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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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 3

Genetic inactivation of Rbfox1 exacerbates cardiac hypertrophy and HF in mice.

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Genetic inactivation of Rbfox1 exacerbates cardiac hypertrophy and HF in...
(A) Mef2 α1/α2 transcript ratios in 3-month-old wild-type (Control) and RBFox1-CKO mouse hearts at basal state (n = 3 from each group). *P < 0.05, **P < 0.01. (B) Ejection fraction values of sham- and TAC-operated control and RBFox1-CKO littermates measured by echocardiography (Sham-control, n = 6; Sham-RBFox1-CKO, n = 6; TAC-control, n = 6; TAC-RBFox1-CKO, n = 8). *P < 0.05, **P < 0.01, TAC-control vs. TAC-RBFox1-CKO; †P < 0.05, Sham-RBFox1-CKO vs. TAC-RBFox1-CKO; ##P < 0.05, Sham-control vs. TAC-control. (C) Cross-sectional myofiber area in LVs of sham- and TAC-operated control and RBFox1-CKO hearts 3 weeks after TAC. The values were averaged from 60 slides prepared from 3 hearts in each group. *P < 0.05, **P < 0.01. (D) LV weight (LVW) and body weight (BW) ratios from sham- and TAC-operated control and RBFox1-CKO mice 3 weeks after TAC (control, n = 10; RBFox1-CKO, n = 9). *P < 0.05. (E) Lung weight and body weight ratios among the sham, control, and RBFox1-CKO mice 3 weeks after TAC (control, n = 10; RBFox1-CKO, n = 9). *P < 0.05. (F) Representative cross-sectional images of hematoxylin & eosin staining of LV tissues from control and RBFox1-CKO mice following sham surgery or 3 weeks after TAC. Original magnification, ×2. (G) Representative Masson’s trichrome staining of sham- and TAC-treated control and RBFox1-CKO mouse heart sections. Original magnification, ×20. Data are representative of at least 3 independent experiments. (H) Anf and Bnp expression levels in the sham- and TAC-treated hearts from control and RBFox1-CKO mice as indicated (n = 4 each group). *P < 0.05, **P < 0.01. Significant differences between groups were determined by Student’s t test (A) or multiway ANOVA (B–E and H).