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Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes

Matthew R Gazzara, Michael J. Mallory, Renat Roytenberg, John Lindberg, Anupama Jha, Kristen W. Lynch, Yoseph Barash
doi: https://doi.org/10.1101/099853
Matthew R Gazzara
1Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104
2Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Michael J. Mallory
2Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Renat Roytenberg
2Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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John Lindberg
2Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Anupama Jha
3Department of Computer and Information Science, School of Engineering and Applied Sciences, University of Pennsylvania Philadelphia, PA 19104
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Kristen W. Lynch
1Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104
2Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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  • For correspondence: klync@mail.med.upenn.edu
Yoseph Barash
1Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104
3Department of Computer and Information Science, School of Engineering and Applied Sciences, University of Pennsylvania Philadelphia, PA 19104
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  • For correspondence: yosephb@upenn.edu
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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 co-regulation 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 co-regulated 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, and Drosophila suggests this antagonism is conserved through evolution.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted January 12, 2017.
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Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes
Matthew R Gazzara, Michael J. Mallory, Renat Roytenberg, John Lindberg, Anupama Jha, Kristen W. Lynch, Yoseph Barash
bioRxiv 099853; doi: https://doi.org/10.1101/099853
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Ancient antagonism between CELF and RBFOX families tunes mRNA splicing outcomes
Matthew R Gazzara, Michael J. Mallory, Renat Roytenberg, John Lindberg, Anupama Jha, Kristen W. Lynch, Yoseph Barash
bioRxiv 099853; doi: https://doi.org/10.1101/099853

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