Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of Diabetes | Zendy

Curtis A. Nutter | Zendy; Elizabeth Jaworski | Zendy; Sunil K. Verma | Zendy; Vaibhav Deshmukh | Zendy; Qiongling Wang | Zendy; Olga Botvinnik | Zendy; M. Lozano | Zendy; Ismail Jamaa Abass | Zendy; Talha Ijaz | Zendy; Allan R. Brasier | Zendy; Nisha Garg | Zendy; Xander H.T. Wehrens | Zendy; G Yeo | Zendy; Muge N. KuyumcuMartinez | Zendy

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

Author(s) -

Curtis A. Nutter,

Elizabeth Jaworski,

Sunil K. Verma,

Vaibhav Deshmukh,

Qiongling Wang,

Olga Botvinnik,

M. Lozano,

Ismail Jamaa Abass,

Talha Ijaz,

Allan R. Brasier,

Nisha Garg,

Xander H.T. Wehrens,

G Yeo,

Muge N. KuyumcuMartinez

Publication year - 2016

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2016.05.002

Subject(s) - ectopic expression , diabetic cardiomyopathy , alternative splicing , downregulation and upregulation , medicine , endocrinology , transcriptome , biology , gene expression , hek 293 cells , microbiology and biotechnology , cardiomyopathy , gene isoform , gene , heart failure , genetics

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.

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