title: G9a mediates Sharp-1-dependent inhibition of skeletal muscle differentiation.
abstract: Sharp-1, a basic helix-loop-helix transcription factor, is a potent repressor of skeletal muscle differentiation and is dysregulated in muscle pathologies. However, the mechanisms by which it inhibits myogenesis are not fully understood. Here we show that G9a, a lysine methyltransferase, is involved in Sharp-1-mediated inhibition of muscle differentiation. We demonstrate that G9a directly interacts with Sharp-1 and enhances its ability to transcriptionally repress the myogenin promoter. Concomitant with a differentiation block, G9a-dependent histone H3 lysine 9 dimethylation (H3K9me2) and MyoD methylation are apparent upon Sharp-1 overexpression in muscle cells. RNA interference-mediated reduction of G9a or pharmacological inhibition of its activity erases these repressive marks and rescues the differentiation defect imposed by Sharp-1. Our findings provide new insights into Sharp-1-dependent regulation of myogenesis and identify epigenetic mechanisms that could be targeted in myopathies characterized by elevated Sharp-1 levels.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Belinda Mei Tze
authors.initials: BM
authors.lastname: Ling
authors.forename: Suma
authors.initials: S
authors.lastname: Gopinadhan
authors.forename: Wai Kay
authors.initials: WK
authors.lastname: Kok
authors.forename: Shilpa Rani
authors.initials: SR
authors.lastname: Shankar
authors.forename: Pooja
authors.initials: P
authors.lastname: Gopal
authors.forename: Narendra
authors.initials: N
authors.lastname: Bharathy
authors.forename: Yaju
authors.initials: Y
authors.lastname: Wang
authors.forename: Reshma
authors.initials: R
authors.lastname: Taneja
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008856:Microscopy, Fluorescence; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D009154:Mutation; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D018008:Myogenin / Q000235:genetics; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C470968:Bhlhb3 protein, mouse; D006657:Histones; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D018008:Myogenin; D014157:Transcription Factors; D008156:Luciferases; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine