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Cell Rep. 2016 Jun 7;15(10):2200-2213. doi: 10.1016/j.celrep.2016.05.002. Epub 2016 May 26.

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

Author information

1
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
2
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
3
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.
4
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92037, USA.
5
Department of Biological Sciences, University of Texas at Dallas, Richardson, TX 75080, USA.
6
Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
7
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.
8
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.
9
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.
10
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.
11
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.

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.

PMID:
27239029
PMCID:
PMC4899142
DOI:
10.1016/j.celrep.2016.05.002
[Indexed for MEDLINE]
Free PMC Article

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