@article{049c54ccd20248bd827ed3dd32d9f7cf,
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.}",
note = "Funding Information: We thank Hong Sun, Yareli Perez, and Rosario Espejo for technical support; Dr. David Konkel for editing the manuscript; Dr. Douglas Black for providing the WT and DN RBFOX2 plasmid DNA constructs; and Dr. Corey Reynolds for his help in quantification of echocardiography data. This work was supported, in part, by a March of Dimes Starter Basil O{\textquoteright}Connor Starter Scholar Award (5FY12-21), an American Heart Association Grant (15GRNT22830010), an UTMB Institute for Human Infections and Immunity Mini Center Pilot Award, UTMB pilot grant, and startup funds to M.N.K.-M. This work was supported, in part, by a grant from the NIH/National Institute of Allergy and Infectious Diseases (2RO1AI05478-08) and UTMB Institute for Human Infections and Immunity Mini Center Pilot Award to N.J.G., NIH (UL1TR000071 UTMB CTSA and NIEHS P30 ES006676) grants to A.R.B., a NIH/National Heart, Blood and Lung Institute grant to I.J.A. (5R25HL09636305), and NIH grants (HG0046590 and NS075449) to G.W.Y. G.W.Y. is an Alfred P. Sloan Research Fellow. O.B.B. is a National Defense Science and Engineering Graduate Fellow and NumFOCUS John Hunter Technical Fellow. T.I. was supported by a Ruth L. Kirschstein National Research Service Award from the National Heart Lung Blood Institute (F30HL128036). X.H.T.W. was supported by NIH grants R01-HL089598, R01-HL091947, R01-HL117641, and R41-HL129570 and American Heart Association grant 13EIA14560061. Publisher Copyright: {\textcopyright} 2016 The Author(s).",
year = "2016",
month = jun,
day = "7",
doi = "10.1016/j.celrep.2016.05.002",
language = "English (US)",
volume = "15",
pages = "2200--2213",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}