Kai Ge, Ph.D.
Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology and Receptor Biology
Building 10, Room 8N307
10 Center Dr
Bethesda, MD 20814
+1 301 451 1998
We study epigenomic regulation of PPARγ and adipogenesis. We also use adipogenesis and mouse embryonic stem (ES) cells as model systems to understand epigenomic regulation of cell fate transition, with a focus on enhancers.
Epigenomic mechanisms, including histone modification and chromatin remodeling play critical roles in gene regulation. Histone acetylation correlates with gene activation while methylation correlates with either activation or repression, depending on the specific lysine (K) residue that gets methylated. Methylations on K4 and K36 of histone H3 (H3K4 and H3K36) correlate with gene activation, whereas methylations on K9 and K27 of histone H3 (H3K9 and H3K27) correlate with gene repression.
Enhancers control cell-type-specific gene expression and are critical for cell differentiation and tissue development. Primed enhancers are marked by H3K4 mono-methylation (H3K4me1). Active enhancers are further marked by H3K27 acetylation (H3K27ac). We identified MLL3 (KMT2C) and MLL4 (KMT2D) as the major H3K4me1 methyltransferases on enhancers (eLife 2013), and CBP and p300 as the H3K27 acetyltransferases in mammalian cells (EMBO J 2011).
Epigenomic regulation of enhancers
PPARγ is a ligand-activated transcription factor (TF) and a master regulator of adipogenesis. In search for novel PPARγ cofactors, we identified a nuclear protein complex that contains MLL3/MLL4 and the H3K27 demethylase UTX (KDM6A) (JBC 2007, PNAS 2007). MLL3/4 and UTX are tumor suppressors highly mutated in many types of cancers as well as Kabuki syndrome and congenital heart disease (reviewed in Gene 2017). We have shown:
- MLL3/4 colocalize with lineage-determining TFs on enhancers and are required for enhancer activation, cell-type-specific gene expression, and cell differentiation (eLife 2013, ). MLL3/4 control cell fate transition by orchestrating H3K27 acetyltransferases CBP/p300-mediated enhancer activation (PNAS 2016, NAR 2017).
- UTX protein, but not its H3K27 demethylase activity, is required for ES cell differentiation and mouse development (PNAS 2012). Interestingly, UTX demethylase activity is required for stem cell-mediated muscle regeneration (JCI 2016).
- MLL4 protein, rather than H3K4me1, controls p300 recruitment to enhancers during ES cell differentiation, suggesting that MLL4 may regulate enhancer activation independent of H3K4me1 (PNAS 2016). Ectopic expression of H3.3K4M, an inhibitor of H3K4 methylation, or deletion of the enzymatic SET domain, destabilizes MLL3/4 proteins and prevents enhancer activation in cell differentiation (NAR 2019).
- The epigenomic reader Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis. Our data suggest a model of sequential actions of epigenomic regulators on enhancers: 1) lineage-determining TFs recruit MLL3/4 to prime enhancer regions and label them with H3K4me1, 2) MLL3/4 facilitate the binding of CBP/p300, which activate enhancers and label them with H3K27ac, 3) Brd4 recognizes active enhancers and recruits Mediator and RNA Polymerase II to activate cell-type-specific gene expression (Nat Commun 2017).
Epigenomic regulation of adipogenesis and PPARγ
Epigenomic mechanisms play critical roles in adipogenesis and PPARγ target gene expression (reviewed in MCB 2019). We have shown:
- H3K4 methyltransferases MLL3/4 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).
- H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis (EMBO J 2013).
- H3K27 methyltransferase Ezh2 constitutively represses Wnt genes to facilitate adipogenesis (PNAS 2010).
- Depletion of Nsd2-mediated H3K36 methylation impairs adipose tissue development and function (Nat Commun 2018).
- Epigenomic profiling of brown adipogenesis in culture (NAR 2017).
- Brd4 binding on active enhancers controls cell identity gene induction in adipogenesis (Nat Commun 2017).
We reported that although ligand-bound glucocorticoid receptor (GR) accelerates adipogenesis in culture, endogenous GR is dispensable for adipogenesis in culture and in mice (MCB 2017a). We also found that KLF4 and Krox20 are dispensable for adipogenesis in vivo (MCB 2017b). These unexpected findings prompted us to study adipogenesis in vivo.We are also interested in epigenomic regulation of PPARγ target gene expression.
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
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.
Lee JE, Park YK, Park S, Jang Y, Waring N, Dey A, Ozato K, Lai B, Peng W, Ge K. Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis. Nat Commun. 2017;8(1):2217.
Zhuang L, Jang Y, Park YK, Lee JE, Jain S, Froimchuk E, Broun A, Liu C, Gavrilova O, Ge K. Depletion of Nsd2-mediated histone H3K36 methylation impairs adipose tissue development and function. Nat Commun. 2018;9(1):1796.
Jang Y, Broun A, Wang C, Park YK, Zhuang L, Lee JE, Froimchuk E, Liu C, Ge K. H3.3K4M destabilizes enhancer H3K4 methyltransferases MLL3/MLL4 and impairs adipose tissue development. Nucleic Acids Res. 2019;47(2):607-620.
Lee JE, Cho YW, Deng CX, Ge K. MLL3/MLL4-associated PAGR1 Regulates Adipogenesis by Controlling Induction of C/EBPβ and C/EBPδ. Mol Cell Biol. 2020.
Related Scientific Focus Areas
Genetics and Genomics
Molecular Biology and Biochemistry
This page was last updated on July 1st, 2020