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bioRxiv · 10.1101/2020.06.15.152884

The long noncoding RNA Meg3 regulates myoblast plasticity and muscle regeneration through epithelial-mesenchymal transition

Dill, T. L.·Carroll, A.·Gao, J.·Naya, F. J.
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Abstract

Formation of skeletal muscle is among the most striking examples of cellular plasticity in animal tissue development, where mononucleated, lineage-restricted progenitor cells are reprogrammed by epithelial-mesenchymal transition (EMT) to produce multinucleated myofibers. While some mediators of EMT have been shown to function in muscle formation, the regulation of this process in this tissue remains poorly understood. The long noncoding RNA (lncRNA) Meg3 is processed from the >200 kb Dlk1-Dio3 polycistron that we have previously shown is involved in skeletal muscle differentiation and regeneration. Here, we demonstrate that Meg3 regulates EMT in myoblast differentiation and skeletal muscle regeneration. Chronic inhibition of Meg3 in C2C12 myoblasts promoted aberrant EMT activation, and suppressed cell state transitions required for fusion and myogenic differentiation. Furthermore, adenoviral Meg3 knockdown compromised muscle regeneration, which was accompanied by abnormal mesenchymal gene expression and interstitial cell proliferation in the regenerating milieu. 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, chemical inhibition of TGF{beta}R1, as well as its downstream effectors ROCK1/2 and p38 MAPK, restored many aspects of myogenic differentiation in Meg3-depleted myoblasts in vitro. Thus, Meg3 regulates myoblast identity to maintain proper cell state for progression into differentiation. Summary statementMuscle differentiation and regeneration are regulated by an evolutionarily conserved long noncoding RNA that restricts gene expression to coordinate cell state transitions

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Dill, T. L., Carroll, A., Gao, J., Naya, F. J.. 2020-06-15. The long noncoding RNA Meg3 regulates myoblast plasticity and muscle regeneration through epithelial-mesenchymal transition. https://doi.org/10.1101/2020.06.15.152884

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