Kai Ge, Ph.D.
Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology and Receptor Biology
Building 10, Room 8N307
10 Center Drive
Bethesda, MD 20814
We study epigenomic regulation of PPARγ and adipogenesis (generation of fat tissue). We also use adipogenesis as a model system to understand epigenomic regulation of cell fate transition, with a focus on enhancers.
Epigenomic mechanisms, including histone acetylation and methylation, play critical roles in gene regulation. Histone acetylation correlates with gene activation while histone methylation associates with either gene activation or repression, depending on the specific lysine (K) residue that gets methylated. Methylation at K4 of histone H3 (H3K4) is associated with gene activation, whereas methylation at K27 of histone H3 (H3K27) is associated with gene repression. Enhancers control cell-type-specific gene expression and are critical for cell differentiation. Primed enhancers are marked by H3K4 mono-methylation (H3K4me1). Active enhancers are further marked by H3K27 acetylation.
PPARγ is a master regulator of adipogenesis. It is a nuclear receptor and thus a ligand-activated transcription factor (TF). In search for novel cofactors for PPARγ, we identified a nuclear protein complex that contains H3K4 methyltransferase MLL3 (KMT2C) or MLL4 (KMT2D), and the H3K27 demethylase UTX (KDM6A) (JBC 2007, PNAS 2007).
Enhancer regulation by H3K4 methyltransferases MLL3 and MLL4
Combining mouse genetics with next generation sequencing and bioinformatics, we have shown:
- MLL3 and MLL4 are major H3K4me1 methyltransferases required for enhancer activation and cell-type-specific gene expression in differentiation. They are essential for the development of adipose tissue, muscle, mammary gland, B cells, T cells, and heart (eLife 2013, Gene 2017).
- Although enhancer priming by MLL3/MLL4 is dispensable for cell-identity maintenance, it controls cell fate transition by orchestrating H3K27 acetyltransferases CBP/p300-mediated enhancer activation (PNAS 2016, Nucleic Acids Res 2017).
- UTX protein, but not its H3K27 demethylase activity, is required for embryonic stem cell differentiation and mouse development (PNAS 2012). Interestingly, UTX demethylase activity is required for stem cell-mediated muscle regeneration (J Clin Invest 2016).
We are investigating how MLL3/MLL4 and the epigenomic reader Brd4 regulate enhancer activation and enhancer-promoter interaction.
Epigenomic and transcriptional regulation of adipogenesis
- H3K4 methyltransferases MLL3/MLL4 and associated PTIP directly control the induction of principal adipogenic TFs PPARγ and C/EBPα and are essential for adipogenesis (Cell Metab 2009, eLife 2013).
- H3K27 methyltransferase Ezh2 uses its enzymatic activity to constitutively represses Wnt genes to facilitate adipogenesis (PNAS 2010).
- H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis (EMBO J 2013).
Using conditional knockout mice and derived preadipocytes, we also examined the roles of TFs glucocorticoid receptor (GR), KLF4 and Krox20 in adipogenesis. We found that GR accelerates, but is dispensable for, adipogenesis (MCB 2017a). We also found that KLF4 and Krox20 are dispensable for adipogenesis in culture and in mice (MCB 2017b). These unexpected results prompted us to study adipogenesis in vivo.
Epigenomic regulation of nuclear receptor target gene expression
We reported that two pairs of histone acetyltransferases (HATs), GCN5/PCAF and CBP/p300, are specifically required for H3K9 acetylation (H3K9ac) and H3K18/27 acetylation, respectively, in cells. CBP/p300 and their HAT activities are essential, while GCN5/PCAF and associated H3K9ac are dispensable, for nuclear receptor target gene expression (EMBO J 2011). GCN5/PCAF-mediated H3K9ac correlates well with, but is surprisingly dispensable for, the expression of endogenous interferon-β and the vast majority of active genes in fibroblasts. Instead, GCN5/PCAF repress interferon-β production and innate antiviral immunity in cells in a HAT-independent and non-transcriptional manner (EMBO Rep 2014). We are interested in epigenomic regulation of PPARγ and GR target gene expression. We showed that ligand-activated GR accelerates expression of early adipogenic genes in cells by recruiting CBP/p300 to activate C/EBPb-primed enhancers (MCB 2017a). We are investigating the role of H3K36 methylation in regulating PPARγ target gene expression and adipogenesis.
Applying our Research
Understanding how epigenomic mechanisms regulate PPARγ and adipogenesis may provide new ways to treat obesity and type 2 diabetes. Synthetic PPARγ ligands have been used to treat millions of patients with type 2 diabetes. Investigating how epigenomic mechanisms regulate ligand-induced nuclear receptor target gene expression will help us better understand how synthetic PPARγ ligands act as antidiabetic agents.
- Postdoctoral Fellow, The Rockefeller University, 2000–2003
- Postdoctoral Fellow, The Wistar Institute, 1997–2000
- Ph.D., Shanghai Institute of Biochemistry, Chinese Academy of Sciences, 1997
- B.S., Fudan University, 1992
Lee JE, Wang C, Xu S, Cho YW, Wang L, Feng X, Baldridge A, Sartorelli V, Zhuang L, Peng W, Ge K. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. Elife. 2013;2:e01503.
Faralli H, Wang C, Nakka K, Benyoucef A, Sebastian S, Zhuang L, Chu A, Palii CG, Liu C, Camellato B, Brand M, Ge K, Dilworth FJ. UTX demethylase activity is required for satellite cell-mediated muscle regeneration. J Clin Invest. 2016;126(4):1555-65.
Jin Q, Yu LR, Wang L, Zhang Z, Kasper LH, Lee JE, Wang C, Brindle PK, Dent SY, Ge K. Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. EMBO J. 2011;30(2):249-62.
Wang C, Lee JE, Lai B, Macfarlan TS, Xu S, Zhuang L, Liu C, Peng W, Ge K. Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition. Proc Natl Acad Sci U S A. 2016;113(42):11871-11876.
Wang L, Xu S, Lee JE, Baldridge A, Grullon S, Peng W, Ge K. Histone H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis. EMBO J. 2013;32(1):45-59.
Related Scientific Focus Areas
Genetics and Genomics
Molecular Biology and Biochemistry
This page was last updated on August 16th, 2017