Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Genome Research
Matthew R GazzaraYoseph Barash

Abstract

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 ...Continue Reading

References

Aug 1, 2000·Trends in Biochemical Sciences·C W Smith, J Valcárcel
Apr 5, 2002·Molecular Cell·Nicolas Charlet-BThomas A Cooper
May 17, 2005·Nucleic Acids Research·Jin Han, Thomas A Cooper
Jul 1, 2005·Molecular and Cellular Biology·Andrea N LaddThomas A Cooper
Nov 2, 2005·Molecular and Cellular Biology·Jason G UnderwoodDouglas L Black
Mar 15, 2006·Differentiation; Research in Biological Diversity·Maya PascualRuben Artero
Mar 16, 2006·The Journal of Biological Chemistry·Julie L PonthierJohn G Conboy
Oct 10, 2007·Molecular and Cellular Biology·Hidehito KuroyanagiMasatoshi Hagiwara
Sep 17, 2008·Genes & Development·Chaolin ZhangMichael Q Zhang
Dec 17, 2008·Proceedings of the National Academy of Sciences of the United States of America·Auinash KalsotraThomas A Cooper
Dec 24, 2008·Proceedings of the National Academy of Sciences of the United States of America·Eric H Davidson, Michael S Levine
Jan 13, 2009·Nature Structural & Molecular Biology·Gene W YeoFred H Gage
Feb 26, 2009·Cell·Thomas A CooperGideon Dreyfuss
Dec 4, 2009·Nature·Thomas Graf, Tariq Enver
Mar 20, 2010·Genes & Development·Auinash KalsotraThomas A Cooper
Oct 29, 2010·Genome Biology·Simon Anders, Wolfgang Huber
Mar 30, 2011·Molecular and Cellular Biology·Michael J MalloryKristen W Lynch
Sep 17, 2011·Nature Reviews. Genetics·Auinash Kalsotra, Thomas A Cooper
Sep 20, 2011·Developmental Biology·Thomas L GallagherJohn G Conboy
Feb 23, 2012·Molecular and Cellular Biology·Kimberly A DittmarRussell P Carstens
Apr 4, 2012·Current Protocols in Molecular Biology·Hairi LiXiang-Dong Fu
Oct 24, 2013·The Journal of Biological Chemistry·Sunil K VermaMuge N Kuyumcu-Martinez
Oct 26, 2013·Genome Biology·Yoseph BarashBrendan J Frey
Aug 13, 2014·Nature Reviews. Genetics·Xiang-Dong Fu, Manuel Ares
Jan 13, 2015·Human Molecular Genetics·Simona PedrottiThomas A Cooper
Apr 15, 2015·Proceedings of the National Academy of Sciences of the United States of America·Michael J MalloryKristen W Lynch
Apr 18, 2015·Genome Research·Eric T WangChristopher B Burge

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Citations

Sep 9, 2017·Bioinformatics·Anupama JhaYoseph Barash
Aug 12, 2018·Blood Cancer Journal·Hilmar QuentmeierUNKNOWN ICGC MMML-Seq Consortium
Oct 17, 2017·Frontiers in Molecular Biosciences·Erik Dassi
Oct 27, 2020·Frontiers in Genetics·Ying LiuZhaolei Zhang
Aug 31, 2018·Biochemical and Biophysical Research Communications·KarryAnne BelangerMuge N Kuyumcu-Martinez
Feb 20, 2020·Seminars in Cell & Developmental Biology·Elena NikonovaMaria L Spletter

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