Modulation of lysine methylation in myocyte enhancer factor 2 during skeletal muscle cell differentiation.
Myocyte enhancer factor 2 (MEF2) is a family of transcription factors that regulates many processes, including muscle differentiation. Due to its many target genes, MEF2D requires tight regulation of transcription activity over time and by location. Epigenetic modifiers have been suggested to regulate MEF2-dependent transcription via modifications to histones and MEF2. However, the modulation of MEF2 activity by lysine methylation, an important posttranslational modification that alters the activities of transcription factors, has not been studied. We report the reversible lysine methylation of MEF2D by G9a and LSD1 as a regulatory mechanism of MEF2D activity and skeletal muscle differentiation. G9a methylates lysine-267 of MEF2D and represses its transcriptional activity, but LSD1 counteracts it. This residue is highly conserved between MEF2 members in mammals. During myogenic differentiation of C2C12 mouse skeletal muscle cells, the methylation of MEF2D by G9a decreased, on which MEF2D-dependent myogenic genes were upregulated. We have also identified lysine-267 as a methylation/demethylation site and demonstrate that the lysine methylation state of MEF2D regulates its transcriptional activity and skeletal muscle cell differentiation.
Department of Biomedical Sciences and Biochemistry and Molecular Biology, National Creative Research Center for Epigenome Reprogramming Network, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 110-799, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 410-769, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, National Research Laboratory for Chromatin Dynamics, College of Pharmacy, Sungkyunkwan University, Suwon 440-746 and WCU Department of Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University, Seoul 110-799, Republic of Korea.
Jinmi
J
Choi
Hyonchol
H
Jang
Hyunsoo
H
Kim
Jong-Hyuk
JH
Lee
Seong-Tae
ST
Kim
Eun-Jung
EJ
Cho
Hong-Duk
HD
Youn
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D057809:HEK293 Cells; D056466:Histone Demethylases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D064326:MEF2 Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D014158:Transcription, Genetic
D002843:Chromatin; D064326:MEF2 Transcription Factors; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D010089:Oxidoreductases, N-Demethylating; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine