RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure

Gao, Chen; Ren, Shuxun; Lee, Jae Hyung; Qiu, Jinsong; Chapski, Douglas J.; Rau, Christoph; Zhou, Yu; Abdellatif, Maha; Nakano, Astushi; Vondriska, Thomas M.; Xiao, Xinshu; Fu, Xiang‐Dong; Chen, Jau-Nian; Wang, Yibin

doi:10.1172/jci84015

Cited by 126 publications

(145 citation statements)

References 52 publications

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“…Inclusion of the α2 exon alters the phosphorylation and interaction partners of MEF2D to activate transcription of key myogenic genes during myogenesis (Sebastian et al 2013). Importantly, previous studies have demonstrated that inclusion of Mef2d exon α2 is dysregulated in heart failure where RBFOX family members are down-regulated (Singh et al 2014;Gao et al 2016). Here, we show that splicing of Mef2d exon α2 is also dysregulated upon overexpression of CELF2 in heart (Fig.…”

Section: Implications Of Celf2/rbfox2 Antagonism For Understanding Husupporting

confidence: 54%

“…S6). Genes containing highly consistent, antagonistically coregulated events have previously been implicated in myogenesis and heart failure, such as Mef2d and Mef2a (Singh et al 2014;Gao et al 2016), and have numerous CELF and RBFOX binding sites proximal to the regulated exon(s) which are conserved in human, mouse, and chicken ( Fig. 5G; Supplemental Figs.…”

Section: Wwwgenomeorgmentioning

confidence: 99%

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Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Gazzara¹,

Mallory

Roytenberg

et al. 2017

Genome Res.

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Over 95% of human multi-exon genes undergo alternative splicing, a process important in normal development and often dysregulated in disease. We sought to analyze the global splicing regulatory network of CELF2 in human T cells, a well-studied splicing regulator critical to T cell development and function. By integrating high-throughput sequencing data for binding and splicing quantification with sequence features and probabilistic splicing code models, we find evidence of splicing antagonism between CELF2 and the RBFOX family of splicing factors. We validate this functional antagonism through knockdown and overexpression experiments in human cells and find CELF2 represses RBFOX2 mRNA and protein levels. Because both families of proteins have been implicated in the development and maintenance of neuronal, muscle, and heart tissues, we analyzed publicly available data in these systems. Our analysis suggests global, antagonistic coregulation of splicing by the CELF and RBFOX proteins in mouse muscle and heart in several physiologically relevant targets, including proteins involved in calcium signaling and members of the MEF2 family of transcription factors. Importantly, a number of these coregulated events are aberrantly spliced in mouse models and human patients with diseases that affect these tissues, including heart failure, diabetes, or myotonic dystrophy. Finally, analysis of exons regulated by ancient CELF family homologs in chicken, Drosophila, and Caenorhabditis elegans suggests this antagonism is conserved throughout evolution.

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Section: Implications Of Celf2/rbfox2 Antagonism For Understanding Husupporting

confidence: 54%

Section: Wwwgenomeorgmentioning

confidence: 99%

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Gazzara¹,

Mallory

Roytenberg

et al. 2017

Genome Res.

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“…Rbfox1 expression decreases in failing human and mouse hearts, and the loss of Rbfox1 aggravates pressure-overload-induced HF in mice. 83 Splicing analysis revealed an isoform switch in the myocyte enhancer factor-2 (Mef2) gene family, involving the mutually exclusive exons α1 and α2, which interferes with the transcriptional activity of Mef2. Remarkably, re-expression of Rbfox1 in pressure-overloaded mouse hearts attenuates cardiac hypertrophy and failure.…”

