Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of Diabetes.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Nutter
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Jaworski
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Verma
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Deshmukh
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Qiongling
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92037, USA.
authors.forename: Olga B
authors.initials: OB
authors.lastname: Botvinnik
authors.affiliation: Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Mario J
authors.initials: MJ
authors.lastname: Lozano
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Ismail J
authors.initials: IJ
authors.lastname: Abass
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Talha
authors.initials: T
authors.lastname: Ijaz
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Nisha J
authors.initials: NJ
authors.lastname: Garg
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine/Cardiology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Xander H T
authors.initials: XHT
authors.lastname: Wehrens
authors.affiliation: Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92037, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92037, USA.
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: nmmartin@utmb.edu.
authors.forename: Muge N
authors.initials: MN
authors.lastname: Kuyumcu-Martinez
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D001665:Binding Sites; D020013:Calcium Signaling; D002454:Cell Differentiation; D002460:Cell Line; D003599:Cytoskeleton / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000473:pathology; D042541:Intracellular Space / Q000378:metabolism; D016688:Mice, Inbred NOD; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000235:genetics / Q000473:pathology; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D000072260:RNA Splicing Factors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D020033:Protein Isoforms; C454924:RBFOX2 protein, human; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; C558929:Rbfox2 protein, mouse; D012097:Repressor Proteins; D012313:RNA