The National Institute of Diabetes & Digestive & Kidney Diseases

B.S., Fudan University, Shanghai, 1992
Ph.D., Shanghai Institute of Biochemistry, Chinese Academy of Sciences, 1997

My laboratory studies epigenetic regulation of PPAR g and adipogenesis.

I. Background:
Epigenetic mechanisms, such as histone acetylation and methylation, play critical roles in regulating gene expression and cell differentiation. Histone acetylation generally correlates with gene activation and is dynamically regulated by acetyltransferases and deacetylases. Histone lysine (K) methylation has been implicated in both gene activation and repression, depending on the specific K residue that gets methylated. For example, methylation at K4 of histone H3 (H3K4) is associated with gene activation, whereas methylations at K9 and K27 of histone H3 (H3K9 and H3K27) are associated with gene repression. Histone lysine methylation is dynamically regulated by site-specific methyltransferases and demethylases.

PPAR g is the master regulator of adipogenesis (generation of fat). PPAR g cooperates with other adipogenic transcription factors to promote adipogenesis. In contrast, the Wnt/β-catenin signaling inhibits adipogenesis. Understanding how epigenetic mechanisms regulate 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.

PPAR g is a nuclear receptor and thus a ligand-activated transcription factor. Synthetic PPAR g ligands have been used to treat type II diabetes patients but have undesirable side effects. Investigating how epigenetic mechanisms regulate ligand-induced nuclear receptor target gene expression may help design the next generation of diabetes drugs.          

II. Recent Work:
Identification and characterization of histone methyltransferases and demethylases          
In search for novel transcription cofactors for PPAR g , we identified the nuclear protein PTIP. We show:

1. In cells, PTIP and a novel protein PA1 are both subunits of a histone H3K4 methyltransferase complex (i.e. MLL3/MLL4 complex) that contains H3K4 methyltransferases MLL3 and MLL4, and the JmjC domain-containing protein UTX (JBC, 2007) [also see Research Images Fig. 1].

2. The JmjC domain-containing proteins UTX and JMJD3 are histone H3K27-specific demethylases (PNAS, 2007).

Based on the direct physical interaction between H3K4 methyltransferases MLL3/MLL4 and H3K27 demethylase UTX, we propose that by adding an active epigenetic mark (methylation on H3K4) and removing a repressive one (methylation on H3K27), the MLL3/MLL4 complex may use two distinct histone modifying activities to synergistically activate target gene expression [see Research Images Fig. 2]. We are investigating the roles of PTIP, PA1, and associated histone modifying enzymes in epigenetic regulation of PPARg and adipogenesis.

3. UTX controls mesoderm differentiation of embryonic stem cells independent of its demethylase activity (PNAS, 2012). We are investigating enzymatic activity-dependent and -independent functions of UTX using knockin cells and mice.

Epigenetic regulation of adipogenesis by histone methylation
We use adipogenesis as a model system to study epigenetic regulation of cell differentiation. We show:

1. Histone H3K4 methylation regulator PTIP directly controls the induction of principal adipogenic transcription factors PPARg and C/EBPa and is essential for adipogenesis (Cell Metabolism, 2009). We are investigating the molecular mechanism by which PTIP controls the induction of  PPARg and C/EBPa in the early phase of adipogenesis.

2. Histone H3K27 methyltransferase Ezh2 uses its enzymatic activity to constitutively represses Wnt genes to facilitate adipogenesis. Acetylation and trimethylation on H3K27 appear to play opposing roles in regulating Wnt expression (PNAS, 2010).

3. Histone H3K9 methyltransferase G9a represses PPARg expression in an enzymatic activity-dependent manner but facilitates Wnt10a expression independent of its enzymatic activity. Accordingly, G9a represses adipogenesis. (EMBO J, 2013).

These results provide an initial view of epigenetic regulation of adipogenesis and suggest that site-specific histone methylations control expression of both positive and negative master regulators of adipogenesis [reviewed in BBA 2012, also see Research Images Fig. 3].

Epigenetic regulation of nuclear receptor target gene expression
We study how epigenetic mechanisms regulate nuclear receptor target gene expression. We report that the two pairs of histone acetyltransferases (HATs), GCN5/PCAF and CBP/p300, are specifically required for H3K9 acetylation (H3K9ac) and H3K18/27 acetylation (H3K18/27ac), respectively, in cells. Further, we show that CBP/p300 and their HAT activities are essential, while GCN5/PCAF and associated H3K9ac are dispensable, for ligand-induced nuclear receptor target gene expression. These results highlight the substrate and site specificities of HATs in cells, demonstrate the distinct roles of GCN5/PCAF- and CBP/p300-mediated histone acetylations in gene activation, and suggest an important role of CBP/p300-mediated H3K18/27ac in nuclear receptor target gene expression (EMBO J, 2011).

