Open AccessThe long noncoding RNA Meg3 regulates myoblast plasticity and muscle regeneration through epithelial-mesenchymal transition
Author(s) -
Tiffany L. Dill,
Alina Carroll,
Amanda Pinheiro,
Jiachen Gao,
Francisco J. Naya
Publication year - 2020
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.194027
Subject(s) - myogenesis , biology , c2c12 , meg3 , myocyte , microbiology and biotechnology , skeletal muscle , epithelial–mesenchymal transition , cellular differentiation , progenitor cell , gene knockdown , regeneration (biology) , long non coding rna , stem cell , endocrinology , genetics , downregulation and upregulation , gene
Formation of skeletal muscle is among the most striking examples of cellular plasticity in animal tissue development, where muscle progenitor cells are reprogrammed by epithelial-mesenchymal transition (EMT) to produce multinucleated myofibers. The regulation of EMT in muscle formation remains poorly understood. Here, we demonstrate that the long noncoding RNA (lncRNA) Meg3 regulates EMT in myoblast differentiation and skeletal muscle regeneration. Chronic inhibition of Meg3 in C2C12 myoblasts induced EMT, and suppressed cell state transitions required for differentiation. Furthermore, adenoviral Meg3 knockdown compromised muscle regeneration, which was accompanied by abnormal mesenchymal gene expression and interstitial cell proliferation. Transcriptomic and pathway analyses of Meg3-depleted C2C12 myoblasts and injured skeletal muscle revealed a significant dysregulation of EMT-related genes, and identified TGFβ as a key upstream regulator. Importantly, inhibition of TGFβR1 and its downstream effectors, and the EMT transcription factor Snai2, restored many aspects of myogenic differentiation in Meg3-depleted myoblasts in vitro. We further demonstrate that reduction of Meg3-dependent Ezh2 activity results in epigenetic alterations associated with TGFβ activation. Thus, Meg3 regulates myoblast identity to maintain proper cell state for progression into differentiation.