Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins

Eric T. Wang, Neal A.L. Cody, Sonali Jog, Michela Biancolella, Thomas T. Wang, Daniel J. Treacy, Shujun Luo, Gary P. Schroth, David E. Housman, Sita Reddy, Eric Lécuyer, Christopher B. Burge

Research output: Contribution to journalArticlepeer-review

374 Scopus citations

Abstract

The muscleblind-like (Mbnl) family of RNA-binding proteins plays important roles in muscle and eye development and in myotonic dystrophy (DM), in which expanded CUG or CCUG repeats functionally deplete Mbnl proteins. We identified transcriptome-wide functional and biophysical targets of Mbnl proteins in brain, heart, muscle, and myoblasts by using RNA-seq and CLIP-seq approaches. This analysis identified several hundred splicing events whose regulation depended on Mbnl function in a pattern indicating functional interchangeability between Mbnl1 and Mbnl2. A nucleotide resolution RNA map associated repression or activation of exon splicing with Mbnl binding near either 3′ splice site or near the downstream 5′ splice site, respectively. Transcriptomic analysis of subcellular compartments uncovered a global role for Mbnls in regulating localization of mRNAs in both mouse and Drosophila cells, and Mbnl-dependent translation and protein secretion were observed for a subset of mRNAs with Mbnl-dependent localization. These findings hold several new implications for DM pathogenesis.

Original languageEnglish
Pages (from-to)710-724
Number of pages15
JournalCell
Volume150
Issue number4
DOIs
StatePublished - 17 Aug 2012
Externally publishedYes

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