title: Sumoylation of the basic helix-loop-helix transcription factor sharp-1 regulates recruitment of the histone methyltransferase G9a and function in myogenesis.
abstract: Sumoylation is an important post-translational modification that alters the activity of many transcription factors. However, the mechanisms that link sumoylation to alterations in chromatin structure, which culminate in tissue specific gene expression, are not fully understood. In this study, we demonstrate that SUMO modification of the transcription factor Sharp-1 is required for its full transcriptional repression activity and function as an inhibitor of skeletal muscle differentiation. Sharp-1 is modified by sumoylation at two conserved lysine residues 240 and 255. Mutation of these SUMO acceptor sites in Sharp-1 does not impact its subcellular localization but attenuates its ability to act as a transcriptional repressor and inhibit myogenic differentiation. Consistently, co-expression of the SUMO protease SENP1 with wild type Sharp-1 abrogates Sharp-1-dependent inhibition of myogenesis. Interestingly, sumoylation acts as a signal for recruitment of the co-repressor G9a. Thus, enrichment of G9a, and histone H3 lysine 9 dimethylation (H3K9me2), a signature of G9a activity, is dramatically reduced at muscle promoters in cells expressing sumoylation-defective Sharp-1. Our findings demonstrate how sumoylation of Sharp-1 exerts an impact on chromatin structure and transcriptional repression of muscle gene expression through recruitment of G9a.
authors: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
authors: Yaju
authors: Y
authors: Wang
authors: Shilpa Rani
authors: SR
authors: Shankar
authors: Devaki
authors: D
authors: Kher
authors: Belinda Mei Tze
authors: BM
authors: Ling
authors: Reshma
authors: R
authors: Taneja
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000502:physiology*; D001665:Binding Sites; D019556:COS Cells; D002454:Cell Differentiation; D002460:Cell Line; D002522:Chlorocebus aethiops; D017124:Conserved Sequence; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000378:metabolism; D057809:HEK293 Cells; D006649:Histocompatibility Antigens / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development; D017570:MyoD Protein / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D058207:Sumoylation; D014158:Transcription, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D006649:Histocompatibility Antigens; D011495:Histone-Lysine N-Methyltransferase; D017570:MyoD Protein; C422085:BHLHE41 protein, human; C057363:MyoD1 myogenic differentiation protein; C445405:EHMT2 protein, human; C404512:SENP1 protein, human
keywords: Chromatin Modification; Differentiation; Epigenetics; Helix-Loop-Helix Transcription Factors; Histone Methylation; Myogenesis; Skeletal Muscle; Sumoylation; Transcription Factors
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