Histone H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis

EMBO J. 2013 Jan 9;32(1):45-59. doi: 10.1038/emboj.2012.306. Epub 2012 Nov 23.


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes, Brown / cytology
  • Adipogenesis / genetics
  • Adipogenesis / physiology*
  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Cell Differentiation
  • Chromatin / genetics
  • Chromatin Immunoprecipitation
  • Epigenesis, Genetic
  • Female
  • Histone Demethylases / metabolism*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism*
  • Lysine / metabolism
  • Male
  • Methylation
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Promoter Regions, Genetic / genetics
  • Sequence Analysis, DNA
  • Sequence Deletion
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*


  • CCAAT-Enhancer-Binding Protein-beta
  • Chromatin
  • Histones
  • Nerve Tissue Proteins
  • PPAR gamma
  • Wnt Proteins
  • Wnt10a protein, mouse
  • Histone Demethylases
  • G9a protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Lysine