Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 1, Pages 195-206Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI84015
Keywords
-
Categories
Funding
- NIH [HL070079, HL103205, HL108186, HL110667, HL096980, HL115238, R01HG006264, U01HG007013]
- UCLA Clinical and Translational Science Institute Cardiovascular Pilot Team Research Grant [UL1TR000124]
- American Heart Association Established Investigator Award
- Eli & Edythe Broad Center Predoctoral Fellowship in Stem Cell Science
- Ruth L. Kirschstein National Research Service Award at UCLA [T32 HL-69766]
- UCLA Cardiovascular Research Laboratories
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000124] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL108186, R21HL110667, R01HL096980, R01HL122737, R01HL070079, R01HL103205, R01HL115238, T32HL069766] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R01HG006264, U01HG007013] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM049369] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available