Jeong Hyeon-Ju, Lee Sang-Jin, Lee Hye-Jin, Kim Hye-Been, Anh Vuong Tuan, Cho Hana, Bae Gyu-Un, Kang Jong-Sun
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Single Cell Network Research Center, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
Drug Information Research Institute, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
Cell Death Differ. 2020 Feb;27(2):573-586. doi: 10.1038/s41418-019-0373-y. Epub 2019 Jun 26.
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.
肌分化因子（MyoD）作为主要调节因子，可诱导肌肉特异性基因表达和成肌分化。在此，我们证明了蛋白质精氨酸甲基转移酶7（Prmt7）通过激活p38丝裂原活化蛋白激酶（p38MAPK）在MyoD介导的成肌细胞分化中发挥积极作用。原代或C2C12成肌细胞中Prmt7的缺失会损害细胞周期退出和成肌分化。此外，Prmt7的缺失会降低MyoD报告基因的活性以及MyoD介导的成纤维细胞向成肌细胞的转化。Prmt7与MyoD一起被招募到肌细胞生成素（Myogenin）启动子区域，Prmt7的缺失会减弱MyoD及其共激活因子的招募。机制研究表明，Prmt7使p38MAPKα的精氨酸残基70甲基化，从而促进其激活，进而增强MyoD的活性。p38MAPKα中精氨酸残基70突变为丙氨酸会阻碍MyoD/E47异二聚体的形成以及Prmt7、MyoD和BRG1相关因子60c（Baf60c）向Myogenin启动子的募集，导致Myogenin表达减弱。总之，Prmt7通过使p38MAPKα的精氨酸残基70甲基化来促进MyoD介导的成肌细胞分化。
