Histone H3K9 Methyltransferase G9a Represses PPAR Expression and Adipogenesis [Affymetrix expression data]

PPAR 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 enriched on the entire PPAR locus. H3K9me2 and G9a levels decrease during adipogenesis, which correlates inversely with induction of PPAR. Removal of H3K9me2 by G9a deletion enhances chromatin opening and binding of adipogenic transcription factor C/EBP-beta to PPAR promoter, which promotes PPAR expression. Interestingly, G9a represses PPAR 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 PPAR expression and facilitating Wnt10a expression, G9a represses adipogenesis.

4

Wang L, Xu S, Lee JE, Baldridge A, Grullon S, Peng W, Ge K