Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins.
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.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Eric T
ET
Wang
Neal A L
NA
Cody
Sonali
S
Jog
Michela
M
Biancolella
Thomas T
TT
Wang
Daniel J
DJ
Treacy
Shujun
S
Luo
Gary P
GP
Schroth
David E
DE
Housman
Sita
S
Reddy
Eric
E
Lécuyer
Christopher B
CB
Burge
D020413:3' Untranslated Regions; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000378:metabolism; D005091:Exons; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D032446:Myoblasts / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins; D009928:Organ Specificity; D022821:RNA Splice Sites; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C479922:Mbnl1 protein, mouse; C529512:Mbnl2 protein, mouse; D009687:Nuclear Proteins; D022821:RNA Splice Sites; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C109271:mbl protein, Drosophila