RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure
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
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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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 6

RBFox1/MEF2 regulatory circuit in cardiomyocyte hypertrophy regulation.

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RBFox1/MEF2 regulatory circuit in cardiomyocyte hypertrophy regulation. ...
(A) Anf and Bnp expression in NRVMs following GFP or RBFox1 expression, with or without coexpressing a scrambled siRNA (ncsiRNA) or an siRNA targeting Mef2d α2 isoform (si-Mef2d-α2) as indicated (n = 3 each sample). (B) Anf and Bnp expression in NRVMs with or without PE treatment or RBFox1 expression or coexpressing a scrambled siRNA or an siRNA targeted to Mef2d α2 isoform (n = 3 each sample). (C) mef2a and mef2d α1/α2 ratio in RBFox1 morpholino–injected hearts compared with control zebrafish embryo hearts (n = 3 each sample). (D) Zebrafish phenotype upon RBFox1 and Mef2a inactivation. Zebrafish embryos were injected with morpholino targeting RBFox1 alone or in combination with Mef2a α1 or α2 isoform–specific morpholino. Embryo phenotype was analyzed at 48 hours after fertilization. Original magnification, ×1 (first column); ×11 (second column). (E) Zebrafish phenotype upon expression of zebrafish Mef2a α1 or zebrafish Mef2a α2, mouse MEF2A α1, and mouse MEF2A α2 at indicated dose imaged at 48 hours after fertilization. Original magnification, ×1 (first column); ×11 (second column). (F) Gene expression profile in the zebrafish embryos 24 hours following expression of individual mef2a α1 or α2 isoforms analyzed by RNA-seq. The heatmap was generated using significantly upregulated (red) and downregulated (green) genes. *P < 0.05, Student’s t test (A–C).