title: Histone H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis.
abstract: PPARγ promotes adipogenesis while Wnt proteins inhibit adipogenesis. However, the mechanisms that control expression of these positive and negative master regulators of adipogenesis remain incompletely understood. By genome-wide histone methylation profiling in preadipocytes, we find that among gene loci encoding adipogenesis regulators, histone methyltransferase (HMT) G9a-mediated repressive epigenetic mark H3K9me2 is selectively enriched on the entire PPARγ locus. H3K9me2 and G9a levels decrease during adipogenesis, which correlates inversely with induction of PPARγ. Removal of H3K9me2 by G9a deletion enhances chromatin opening and binding of the early adipogenic transcription factor C/EBPβ to PPARγ promoter, which promotes PPARγ expression. Interestingly, G9a represses PPARγ expression in an HMT activity-dependent manner but facilitates Wnt10a expression independent of its enzymatic activity. Consistently, deletion of G9a or inhibiting G9a HMT activity promotes adipogenesis. Finally, deletion of G9a in mouse adipose tissues increases adipogenic gene expression and tissue weight. Thus, by inhibiting PPARγ expression and facilitating Wnt10a expression, G9a represses adipogenesis.
authors.affiliation: Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Wang
authors.forename: Shiliyang
authors.initials: S
authors.lastname: Xu
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Anne
authors.initials: A
authors.lastname: Baldridge
authors.forename: Sean
authors.initials: S
authors.lastname: Grullon
authors.forename: Weiqun
authors.initials: W
authors.lastname: Peng
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
mesh_terms: D041721:3T3-L1 Cells; D052437:Adipocytes, Brown / Q000166:cytology; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002843:Chromatin / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D005260:Female; D056466:Histone Demethylases / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008297:Male; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D002843:Chromatin; D006657:Histones; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; D051153:Wnt Proteins; C484143:Wnt10a protein, mouse; D056466:Histone Demethylases; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine