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

Epigenetic Regulation of PPARg and Adipogenesis
My laboratory studies epigenetic regulation of: 1) PPARg expression and adipogenesis; 2) ligand-induced nuclear receptor target gene expression.

I. Background:
        Epigenetic mechanisms, such as histone acetylation and methylation, play critical roles in regulation of gene expression. 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 a member of the nuclear receptor superfamily of ligand-activated transcription factors and is the master regulator of adipogenesis (generation of fat). PPARg expression is strongly induced in the early phase of adipogenesis. Understanding how epigenetic mechanisms regulate PPARg expression and adipogenesis may provide new ways to treat obesity and lipodystrophy, the two diseases which are tightly associated with type II diabetes.
        While the endogenous PPARg ligands remain to be determined, highly specific synthetic ligands for PPARg have been used to treat millions of patients with type II diabetes. Investigating how epigenetic mechanisms regulate ligand-induced PPARg target gene expression will help understand the mechanism of action of synthetic PPARg ligands as anti-diabetic agents, which may facilitate the development of the next generation of diabetes drugs.

II. Recent Work:
        In search for novel transcriptional cofactors for PPARg, we identified the nuclear protein PTIP. We have been studying the roles of PTIP and associated histone modifying enzymes in epigenetic regulation of PPARg and adipogenesis. We show that:

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).

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

Methylation on H3K4 is an activating epigenetic mark while methylation on H3K27 is a repressive one. Based on our finding that H3K4 methyltransferases MLL3/MLL4 physically associate with H3K27 demethylase UTX, we propose that by adding an activating epigenetic mark and removing a repressive one, the MLL3/MLL4 complex may use two distinct histone modifying activities to synergistically activate target gene expression.

3. Histone methylation regulator PTIP is essential for the robust induction of PPARg and C/EBP a , the two principal adipogenic transcription factors, during adipogenesis. Accordingly, PTIP-/- cells show striking defects in adipogenesis (Cell Metab, 2009).

III. Current Efforts:

1. Generation and characterization of mice deficient for MLL3, MLL4, UTX and PA1.

2. Epigenetic regulation of PPARg expression during adipogenesis by MLL3/MLL4 and UTX

3. Regulation of ligand-induced PPARg target gene expression by MLL3/MLL4 complex

4. Epigenetic regulation of adipogenesis by histone H3K27 methylation

5. Epigenetic regulation of ligand-induced nuclear receptor target gene expression

8. Wang S, Ge K, Roeder RG, Hankinson O. Role of mediator in transcriptional activation by the aryl hydrocarbon receptor. J Biol Chem(279): 13593-600, 2004. [ Full Text/Abstract ]

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

10. Mueller E, Drori S, Aiyer A, Yie J, Sarraf P, Chen H, Hauser S, Rosen ED, Ge K, Roeder RG, Spiegelman BM. Genetic analysis of adipogenesis through peroxisome proliferator-activated receptor gamma isoforms. J Biol Chem(277): 41925-30, 2002. [ Full Text/Abstract ]

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

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

13. Ge K, Minhas F, Duhadaway J, Mao NC, Wilson D, Buccafusca R, Sakamuro D, Nelson P, Malkowicz SB, Tomaszewski J, Prendergast GC. Loss of heterozygosity and tumor suppressor activity of Bin1 in prostate carcinoma. Int J Cancer(86): 155-61, 2000. [ Full Text/Abstract ]

14. Ge K, Duhadaway J, Sakamuro D, Wechsler-Reya R, Reynolds C, Prendergast GC. Losses of the tumor suppressor BIN1 in breast carcinoma are frequent and reflect deficits in programmed cell death capacity. Int J Cancer(85): 376-83, 2000. [ Full Text/Abstract ]

15. Elliott K, Ge K, Du W, Prendergast GC. The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program. Oncogene(19): 4669-84, 2000. [ Full Text/Abstract ]

16. Ge K, DuHadaway J, Du W, Herlyn M, Rodeck U, Prendergast GC. 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, 1999. [ Full Text/Abstract ]

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