RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure
Chen Gao, … , Jau-Nian Chen, Yibin Wang
Chen Gao, … , Jau-Nian Chen, Yibin Wang
Published November 30, 2015
Citation Information: J Clin Invest. 2016;126(1):195-206. https://doi.org/10.1172/JCI84015.
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Research Article Cardiology

RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure

Abstract

RNA splicing is a major contributor to total transcriptome complexity; however, the functional role and regulation of splicing in heart failure remain poorly understood. Here, we used a total transcriptome profiling and bioinformatic analysis approach and identified a muscle-specific isoform of an RNA splicing regulator, RBFox1 (also known as A2BP1), as a prominent regulator of alternative RNA splicing during heart failure. Evaluation of developing murine and zebrafish hearts revealed that RBFox1 is induced during postnatal cardiac maturation. However, we found that RBFox1 is markedly diminished in failing human and mouse hearts. In a mouse model, RBFox1 deficiency in the heart promoted pressure overload–induced heart failure. We determined that RBFox1 is a potent regulator of RNA splicing and is required for a conserved splicing process of transcription factor MEF2 family members that yields different MEF2 isoforms with differential effects on cardiac hypertrophic gene expression. Finally, induction of RBFox1 expression in murine pressure overload models substantially attenuated cardiac hypertrophy and pathological manifestations. Together, this study identifies regulation of RNA splicing by RBFox1 as an important player in transcriptome reprogramming during heart failure that influence pathogenesis of the disease.

Authors

Chen Gao, Shuxun Ren, Jae-Hyung Lee, Jinsong Qiu, Douglas J. Chapski, Christoph D. Rau, Yu Zhou, Maha Abdellatif, Astushi Nakano, Thomas M. Vondriska, Xinshu Xiao, Xiang-Dong Fu, Jau-Nian Chen, Yibin Wang

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Figure 5

RBFox1 plays important role in cardiomyocyte hypertrophy.

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RBFox1 plays important role in cardiomyocyte hypertrophy. (A) Representa...
(A) Representative bright-field images of NRVMs 48 hours after treatment with PE and infection with GFP (Control) or RBFox1-expressing adenovirus (RBFox1). Original magnification, ×20. (B) Phalloidin staining of NRVMs treated with PE alone or in combination with RBFox1-expressing adenovirus. Green, phalloidin; blue, Hoechst. Original magnification, ×40. Data are representative of at least 3 independent experiments. (C) Cell surface area of NRVMs from the same experimental groups as in A. Cells were stained with wheat germ agglutinin. 100 cells were measured from total of 3 independent experimental samples. Protein synthesis rates as quantified by puromycin incorporation in NRVMs from the same experimental samples as in A following 30 minutes of puromycin labeling (n = 3 each sample). (D) Anf, Bnp, and Myh7 expression in NRVMs following 48 hours of PE treatment in combination with GFP or RBFox1 adenovirus infection (n = 3 each group). (E) Relative Mef2d α1/α2 transcript ratios from the same sample group as in C. *P < 0.05, **P < 0.01, Student’s t test (C–E).