Kai Ge, Ph.D.
Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology & Receptor Biology
We investigate epigenomic regulation of cell fate transition, with a focus on transcriptional enhancers. We also study epigenomic and transcriptional regulation of adipose tissue development and expansion.
Epigenomic regulation of enhancers
Epigenomic mechanisms, including histone modification and chromatin remodeling, play critical roles in gene regulation. Enhancers control cell-type-specific gene expression and are critical for cell differentiation and tissue development. Primed enhancers are marked by histone H3K4 mono-methylation (H3K4me1). Active enhancers are further marked by H3K27 acetylation (H3K27ac). We identified MLL3 (KMT2C) and MLL4 (KMT2D) as major H3K4me1 methyltransferases on enhancers (eLife 2013), and CBP and p300 as the H3K27 acetyltransferases in mammalian cells (EMBO J 2011).
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, MCB 2020). We have shown:
- MLL3/4 colocalize with lineage-determining TFs (LDTFs) 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 (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) LDTFs recruit MLL3/4 to prime enhancers, 2) MLL3/4 facilitate the binding of CBP/p300, which activate enhancers, 3) Brd4 recognizes active enhancers and recruits Mediator and RNA Polymerase II to activate cell-type-specific gene expression (Nat Commun 2017).
- A positive feedback between MLL4 and the SWI/SNF chromatin remodeling complex BAF in promoting LDTF-dependent activation of cell type-specific enhancers (Nat Commun 2021).
- While the MED1 subunit of the Mediator coactivator complex marks active enhancers, it is not generally required for transcription (Genes Dev 2021).
Epigenomic regulation of adipose tissue development and expansion
Epigenomic mechanisms play critical roles in adipose tissue development (adipogenesis, reviewed in MCB 2019) and expansion. 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). MLL3/4-associated PAGR1 regulates adipogenesis by controlling induction of C/EBPβ and C/EBPδ (MCB 2020).
- H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis (EMBO J 2013) while H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis (PNAS 2010). Depletion of H3K36 methyltransferase Nsd2 impairs adipose tissue development and function (Nat Commun 2018).
- Brd4 binding on active enhancers controls cell identity gene induction in adipogenesis (Nat Commun 2017).
- BAF is the SWI/SNF complex that colocalizes with MLL4 and LDTFs on active enhancers. BAF is required for adipogenesis while the promoter enriched SWI/SNF complex PBAF is dispensable (Nat Commun 2021).
- Although ligand-bound glucocorticoid receptor (GR) accelerates adipogenesis in culture, endogenous GR is dispensable for adipogenesis in culture and in mice (MCB 2017a). KLF4 and Krox20 are dispensable for adipogenesis (MCB 2017b).
- MED1 is a lipogenesis coactivator required for postnatal adipose expansion (Genes Dev 2021).
Applying our Research
Understanding how epigenomic mechanisms regulate adipose tissue development and expansion may provide new ways to treat obesity. 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
- Park YK, Lee JE, Yan Z, McKernan K, O'Haren T, Wang W, Peng W, Ge K. Interplay of BAF and MLL4 promotes cell type-specific enhancer activation. Nat Commun. 2021;12(1):1630.
- Jang Y, Park YK, Lee JE, Wan D, Tran N, Gavrilova O, Ge K. MED1 is a lipogenesis coactivator required for postnatal adipose expansion. Genes Dev. 2021;35(9-10):713-728.
- 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;40(17).
- 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, Schmidt H, Lai B, Ge K. Transcriptional and Epigenomic Regulation of Adipogenesis. Mol Cell Biol. 2019;39(11).
Related Scientific Focus Areas
Genetics and Genomics
Molecular Biology and Biochemistry
This page was last updated on Wednesday, August 17, 2022