The long noncoding RNA Meg3 regulates myoblast plasticity and muscle regeneration through epithelial-mesenchymal transition
The long noncoding RNA Meg3 regulates myoblast plasticity and muscle regeneration through epithelial-mesenchymal transition
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DOI：
10.1242/dev.194027
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发表时间：
2021-01-01
期刊：
影响因子：
4.6
通讯作者：
Naya, Francisco J.
中科院分区：
文献类型：
--
作者：
Dill, Tiffany L.;Carroll, Alina;Naya, Francisco J.
Formation of skeletal muscle is among the most striking examples of cellular plasticity in animal tissue development, and while muscle progenitor cells are reprogrammed by epithelial-mesenchymal transition (EMT) to migrate during embryonic development, the regulation of EMT in post-natal myogenesis remains poorly understood. Here, we demonstrate that the long noncoding RNA (IncRNA) 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 TGF beta as a key upstream regulator. Importantly, inhibition of TGF beta R1 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 TGF beta activation. Thus, Meg3 regulates myoblast identity to facilitate progression into differentiation.
