title: 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.forename: Chen
authors.initials: C
authors.lastname: Gao
authors.forename: Shuxun
authors.initials: S
authors.lastname: Ren
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Lee
authors.forename: Jinsong
authors.initials: J
authors.lastname: Qiu
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Chapski
authors.forename: Christoph D
authors.initials: CD
authors.lastname: Rau
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Maha
authors.initials: M
authors.lastname: Abdellatif
authors.forename: Astushi
authors.initials: A
authors.lastname: Nakano
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Vondriska
authors.forename: Xinshu
authors.initials: X
authors.lastname: Xiao
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
authors.forename: Jau-Nian
authors.initials: JN
authors.lastname: Chen
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000209:etiology* / Q000235:genetics; D006333:Heart Failure / Q000209:etiology* / Q000235:genetics; D006801:Humans; D064326:MEF2 Transcription Factors / Q000235:genetics; D051379:Mice; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000502:physiology*; D059467:Transcriptome
chemical_list: D064326:MEF2 Transcription Factors; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins