Epigenetic and Transcriptional Regulation of Adipogenesis
Presentation Number: OR17-5
Date of Presentation: April 2nd, 2017
Kai Ge*, Ji-Eun Lee and Young-Kwon Park
NIH, Bethesda, MD
PPARγ is a master regulator of adipogenesis. In contrast, the Wnt/β-catenin signaling inhibits adipogenesis. Understanding the mechanisms that control these positive and negative master regulators of adipogenesis may provide new ways to treat obesity and lipodystrophy, the two diseases that are tightly associated with type-II diabetes.
Epigenetic mechanisms, in particular histone methylation, play critical roles in regulation of gene expression and cell differentiation. Histone methylation is implicated in both gene activation and repression, depending on the specific lysine (K) residue that gets methylated. For example, methylation on K4 of histone H3 (H3K4) is associated with gene activation, whereas methylation on K9 or K27 of histone H3 (H3K9 or H3K27) is associated with gene repression.
We are interested in how histone methylations regulate adipogenesis. We have shown: 1) H3K4 methyltransferases MLL3/MLL4 and associated PTIP protein directly control the induction of principal adipogenic transcription factors (TFs) PPARγ and C/EBPα and are essential for adipogenesis; 2) H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis; 3) H3K27 methyltransferase Ezh2 and its methyltransferase activity are required for adipogenesis. Ezh2 directly represses Wntgenes to facilitate adipogenesis. These results indicate that site-specific histone methylations control expression of both positive and negative master regulators of adipogenesis. We are currently investigating the roles of H3K36 methyltransferases and Brd4 in adipogenesis. The progress will be updated at the meeting.
Adipogenesis is induced by treating confluent preadipocytes in culture with the adipogenic cocktail, which activates TFs glucocorticoid receptor (GR) and CREB within minutes and increases expression of TFs C/EBPb, C/EBPd, KLF4 and Krox20 within hours. Using conditional knockout mice and derived preadipocytes, we show that GR accelerates, but is dispensable for, adipogenesis. We also show that endogenous KLF4 and Krox20 are dispensable for adipogenesis in culture and in mice. These unexpected results challenge the existing model on transcriptional regulation in the early phase of adipogenesis and highlight the need of studying adipogenesis in vivo.
Nothing to Disclose: KG, JEL, YKP