Cell Death Differ. February, 2020 27(2): 573-586
MyoD family functions as master regulators to induce muscle-specific gene expression and myogenic differentiation in non-muscle cells, like fibroblasts. Protein arginine methyltransferases (Prmts) catalyze symmetric or asymmetric dimethylation of arginine residues on both histone and non-histone substrates to modulate signaling pathways and gene expression involved in diverse biological processes, including myoblast differentiation. Prmt7 has been known to be involved in muscle differentiation and regeneration. However, the detailed mechanisms and non-histone substrates by which Prmt7 regulates myogenic differentiation is currently unknown. In this study, we demonstrate a positive role of Prmt7 in MyoD-mediated myoblast differentiation.
Prmt7 depletion in primary or C2C12 myoblasts impairs cell cycle withdrawal and myogenic differentiation. Furthermore, Prmt7 depletion decreases the MyoD-reporter activities and the MyoD-mediated myogenic conversion of fibroblasts. Together with MyoD, Prmt7 is recruited to the Myogenin promoter region and Prmt7 depletion attenuates the recruitment of MyoD and its coactivators. The mechanistic study reveals that Prmt7 methylates p38MAPKα at the arginine residue 70, thereby promoting its activation which in turn enhances MyoD activities. The arginine residue 70 to alanine mutation in p38MAPKα impedes MyoD/E47 heterodimerization and the recruitment of Prmt7, MyoD and Baf60c to the Myogenin promoter resulting in blunted Myogenin expression.
In conclusion, we demonstrate a promyogenic role of Prmt7 that augments MyoD-mediated myogenic differentiation through p38MAPK activation. The arginine residue 70 of p38MAPK is the critical target of Prmt7 in MyoD activation and myoblast differentiation.
