RNA and Disease

Cooper, Thomas A.; Wan, Lili; Dreyfuss, Gideon

doi:10.1016/j.cell.2009.02.011

Cited by 1,044 publications

(962 citation statements)

References 150 publications

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“…Finally, misregulation or misexpression of both CELF2 and RBFOX2 have been implicated as contributors to human disease including cancer, muscular dystrophies, heart failure, and Type 1 diabetes (Kuyumcu-Martinez et al 2007;Cooper et al 2009;Verma et al 2013;Nutter et al 2016). Our finding of mutual antagonism between these proteins suggests that disease-relevant splicing attributed previously to CELF2 or RBFOX2 may also be impacted by altered expression of the other.…”

Section: Implications Of Celf2/rbfox2 Antagonism For Understanding Humentioning

confidence: 76%

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 Humentioning

confidence: 76%

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Gazzara¹,

Mallory

Roytenberg

et al. 2017

Genome Res.

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“…3,4 Aberrations of alternative splicing are mediated by either mutations disrupting splicing cis-elements or dysregulation of splicing trans-factors. 5,6 Myotonic dystrophy is an autosomal dominant multisystem disorder affecting the skeletal muscles, eye, heart, endocrine system and central nervous system. The clinical symptoms include muscle weakness and wasting, myotonia, cataract, insulin resistance, hypogonadism, cardiac conduction defects, frontal balding and intellectual disabilities.…”

Section: Introductionmentioning

confidence: 99%

Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy

et al. 2012

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Myotonic dystrophy type 1 (DM1) is an RNA gain-of-function disorder in which abnormally expanded CTG repeats of DMPK sequestrate a splicing trans-factor MBNL1 and upregulate another splicing trans-factor CUGBP1. To identify a diverse array of aberrantly spliced genes, we performed the exon array analysis of DM1 muscles. We analyzed 72 exons by RT-PCR and found that 27 were aberrantly spliced, whereas 45 were not. Among these, 25 were novel and especially splicing aberrations of LDB3 exon 4 and TTN exon 45 were unique to DM1. Retrospective analysis revealed that four parameters efficiently detect aberrantly spliced exons: (i) the signal intensity is high; (ii) the ratio of probe sets with reliable signal intensities (that is, detection above background P-value ¼ 0.000) is high within a gene; (iii) the splice index (SI) is high; and (iv) SI is deviated from SIs of the other exons that can be estimated by calculating the deviation value (DV). Application of the four parameters gave rise to a sensitivity of 77.8% and a specificity of 95.6% in our data set. We propose that calculation of DV, which is unique to our analysis, is of particular importance in analyzing the exon array data. INTRODUCTIONAlternative splicing regulates developmental stage-specific and tissuespecific gene expressions and markedly expands the proteome diversity with a limited number of genes. High-throughput sequencing of total mRNAs expressed in cells has revealed that 98% or more of multiexon genes are alternatively spliced, 1 with an average of seven alternative splicing per multiexon gene. 2 Alternative splicing is achieved by exonic/intronic splicing enhancers/silencers (ESE, ISE, ESS, ISS) in combination with spatial and temporal expression of trans-acting splicing factors, such as serine/arginine-rich (SR) proteins and heterogeneous nuclear ribonucleoproteins. 3,4 Aberrations of alternative splicing are mediated by either mutations disrupting splicing cis-elements or dysregulation of splicing trans-factors. 5,6 Myotonic dystrophy is an autosomal dominant multisystem disorder affecting the skeletal muscles, eye, heart, endocrine system and central nervous system. The clinical symptoms include muscle weakness and wasting, myotonia, cataract, insulin resistance, hypogonadism, cardiac conduction defects, frontal balding and intellectual

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“…It is estimated that >90% of human genes undergo alternative splicing 1 . The process is highly regulated 2 and disruption of the splicing regulatory networks can contribute to several diseases 3 . Regulation of alternative splicing involves cisacting regulatory elements that are bound by trans-acting factors to enhance or silence splicing of alternative exons.…”

Section: Introductionmentioning

confidence: 99%

Structural basis of G-tract recognition and encaging by hnRNP F quasi-RRMs

Dominguez

Fisette

Chabot

et al. 2010

Nat Struct Mol Biol

139

174

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The heterogeneous nuclear ribonucleoprotein (hnRNP) F is involved in the regulation of mRNA metabolism by specifically recognizing G-tract RNA sequences. We have determined the solution structures of the three quasi RNA recognition motifs (qRRMs) of hnRNP F in complex with G-tract RNA. These structures show that qRRMs bind RNA in a very unusual manner, the G-tract being "encaged", making the qRRM a novel RNA binding domain. We defined a consensus signature sequence for qRRMs and identified other human qRRM-containing proteins, which also specifically recognize G-tract RNAs. Our structures explain how qRRMs can sequester G-tracts maintaining them in a single-stranded conformation. We also show that isolated qRRMs of hnRNP F are sufficient to regulate the alternative splicing of the Bcl-x premRNA strongly suggesting that hnRNP F would act by remodeling RNA secondary and tertiary structures.3

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RNA and Disease

Cited by 1,044 publications

References 150 publications

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Four parameters increase the sensitivity and specificity of the exon array analysis and disclose 25 novel aberrantly spliced exons in myotonic dystrophy

Structural basis of G-tract recognition and encaging by hnRNP F quasi-RRMs

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