III. Current Efforts:
1. Regulation of early adipogenic transcription program by PA1
2. Regulation of gene expression and cell differentiation by MLL4 and UTX
3. Regulation of adipogenic transcription program by PTIP and MLL4
4. Generation and characterization of mice lacking brown adipose tissue
5. Epigenomic analysis of brown adipogenesis  

 [ Search PubMed for Dr. Ge's Publications ]

1.      Wang L, Xu S, Lee JE, Baldridge A, Grullon S, Peng W, Ge K. (2013) Histone H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis. EMBO J 32: 45 - 59. [Full Text/Abstract, with Editorial comment, highlighted in Nat Rev Mol Cell Biol]

2.      Wang C, Lee J, Cho YW, Xiao Y, Jin Q, Liu C, Ge K. (2012) UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity. Proc Natl Acad Sci U S A 109:15324-9. [Full Text/Abstract]

3.      Ge K. (2012) Epigenetic regulation of adipogenesis by histone methylation (review). Biochim Biophys Acta 1819(7):727-32. [Full Text/Abstract]

4.      Cho YW, Hong S, Ge K. (2012) Affinity purification of MLL3/MLL4 histone H3K4 methyltransferase complex. Methods Mol Biol 809:465-72. [Full Text/Abstract]

5.      Wang C, Liu Z, Woo-C, Li Z, Wang L, Wei JS, Marquez VE, Bates SE, Jin Q, Khan J, Ge K, Thiele CJ. (2012) EZH2 mediates epigenetic silencing of neuroblastoma suppressor genes CASZ1, CLU, RUNX3 and NGFR. Cancer Res 72:315-24. [Full Text/Abstract]

6.      Jin Q, Yu LR, Wang L, Zhang Z, Kasper LH, Lee JE, Wang C, Brindle PK, Dent SY, Ge K. (2011) Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. EMBO J 30: 249-62. [Full Text/Abstract]

7.      Wang L, Jin Q, Lee JE, Su IH, Ge K. (2010) Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis. Proc Natl Acad Sci U S A 107: 7317-22. [Full Text/Abstract]

8.      Cho YW, Hong S, Jin Q, Wang L, Lee JE, Gavrilova O, Ge K. (2009) Histone methylation regulator PTIP is required for PPARg and C/EBPa expression and adipogenesis. Cell Metab 10: 27–39. [Abstract] [Full Text]

9.      Gong Z, Cho YW, Kim J, Ge K, Chen J. (2009) Accumulation of PTIP to sites of DNA breaks via RNF8-dependent pathway is required for cell survival following DNA damage. J Biol Chem 284: 7284-93. [Full Text/Abstract]

10.   Ge K, Cho YW, Guo H, Hong TB, Guermah M, Ito M, Yu H, Kalkum M, Roeder RG. (2008) Alternative mechanisms by which Mediator subunit MED1/TRAP220 regulates PPARg-stimulated adipogenesis and target gene expression. Mol Cell Biol 28: 1081-91. [Full Text/Abstract]

11.   Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K. (2007) Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci U S A 104: 18439-44. [Full Text/Abstract]

12.   Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, Ge K. (2007) PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. [JBC Paper of the Week]. J Biol Chem 282: 20395-406. [Full Text/Abstract]

13.   Guermah M, Ge K, Chiang CM, Roeder RG. (2003) The TBN protein, which is essential for early embryonic mouse development, is an inducible TAFII implicated in adipogenesis. Mol Cell 12: 991-1001. [Full Text/Abstract]

14.   Ge K, Guermah M, Yuan CX, Ito M, Wallberg AE, Spiegelman BM, Roeder RG. (2002) Transcription coactivator TRAP220 is required for PPARgamma 2-stimulated adipogenesis. Nature 417: 563-7. [Full Text/Abstract]

15.   Ge K and Prendergast GC. (2000) Bin2, a functionally nonredundant member of the BAR adaptor gene family. Genomics 67: 210-20. [Full Text/Abstract]

16.   Ge K, DuHadaway J, Du W, Herlyn M, Rodeck U, Prendergast GC. (1999) Mechanism for elimination of a tumor suppressor: aberrant splicing of a brain-specific exon causes loss of function of Bin1 in melanoma. Proc Natl Acad Sci U S A 96: 9689-94. [Full Text/Abstract]

17.   Ge K, Xu L, Zheng Z, Xu D, Sun L, Liu X. (1997) Transduction of cytosine deaminase gene makes rat glioma cells highly sensitive to 5-fluorocytosine. Int J Cancer 71: 675-9. [Full Text/Abstract]