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

Curtis A. Nutter; Elizabeth A. Jaworski; Sunil K. Verma; Vaibhav Deshmukh; Qiongling Wang; Olga B. Botvinnik; Mario J. Lozano; Ismail J. Abass; Talha Ijaz; Allan R. Brasier; Nisha J. Garg; Xander H.T. Wehrens; Gene W. Yeo; Muge N. Kuyumcu-Martinez

doi:10.1016/j.celrep.2016.05.002

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

Curtis A. Nutter, Elizabeth A. Jaworski, Sunil K. Verma, Vaibhav Deshmukh, Qiongling Wang, Olga B. Botvinnik, Mario J. Lozano, Ismail J. Abass, Talha Ijaz, Allan R. Brasier, Nisha J. Garg, Xander H.T. Wehrens, Gene W. Yeo, Muge N. Kuyumcu-Martinez

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65 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2200-2213
Number of pages	14
Journal	Cell Reports
Volume	15
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2016.05.002
State	Published - Jun 7 2016

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Nutter, C. A., Jaworski, E. A., Verma, S. K., Deshmukh, V., Wang, Q., Botvinnik, O. B., Lozano, M. J., Abass, I. J., Ijaz, T., Brasier, A. R., Garg, N. J., Wehrens, X. H. T., Yeo, G. W., & Kuyumcu-Martinez, M. N. (2016). Dysregulation of RBFOX2 Is an Early Event in Cardiac Pathogenesis of Diabetes. Cell Reports, 15(10), 2200-2213. https://doi.org/10.1016/j.celrep.2016.05.002

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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.",

author = "Nutter, {Curtis A.} and Jaworski, {Elizabeth A.} and Verma, {Sunil K.} and Vaibhav Deshmukh and Qiongling Wang and Botvinnik, {Olga B.} and Lozano, {Mario J.} and Abass, {Ismail J.} and Talha Ijaz and Brasier, {Allan R.} and Garg, {Nisha J.} and Wehrens, {Xander H.T.} and Yeo, {Gene W.} and Kuyumcu-Martinez, {Muge N.}",

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AU - Nutter, Curtis A.

AU - Jaworski, Elizabeth A.

AU - Verma, Sunil K.

AU - Deshmukh, Vaibhav

AU - Wang, Qiongling

AU - Botvinnik, Olga B.

AU - Lozano, Mario J.

AU - Abass, Ismail J.

AU - Ijaz, Talha

AU - Brasier, Allan R.

AU - Garg, Nisha J.

AU - Wehrens, Xander H.T.

AU - Yeo, Gene W.

AU - Kuyumcu-Martinez, Muge N.

PY - 2016/6/7

Y1 - 2016/6/7

N2 - 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.

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.

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

Abstract

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