Dysregulation of RBFOX2 is an Early Event in Cardiac Pathogenesis of Diabetes

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dc.contributor.authorNutter, C. A.en_US
dc.contributor.authorJaworski, E. A.en_US
dc.contributor.authorVerma, S. K.en_US
dc.contributor.authorDeshmukh, V.en_US
dc.contributor.authorWang, Q.en_US
dc.contributor.authorBotvinnik, O. B.en_US
dc.contributor.authorLozano, Mario J.en_US
dc.contributor.authorAbass, I. J.en_US
dc.contributor.authorIjaz, T.en_US
dc.contributor.authorBrasier, A.en_US
dc.contributor.authorGarg, N.en_US
dc.contributor.authorWehrens, X.en_US
dc.contributor.authorYeo, G.en_US
dc.contributor.authorKuyumcu-Martinez, M.en_US
dc.contributor.utdAuthorLozano, Mario J.
dc.date.accessioned2018-05-15T22:20:35Z
dc.date.available2018-05-15T22:20:35Z
dc.date.created2016-06-07en_US
dc.descriptionIncludes supplementary materialen_US
dc.description.abstractAlternative 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. Nutter et al. show that the majority of transcripts mis-spliced in diabetic hearts have RBFOX2-binding sites. In diabetic hearts, a DN isoform of RBFOX2 with inhibitory splicing function is generated in response to high protein levels of WT RBFOX2. DN RBFOX2 upregulation occurs before cardiac complications manifest. © 2016 The Author(s).en_US
dc.description.sponsorshipAmerican Heart Association grants (15GRNT22830010, 13EIA14560061); NIH/National Institute of Allergy and Infectious Diseases grant (2RO1AI05478-08); NIH grants (UL1TR000071, HG0046590, NS075449, R01-HL089598, R01-HL091947, R01-HL117641, R41-HL129570); NIEHS P30 grant (ES006676); NIH/National Heart, Blood and Lung Institute grants (5R25HL09636305, NS075449);en_US
dc.identifier.bibliographicCitationNutter, C. A., E. A. Jaworski, S. K. Verma, V. Deshmukh, et al. 2016. "Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of Diabetes." Cell Reports 15(10), doi:10.1016/j.celrep.2016.05.002en_US
dc.identifier.issn2211-1247en_US
dc.identifier.issue10en_US
dc.identifier.urihttp://hdl.handle.net/10735.1/5745
dc.identifier.volume15en_US
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.relation.urihttp://dx.doi.org/10.1016/j.celrep.2016.05.002en_US
dc.rightsCC BY-NC-ND 4.0 (Attribution-NonCommercial-NoDerivatives)en_US
dc.rights©2016en_US
dc.sourceCell Reports
dc.subjectDiabetes Mellitusen_US
dc.subjectDiabetic Cardiomyopathiesen_US
dc.subjectRBFOX2 proteinen_US
dc.subjectRNA-Binding Proteinsen_US
dc.subjectHearten_US
dc.subjectGenesen_US
dc.subjectCalciumen_US
dc.subjectMice, Obeseen_US
dc.subjectHypertensionen_US
dc.subjectExonsen_US
dc.titleDysregulation of RBFOX2 is an Early Event in Cardiac Pathogenesis of Diabetesen_US
dc.type.genrearticleen_US

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