Rbfox2-Coordinated Alternative Splicing of Mef2d and Rock2 Controls Myoblast Fusion during Myogenesis

Singh, Ravi; Xia, Zheng; Bland, Christopher S.; Kalsotra, Auinash; Scavuzzo, Marissa A.; Curk, Tomaž; Ule, Jernej; Li, Wei; Cooper, Thomas A.

doi:10.1016/j.molcel.2014.06.035

Cited by 106 publications

(181 citation statements)

References 47 publications

(75 reference statements)

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“…At one extreme, CELF2 is highly expressed in thymus/immune tissues where the RBFOX proteins show minimal expression (Mallory et al 2011and this study), while at the other end of the spectrum, heart and skeletal muscle down-regulate CELF protein expression during development but express abundant levels of RBFOX proteins (Kalsotra et al 2008;Singh et al 2014). Notably, both CELF2 and RBFOX2 are highly expressed and nuclear-localized in the brain (Otsuka et al 2009;Lee et al 2016).…”

Section: Celf2 Represses Expression Of Rbfox2 While Rbfox2 Counters mentioning

confidence: 58%

“…1D). Secondly, the CELF and RBFOX families have both been implicated in the development and maintenance of normal function of heart, muscle, and brain (Zhang et al 2002;Kalsotra et al 2008;Gehman et al 2012;Singh et al 2014) but have yet to be directly studied in connection to one another.…”

Section: Rbfox Motifs and Binding Are Enriched Downstream Of Celf2-rementioning

confidence: 99%

“…Previous work has shown that CELF1 and CELF2 promote embryonic splicing patterns in murine muscle and heart that are reversed when both proteins are dramatically down-regulated post-natally (Ladd et al 2005;Kalsotra et al 2008). On the other hand, RBFOX1 and RBFOX2 have been implicated as key in promoting splicing changes during myogenesis and across heart and muscle development (Gallagher et al 2011;Gehman et al 2012;Singh et al 2014;Pedrotti et al 2015), yet these two protein families have not been studied in relation to one another in these contexts.…”

Section: Celf2 Represses Rbfox2 Mrna and Protein Levels In T Cellsmentioning

confidence: 99%

“…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%

“…Although these studies have not demonstrated a causal role of CELF2 in the observed splicing changes, CELF2 expression does increase in developing thymocytes and activated T cells and regulates splicing to promote T cell receptor expression and signaling (Mallory et al 2011;Martinez et al 2015). Similarly, proper expression of RBFOX2 in brain and muscle of several species is required for appropriate splicing and tissue function (Kuroyanagi et al 2007;Gallagher et al 2011;Singh et al 2014). Interestingly, despite the overlap in expression and function of CELF2 and RBFOX2 in many tissues and across species, physical or functional interplay between these proteins has not been well studied.…”

mentioning

confidence: 96%

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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: Celf2 Represses Expression Of Rbfox2 While Rbfox2 Counters mentioning

confidence: 58%

Section: Rbfox Motifs and Binding Are Enriched Downstream Of Celf2-rementioning

confidence: 99%

Section: Celf2 Represses Rbfox2 Mrna and Protein Levels In T Cellsmentioning

confidence: 99%

Section: Wwwgenomeorgmentioning

confidence: 99%

mentioning

confidence: 96%

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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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RBFOX2/GOLIM4 Splicing Axis Activates Vesicular Transport Pathway to Promote Nasopharyngeal Carcinogenesis

Luo

Liu

et al. 2021

Advanced Science

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20–30% of patients with nasopharyngeal carcinoma (NPC) develop distant metastasis or recurrence leading to poor survival, of which the underlying key molecular events have yet to be addressed. Here alternative splicing events in 85 NPC samples are profiled using transcriptome analysis and it is revealed that the long isoform of GOLIM4 (‐L) with exon‐7 is highly expressed in NPC and associated with poor prognosis. Lines of evidence demonstrate the pro‐tumorigenic function of GOLIM4‐L in NPC cells. It is further revealed that RBFOX2 binds to a GGAA motif in exon‐7 and promotes its inclusion forming GOLIM4‐L. RBFOX2 knockdown suppresses the tumorigenesis of NPC cells, phenocopying GOLIM4‐L knockdown, which is significantly rescued by GOLIM4‐L overexpression. High expression of RBFOX2 is correlated with the exon‐7 inclusion of GOLIM4 in NPC biopsies and associated with worse prognosis. It is observed that RBFOX2 and GOLIM4 can influence vesicle‐mediated transport through maintaining the organization of Golgi apparatus. Finally, it is revealed that RAB26 interacts with GOLIM4 and mediates its tumorigenic potentials in NPC cells. Taken together, the findings provide insights into how alternative splicing contributes to NPC development, by highlighting a functional link between GOLIM4‐L and its splicing regulator RBFOX2 activating vesicle‐mediated transport involving RAB26.

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FBXO7 Confers Mesenchymal Properties and Chemoresistance in Glioblastoma by Controlling Rbfox2‐Mediated Alternative Splicing

Li,

Chen,

Xie

et al. 2023

Advanced Science

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Mesenchymal glioblastoma (GBM) is highly resistant to radio‐and chemotherapy and correlates with worse survival outcomes in GBM patients; however, the underlying mechanism determining the mesenchymal phenotype remains largely unclear. Herein, it is revealed that FBXO7, a substrate‐recognition component of the SCF complex implicated in the pathogenesis of Parkinson's disease, confers mesenchymal properties and chemoresistance in GBM by controlling Rbfox2‐mediated alternative splicing. Specifically, FBXO7 ubiquitinates Rbfox2 Lys249 through K63‐linked ubiquitin chains upon arginine dimethylation at Arg341 and Arg441 by PRMT5, leading to Rbfox2 stabilization. FBXO7 controls Rbfox2‐mediated splicing of mesenchymal genes, including FoxM1, Mta1, and Postn. FBXO7‐induced exon Va inclusion of FoxM1 promotes FoxM1 phosphorylation by MEK1 and nuclear translocation, thereby upregulates CD44, CD9, and ID1 levels, resulting in GBM stem cell self‐renewal and mesenchymal transformation. Moreover, FBXO7 is stabilized by temozolomide, and FBXO7 depletion sensitizes tumor xenografts in mice to chemotherapy. The findings demonstrate that the FBXO7‐Rbfox2 axis‐mediated splicing contributes to mesenchymal transformation and tumorigenesis, and targeting FBXO7 represents a potential strategy for GBM treatment.

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Rbfox2-Coordinated Alternative Splicing of Mef2d and Rock2 Controls Myoblast Fusion during Myogenesis

Cited by 106 publications

References 47 publications

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

RBFOX2/GOLIM4 Splicing Axis Activates Vesicular Transport Pathway to Promote Nasopharyngeal Carcinogenesis

FBXO7 Confers Mesenchymal Properties and Chemoresistance in Glioblastoma by Controlling Rbfox2‐Mediated Alternative Splicing

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