H3K9 Methyltransferase G9a Represses PPARgamma Expression and Adipogenesis

Thursday, October 11, 2012 — Poster Session III
10:00 a.m. – Noon	Natcher Conference Center, Building 45	NIDDK	EPIGEN/TRANS/CHROM-6

Authors

• L Wang
• K Ge

Abstract

Understanding the molecular mechanisms underlying adipogenesis may lead to novel approaches to the treatment of obesity and type II diabetes. Adipogenic transcription factor PPARgamma promotes adipogenesis while Wnt proteins inhibit adipogenesis. However, the mechanisms that control the expression of these positive and negative master regulators of adipogenesis remain unclear. We investigate the role of histone H3K9 methyltransferase G9a in regulation of these positive and negative regulators of adipogenesis. Here we show histone methyltransferase G9a represses adipogenesis by inhibiting PPARgamma expression and facilitating Wnt10a expression. By genome-wide profiling in preadipocytes, histone methyltransferase G9a-mediated repressive histone mark H3K9me2 is selectively enriched on the entire PPARgamma gene locus. H3K9me2 and G9a levels decrease during adipogenesis, which correlates inversely with induction of PPARgamma. Removal of H3K9me2 by G9a deletion enhances chromatin opening and binding of adipogenic transcription factor C/EBPbeta to PPARgamma promoter, which promotes PPARgamma expression. Interestingly, G9a represses PPARgamma 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 tissue increases adipogenic gene expression and tissue weight. Taken together, by inhibiting PPARgamma expression and facilitating Wnt10a expression, G9a represses adipogenesis.

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