Kai Ge, Ph.D. : NIDDK

Kai Ge, Ph.D.

NIDDK, National Institutes of Health
Building 10, Room 8N307C
10 Center Dr.
Bethesda, MD 20892-1772
Tel: 301-451-1998
Fax: 301-480-1021
Email: kaig@niddk.nih.gov

Education / Previous Training and Experience:
Dr. Kai Ge received B.S. from Fudan University in Shanghai in 1992, and Ph.D. from Shanghai Institute of Biochemistry, Chinese Academy of Sciences in 1997. He then started postdoctoral training with George Prendergast in The Wistar Institute and University of Pensylvania. In February 2000, he moved to The Rockefeller University where he continued his postdoctoral training with Robert Roeder, studying the role of the Mediator complex in the transcriptional regulation of adipogenesis by PPARgamma. In September 2003, he joined NIDDK as a tenure-track Investigator.

Research Statement:

The Role of Chromatin in Transcriptional Regulation by PPARgamma and PPARdelta

PPARgamma and PPARdelta are members of the nuclear receptor superfamily of ligand activated transcription factors. PPARgamma is a master regulator of adipogenesis and PPARdelta is a major regulator of fat metabolism. Highly selective PPARgamma and PPARdelta ligands are promising drugs or drug candidates for the treatment of type II diabetes and obesity. However, the molecular mechanism by which these ligands act as anti-diabetes and/or anti-obesity agents has largely remained unclear.

The tripartite nature of the nuclear receptor biology suggests that the biological effect of a ligand is determined by the combinatorial collaboration among three parts: ligand, nuclear receptor, and cofactors (coactivators or corepressors) recruited by ligand-bound nuclear receptor on the target gene promoters. Nuclear receptors require various transcription coactivators to activate transcription of specific target genes. These transcription coactivators often exist as multi-protein complexes. They may act either through chromatin remodeling and histone modification, after recruitment by promoter-bound nuclear receptors, or at steps involving subsequent transcription initiation and elongation.

Covalent modifications of histones, such as acetylation and methylation, have been shown to play important roles in the regulation of both global and tissue- and developmental stage-specific gene expression. Histone lysine methylation has been implicated in both gene activation and repression, depending upon the specific lysine (K) residue that becomes methylated and the state of methylation (mono-, di- or trimethylation). For example, di- and trimethylation at K4 of histone H3 (H3K4) are associated with gene activation, while di- and trimethylation at K27 of histone H3 (H3K27) are associated with gene repression. Histone methylation is dynamically regulated by site-specific histone methyltransferases and demethylases. In human cells, Set1-like histone methyltransferase complexes specifically methylate H3K4 while the Polycomb repressive complex 2 methylates H3K27. Demethylases that specifically antagonize methylation on each of the K4, K9 and K36 residues of histone H3 have been reported. Recently, we and others identified the JmjC domain-containing UTX and JMJD3 as histone H3K27-specific demethylases.

To understand the role of chromatin in transcriptional regulation of fat metabolism by PPARgamma and PPARdelta, three projects are underway in the laboratory:

I. Isolation and characterization of a histone H3K4 methyltransferase complex that associates with a histone H3K27 demethylase. II. Regulation of PPARgamma by a histone H3K4 methyltransferase complex. III. The roles of histone modifications and chromatin remodeling in the ligand-dependent target gene activation by PPARgamma and PPARdelta.

Selected Publications:

1. Ge K*, Cho YW, Guo H, Hong TB, Guermah M, Ito M, Yu H, Kalkum M, Roeder RG*. Alternative mechanisms by which Mediator subunit MED1/TRAP220 regulates PPAR{gamma}-stimulated adipogenesis and target gene expression. *Corresponding author. Mol Cell Biol, 2007. [Full Text/Abstract]

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

3. Rampalli S, Li L, Mak E, Ge K, Brand M, Tapscott SJ, Dilworth FJ. p38 MAPK signaling regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation. Nat Struct Mol Biol, 2007. [Full Text/Abstract]

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

5. Park SW, Li G, Lin YP, Barrero MJ, Ge K, Roeder RG, Wei LN. Thyroid Hormone-Induced Juxtaposition of Regulatory Elements/Factors and Chromatin Remodeling of Crabp1 Dependent on MED1/TRAP220. Mol Cell(19): 643-53, 2005. [Full Text/Abstract]

6. Jia Y, Guo GL, Surapureddi S, Sarkar J, Qi C, Guo D, Xia J, Kashireddi P, Yu S, Cho YW, Rao MS, Kemper B, Ge K, Gonzalez FJ, Reddy JK. Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity. Proc Natl Acad Sci U S A(102): 12531-6, 2005. [Full Text/Abstract]

7. 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]

8. 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]

9. 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]

10. 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]

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

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

Page last updated: December 15, 2008

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