Abstract

MyoD functions as a master regulator to induce muscle-specific gene expression and myogenic differentiation. Here, we demonstrate a positive role of Protein arginine methyltransferase 7 (Prmt7) in MyoD-mediated myoblast differentiation through p38MAPK activation. 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, Prmt7 promotes MyoD-mediated myoblast differentiation through methylation of p38MAPKα at arginine residue 70.

Highlights

  • Skeletal muscle regeneration proceeds through multiple steps, including activation of quiescent satellite cells, These authors contributed : Hyeon-Ju Jeong, Sang-Jin LeeEdited by B

  • To the expression pattern of Myogenin and myosin heavy chain (MHC), Protein arginine methyltransferase 7 (Prmt7) was enhanced at differentiation day 1 (D1) and further increased at D3, while Prmt4 and Prmt5 levels were gradually reduced during differentiation (Fig. 1a and S1a)

  • C2C12 cells were stably transfected with control pSuper or Prmt7 shRNA vectors and their differentiation was assessed by immunoblotting and MHC immunostaining (Fig. 1b, c and S1b)

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Summary

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Skeletal muscle regeneration proceeds through multiple steps, including activation of quiescent satellite cells, These authors contributed : Hyeon-Ju Jeong, Sang-Jin Lee. In the DNA damage response, Prmt interacts with Brg and Baf subunits of SWI/SNF chromatin remodeling proteins to suppress DNA repair gene expression through symmetric dimethylation of histone H2AR3 and histone H4R3 at the target DNA repair genes [1]. Both Prmt and Prmt are recently found in euchromatic regions and mediate symmetric methylation of histone H3R2, thereby facilitating the recruitment of transcription regulators in cell differentiation [21]. The arginine residue 70 of p38MAPK is the critical target of Prmt in MyoD activation and myoblast differentiation

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