Lysine methyltransferase G9a methylates the transcription factor MyoD and regulates skeletal muscle differentiation.
Skeletal muscle cells have served as a paradigm for understanding mechanisms leading to cellular differentiation. The proliferation and differentiation of muscle precursor cells require the concerted activity of myogenic regulatory factors including MyoD. In addition, chromatin modifiers mediate dynamic modifications of histone tails that are vital to reprogramming cells toward terminal differentiation. Here, we provide evidence for a unique dimension to epigenetic regulation of skeletal myogenesis. We demonstrate that the lysine methyltransferase G9a is dynamically expressed in myoblasts and impedes differentiation in a methyltransferase activity-dependent manner. In addition to mediating histone H3 lysine-9 di-methylation (H3K9me2) on MyoD target promoters, endogenous G9a interacts with MyoD in precursor cells and directly methylates it at lysine 104 (K104) to constrain its transcriptional activity. Mutation of K104 renders MyoD refractory to inhibition by G9a and enhances its myogenic activity. Interestingly, MyoD methylation is critical for G9a-mediated inhibition of myogenesis. These findings provide evidence of an unanticipated role for methyltransferases in cellular differentiation states by direct posttranslational modification of a transcription factor.
Department of Physiology, National University of Singapore, Singapore 117597.
Belinda Mei Tze
BM
Ling
Narendra
N
Bharathy
Teng-Kai
TK
Chung
Wai Kay
WK
Kok
SiDe
S
Li
Yong Hua
YH
Tan
Vinay Kumar
VK
Rao
Suma
S
Gopinadhan
Vittorio
V
Sartorelli
Martin J
MJ
Walsh
Reshma
R
Taneja
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000166:cytology* / Q000201:enzymology*; D017570:MyoD Protein / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding
D017570:MyoD Protein; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine