Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteins
| Autor: | Thomas A. Cooper, Daniel J. Treacy, Amanda J. Ward, Christopher B. Burge, Eric T. Wang, Tanvi Saxena, Peter Freese, Jennifer M. Cherone, Jimena Giudice, Nicole J. Lambert, Thomas T. Wang |
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| Přispěvatelé: | Massachusetts Institute of Technology. Computational and Systems Biology Program, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Wang, Eric Tzy-shi, Ward, Amanda, Cherone, Jennifer Michelle, Wang, Thomas T., Treacy, Daniel J., Lambert, Nicole J., Freese, Peter Dale, Saxena, Tanvi, Burge, Christopher B. |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Untranslated region
RNA Splicing Down-Regulation RNA-binding protein Mice Transgenic Nerve Tissue Proteins Biology CELF1 Protein 03 medical and health sciences Exon Mice 0302 clinical medicine Genetics Animals CELF Proteins Humans Myotonic Dystrophy Protein Isoforms RNA Messenger Muscle Skeletal Gene Genetics (clinical) 030304 developmental biology 0303 health sciences Messenger RNA Sequence Analysis RNA Research RNA Gene Expression Regulation Developmental RNA-Binding Proteins Heart Exons 3. Good health Gene Expression Regulation RNA splicing Transcriptome 030217 neurology & neurosurgery |
| Zdroj: | Cold Spring Harbor Laboratory Press |
| Popis: | RNA binding proteins of the conserved CUGBP1, Elav-like factor (CELF) family contribute to heart and skeletal muscle development and are implicated in myotonic dystrophy (DM). To understand their genome-wide functions, we analyzed the transcriptome dynamics following induction of CELF1 or CELF2 in adult mouse heart and of CELF1 in muscle by RNA-seq, complemented by crosslinking/immunoprecipitation-sequencing (CLIP-seq) analysis of mouse cells and tissues to distinguish direct from indirect regulatory targets. We identified hundreds of mRNAs bound in their 3′ UTRs by both CELF1 and the developmentally induced MBNL1 protein, a threefold greater overlap in target messages than expected, including messages involved in development and cell differentiation. The extent of 3′ UTR binding by CELF1 and MBNL1 predicted the degree of mRNA repression or stabilization, respectively, following CELF1 induction. However, CELF1's RNA binding specificity in vitro was not detectably altered by coincubation with recombinant MBNL1. These findings support a model in which CELF and MBNL proteins bind independently to mRNAs but functionally compete to specify down-regulation or localization/stabilization, respectively, of hundreds of mRNA targets. Expression of many alternative 3′ UTR isoforms was altered following CELF1 induction, with 3′ UTR binding associated with down-regulation of isoforms and genes. The splicing of hundreds of alternative exons was oppositely regulated by these proteins, confirming an additional layer of regulatory antagonism previously observed in a handful of cases. The regulatory relationships between CELFs and MBNLs in control of both mRNA abundance and splicing appear to have evolved to enhance developmental transitions in major classes of heart and muscle genes. Myotonic Dystrophy Foundation National Institutes of Health (U.S.) (Grant OD017865-02) National Science Foundation (U.S.) (Award 0821391) National Institutes of Health (U.S.) (Grant R01GM085319) National Institutes of Health (U.S.) (Grant RC2HG005624) |
| Databáze: | OpenAIRE |
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