Section: Splice Factors In the Diseased Heartmentioning

confidence: 99%

RNA Splicing

Hoogenhof

Pinto

Creemers

2016

Circulation Research

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RNA splicing, a post-transcriptional process necessary to form a mature mRNA, was discovered in the late 1970s. 1 Two different modes of splicing have been defined, that is, constitutive splicing and alternative splicing. Constitutive splicing is the process of removing introns from the premRNA, and joining the exons together to form a mature mRNA. Alternative splicing, on the other hand, is the process where exons can be included or excluded in different combinations to create a diverse array of mRNA transcripts from a single pre-mRNA and therefore serves as a process to increase the diversity of the transcriptome. The estimated number of alternative splicing events in the human transcriptome has risen sharply over the past decades. In the 1980s, it was thought that about 5% of human genes were subjected to alternative splicing.2 In 2002, this number had risen to 60%, 3 and now, after implementation of next-generation-sequencing technologies, we know that the vast majority, >95% of mRNAs, are subjected to alternative splicing. 4 Nevertheless, the function of a large fraction of these splice isoforms remains to be elucidated. Furthermore, it is anticipated that in different tissues, or in tissues with different disease states, new isoforms still remain to be identified. 5The process of splicing is highly conserved during evolution. Splicing is more prevalent in multicellular than in unicellular eukaryotes because of the lower number of introncontaining genes in the latter. 6 Later in evolution, alternative splicing becomes more prevalent in vertebrates than in invertebrates. Interestingly, just a single exon-skipping event in the RNA-binding protein (RBP), polypyrimidine tract binding protein 1 has been shown to direct numerous alternative splicing changes between species, indicating that a single splicing event can amplify transcriptome diversity between species. 7The recent observation that the total number of protein-coding genes does not differ much between species, fueled the hypothesis that alternative splicing largely contributes to organism diversity. And indeed, as we move up the phylogenetic tree, alternative splicing complexity increases, with the highest complexity in primates. 8,9The aim of this review is to give a comprehensive overview of all aspects of constitutive and alternative splicing and their regulators, as well as the importance of these different aspects in human disease, with a focus on the heart. In addition, we discuss possible therapeutic interventions and try to uncover potential future directions of research. Major and Minor SpliceosomeRNA splicing is performed by the spliceosome, a large and dynamic ribonucleoprotein complex composed of proteins and small nuclear RNAs (snRNAs), which assembles on the pre-mRNA (Figure 1). Ribonucleoproteins consist of 1 or 2 small nuclear RNAs (snRNAs; U1, U2, U4/U6, or U5), and a variable number of complex-specific proteins.

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“…In this work, we found the expression of Rbfox1 was dramatically decreased in human DCM when compared with non-failing hearts, which is consistent with Gao's report in which they indicated the expression of Rbfox1 was markedly diminished in human DCM and in transverse aortic restrictioninduced murine heart failure. 12 These imply Rbfox1 indeed takes part in the alternative splicing regulation of diseased hearts. Although Rbfox1 was reported to enhance the inclusion of Ca V 1.2 alternative exon 33 in , in contrast we found the expression of Rbfox1 was negatively correlated with the expression of exon 33 in human hearts.…”

Section: Discussionmentioning

confidence: 98%

“…8,9 To date, Rbfox1/2 was reported to be crucial in cardiac development and different cardiomyopathies via regulation of serial splicing events, [10][11][12][13][14] indicating a plausible role in the regulation of alternative exon 33 of Ca V 1.2 calcium channels in the heart. In this follow-up study of our previous work, we measured Rbfox1/2 mRNA levels in human failing and non-failing heart samples, in order to explore the possible association between the expressions of Rbfox and exon 33 of Ca V 1.2 in cardiomyopathies.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Ca_V1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and Ca_V1.2 exon 33 expressions in human heart failure

Wang

et al. 2018

Channels

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Recently, we reported that homozygous deletion of alternative exon 33 of Ca V 1.2 calcium channel in the mouse resulted in ventricular arrhythmias arising from increased Ca V 1.2 D33 I CaL current density in the cardiomyocytes. We wondered whether heterozygous deletion of exon 33 might produce cardiac phenotype in a dose-dependent manner, and whether the expression levels of RNA splicing factors known to regulate alternative splicing of exon 33 might change in human heart failure. Unexpectedly, we found that exon 33 C/¡ cardiomyocytes showed similar Ca V 1.2 channel properties as wild-type cardiomyocyte, even though Ca V 1.2 D33 channels exhibit a gain-in-function. In human hearts, we found that the mRNA level of splicing factor Rbfox1, but not Rbfox2, was downregulated in dilated cardiomyopathy, and CACNA1C mRNA level was dramatically decreased in the both of dilated and ischemic cardiomyopathy. These data imply Rbfox1 may be involved in the development of cardiomyopathies via regulating the alternative splicing of Ca V 1.2 exon 33. (149 words) KEYWORDS alternative splicing; cardiomyopathy; Ca V 1.2 calcium channel; heterozygous knockout; Rbfox

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RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure

Cited by 126 publications

References 52 publications

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

RNA Splicing

Characterization of Ca_V1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and Ca_V1.2 exon 33 expressions in human heart failure

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RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure

Cited by 126 publications

References 52 publications

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

RNA Splicing

Characterization of CaV1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and CaV1.2 exon 33 expressions in human heart failure

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Characterization of Ca_V1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and Ca_V1.2 exon 33 expressions in human heart failure