The National Institute of Diabetes & Digestive & Kidney Diseases

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

My laboratory studies epigenetic regulation of adipogenesis and nuclear receptor target gene expression.

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 methylation at K27 of histone H3 (H3K27) is associated with gene repression. Histone lysine methylation is dynamically regulated by site-specific methyltransferases and demethylases.

PPARg is the master regulator of adipogenesis (generation of fat). PPARg 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.

PPARg is a nuclear receptor and thus a ligand-activated transcription factor. Synthetic PPARg ligands have been used to treat millions of patients with type II diabetes. Investigating how epigenetic mechanisms regulate ligand-induced nuclear receptor target gene expression will help understand the mechanism of action of synthetic PPARg ligands as anti-diabetic agents.

II. Recent Work:
Identification and characterization of histone methyltransferases and demethylases
In search for novel transcription cofactors for PPARg, 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 our finding that H3K4 methyltransferases MLL3/MLL4 physically associate with 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 will investigate 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).

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 is essential for the robust induction of PPARg and C/EBPa, the two principal adipogenic transcription factors, during adipogenesis. Accordingly, PTIP is required for adipogenesis (Cell Metabolism, 2009).

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

These results provide an initial view of epigenetic regulation of adipogenesis and suggest that histone methylation regulates 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 are interested in 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. Epigenetic regulation of adipogenesis by H3K9 methylation
2. Regulation of adipogenic transcription program by PTIP and PA1
3. Regulation of gene expression and cell differentiation by UTX and MLL4
4. Regulation of gene expression and adipogenesis by GCN5

[Search PubMed for Dr. Ge's Publications]

1. 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 (in press). [Full Text/Abstract]

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

3. 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]

4. 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]

5. 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]

6. 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]

7. 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]

8. 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]

9. 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]

10. 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]

11. 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]

12. 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]

13. 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]

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

15. 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]

16. 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]