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- Title
RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure.
- Authors
Chen Gao; Shuxun Ren; Jae-Hyung Lee; Jinsong Qiu; Chapski, Douglas J.; Rau, Christoph D.; Yu Zhou; Abdellatif, Maha; Astushi Nakano; Vondriska, Thomas M.; Xinshu Xiao; Xiang-Dong Fu; Jau-Nian Chen; Yibin Wang; Gao, Chen; Ren, Shuxun; Lee, Jae-Hyung; Qiu, Jinsong; Zhou, Yu; Nakano, Astushi
- 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.
- Subjects
RNA splicing; RNA-binding proteins; HEART failure; ALTERNATIVE RNA splicing; TRANSCRIPTION factors; LABORATORY zebrafish; LABORATORY mice; ANIMAL experimentation; CARDIAC hypertrophy; MICE; MUSCLE proteins; PROTEINS; RESEARCH funding; RNA; GENE expression profiling
- Publication
Journal of Clinical Investigation, 2016, Vol 126, Issue 1, p195
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI84015