Yanming Wang Assistant Professor of Biochemistry and Molecular Biology 454 North Frear Laboratory University Park, PA 16802 Telephone: (814) 865-3775 E-mail:yuw12@psu.edu B.A. in Biochemistry, Shandong University, China Ph.D. in Molecular, Cellular, and Developmental Biology, Iowa State University Postdoctoral Fellow, The Rockefeller University Wang Lab Web Site Member of Center for Eukaryotic Gene Regulation

Epigenetic Histone modifications in Cell Differentiation and Cancer

Our laboratory is interested in the roles of epigenetic histone modifications in cell growth, proliferation and differentiation (Figure 1). We are interested in the epigenetic mechanisms that regulate the expression of tumor suppressor genes (e.g. p53 target genes), which play important roles in cell cycle control and apoptosis. The goal of our research is to unveil molecular mechanisms underlying epigenetic gene silencing, and identify novel drug target for cancer treatment. Our research has a broad implication to human physiology and diseases, including cancer, innate immunity, and autoimmune diseases.

Focus 1: To investigate the roles of histone Arg modifications in transcription (Figure 2). Recent work by us and many others have found that (1) promoter-specific conversion of methyl-Arg to citrullination via demethylimination regulates the expression of specific genes, such as p53 and estrogen receptor target-genes; (2) it is also formally possible that reversible Arg methylation and demethylation plays important role in gene regulation; (3) histone hypercitrullination by peptidylarginine deiminase 4 plays a role in high order chromatin structure.

Focus 2: To understand how histone modifications regulate higher order chromatin structure (Figure 3). Multiple residues on the histone (e.g., H3) tails are modified by acetylation, citrullination, methylation, and phosphorylation, collectively referred as a “histone code” (Figure 3). DNA/chromatin folding is regulated at multiple ways in interphase cell nuclei, such as (1) organization of DNA with histones to form a nuclesome core particle (NPC, ~11nm in diameter); (2) compaction of NPCs to form arrays; (3) further compaction of nucleosomal arrays by linker histone H1 to form ~30 nm chromatin fiber; (4) organization of chromatin fibers under nuclear envelope; (5) organization of chromatin domains around nucleolus. Currently, we investigate how these processes are reversed to unfold chromatin in neutrophils after bacterial infection.

Representative Publications:

• Jin Y, Wang Y, Walker DL, Dong H, Conley C, Johansen J, Johansen KM. (1999) JIL-1: A novel chromosomal tandem kinase implicated in transcriptional regulation in Drosophila. Molecular Cell 4: 129-35.

• Jin Y*, Wang Y*, Johansen J, Johansen KM. (2000) JIL-1, a chromosomal kinase implicated in regulation of chromatin structure, associates with the MSL dosage compensation complex. Journal of Cell Biology 149: 1005-10. (* authors of equal contribution)
• Wang Y, Zhang W, Jin Y, Johansen J, Johansen KM. (2001) The JIL-1 tandem kinase mediates histone H3 phosphorylation and is required for maintenance of chromatin structure in Drosophila. Cell 105: 433-43.
• Nishioka K, Rice JC, Sarma K, Erdjument-Bromage H, Werner J, Wang Y, Chuikov S, Valenzuela P, Tempst P, Steward R, Lis JT, Allis CD, Reinberg D. (2002) PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Molecular Cell 9:1201-13.

• Zhang W, Wang Y, Long J, Girton J, Johansen J, Johansen KM. (2003) A developmentally regulated splice-variant from the complex lola locus encoding multiple different zinc-finger domain proteins interacts with the chromosomal kinase JIL-1. Journal of Biological Chemistry 278(13): 11696-704.

• Fischle W*, Wang Y*, Jacobs SA*, Kim Y, Allis CD, Khorasanizadeh S. (2003) Molecular basis for the discrimination of repressive methyl-lysine marks in histone H3 by polycomb and HP1 chromodomains. Genes & Development 17: 1870-81. (* authors of equal contribution)

• Fischle, W.*, Wang, Y.*, and Allis, C.D. (2003) Histone and Chromatin Cross-talk.  Current Opinion in Cell Biology 15: 172-83. (* authors of equal contribution)

• Fischle, W., Wang, Y., and Allis, C.D. (2003) Binary switches and modification cassettes in histone biology and beyond. Nature 425, 475-9.

• Wang Y, Wysocka J, Sayegh J, Lee YH, Perlin JR, Leonelli L, Sonbuchner LS, McDonald CH, Cook RG, Dou Y, Roeder RG, Clarke S, Stallcup MR, Allis CD*, Coonrod SA*. (2004) Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306, 279-83. (Featured in Nature News and Views (2004), Nature, 431:637-9) (* indicates corresponding authors).

• Sarmento OF, Digilio LC, Wang Y, Perlin J, Herr JC, Allis CD, Coonrod SA. (2004) Dynamic alterations of specific histone modifications during early murine development. Journal of Cell Science 117, 4449-59.

• Wang, Y., Fischle, W., Cheung, W., Jacobs, S., Khorasanizadeh, S., and Allis, C.D. (2004) Beyond the double helix: writing and reading the histone code. In: Reversible protein acetylation. Novartis Foundation Symposium 259, 3-20 Wiley, Chichester.

• Wang, Y., Wysocka, J., Perlin, J.R., Leonelli, L., Allis, C.D., and Coonrod, S.A. (2004) Linking histone modifications to epigenetics: the rigidity and plasticity of the marks. The 69th Cold Spring Harbor Symposium on Quantitative Biology 161-170.

• Bao X, Zhang W, Krencik R, Deng H, Wang Y, Girton J, Johansen J, Johansen KM. (2005) The JIL-1 kinase interacts with lamin Dm0 and regulates nuclear lamina morphology of Drosophila nurse cells. Journal of Cell Science 118, 5079-87.

• Wang, Y. (2006) Methylation and demethylation of histone Lys and Arg residues in chromatin structure and function. In the ENZYMES protein methyltransferases XXIV, 123-153.

• Li P, Yao H, Zhang Z, Li M, Luo Y, Thompson PR, Gilmour DS, Wang Y. (2008) Regulation of p53 target gene expression by peptidylarginine deiminase 4. Molecular and Cellular Biology 28, 4745-58.
• Yao H, Li P, Venters BJ, Zheng S, Thompson PR, Pugh BF, Wang Y. (2008) Histone Arg modifications and p53 regulate the expression of OKL38, a mediator of apoptosis. Journal of Biological Chemistry 283, 20060-8.
• Wang Y*, Li M, Stadler S, Correll S, Li P, Wang D, Hayama R, Leonelli L, Han H, Grigoryev S, Allis CD, Coonrod SA* (2009) Histone hypercitrullination mediates chromatin decondensation and nuetrophil extracellular trap formation.  Journal of Cell Biology (accepted) (*authors of correspondence).
• Hao G, Wang D, Gu J, Shen Q, Gross SS, and Wang Y (2009) Neutral loss of isocyanic acid in peptide CID spectra: a novel diagnostic marker for mass spectrometric identification of protein citrullination. Journal of American Society of Mass Spectrometry (accepted).

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