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Opposing roles of miR‐294 and MBNL 1/2 in shaping the gene regulatory network of embryonic stem cells
Author(s) -
Wu DaRen,
Gu KaiLi,
Yu JianCheng,
Fu Xing,
Wang XiWen,
Guo WenTing,
Liao LeQi,
Zhu Hong,
Zhang XiaoShan,
Hui Jingyi,
Wang Yangming
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201745657
Subject(s) - embryonic stem cell , gene regulatory network , microbiology and biotechnology , biology , gene , genetics , stem cell , gene expression , computational biology
Alternative pre‐ mRNA splicing plays important roles in regulating self‐renewal and differentiation of embryonic stem cells ( ESC s). However, how specific alternative splicing programs are established in ESC s remains elusive. Here, we show that a subset of alternative splicing events in ESC s 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 mi RNA 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 mi RNA s and splicing factors, highlighting their roles in regulating cell type‐specific alternative splicing and defining gene expression programs during development and cellular differentiation.