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Opposing roles of miR-294 and MBNL1/2 in shaping the gene regulatory network of embryonic stem cells.


ABSTRACT: Alternative pre-mRNA splicing plays important roles in regulating self-renewal and differentiation of embryonic stem cells (ESCs). However, how specific alternative splicing programs are established in ESCs remains elusive. Here, we show that a subset of alternative splicing events in ESCs is dependent on miR-294 expression. Remarkably, roughly 60% of these splicing events are affected by the depletion of Muscleblind-Like Splicing Regulator 1 and 2 (Mbnl1/2). Distinct from canonical miRNA function, miR-294 represses Mbnl1/2 through both posttranscriptional and epigenetic mechanisms. Furthermore, we uncover non-canonical functions of MBNL proteins that bind and promote the expression of miR-294 targets, including Cdkn1a and Tgfbr2, thereby opposing the role of miR-294 in regulating cell proliferation, apoptosis, and epithelial-mesenchymal transition (EMT). Our study reveals extensive interactions between miRNAs and splicing factors, highlighting their roles in regulating cell type-specific alternative splicing and defining gene expression programs during development and cellular differentiation.

SUBMITTER: Wu DR 

PROVIDER: S-EPMC5989781 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Opposing roles of miR-294 and MBNL1/2 in shaping the gene regulatory network of embryonic stem cells.

Wu Da-Ren DR   Gu Kai-Li KL   Yu Jian-Cheng JC   Yu Jian-Cheng JC   Fu Xing X   Wang Xi-Wen XW   Guo Wen-Ting WT   Liao Le-Qi LQ   Zhu Hong H   Zhang Xiao-Shan XS   Hui Jingyi J   Wang Yangming Y  

EMBO reports 20180507 6


Alternative pre-mRNA splicing plays important roles in regulating self-renewal and differentiation of embryonic stem cells (ESCs). However, how specific alternative splicing programs are established in ESCs remains elusive. Here, we show that a subset of alternative splicing events in ESCs is dependent on miR-294 expression. Remarkably, roughly 60% of these splicing events are affected by the depletion of Muscleblind-Like Splicing Regulator 1 and 2 (Mbnl1/2). Distinct from canonical miRNA functi  ...[more]

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2017-03-08 | GSE80168 | GEO