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| Yi Zhang, Ph.D.
Professor |  |
Research Interests
Epigenetic modifications, particularly DNA methylation and covalent histone modifications, play an important role in regulating chromatin dynamics and therefore has significant impact in gene expression. Our lab is interested in how epigenetic-mediated dynamic changes in chromatin structure affect gene expression, cell lineage commitment and cancer development. Our long-term goal is to apply this basic research to studies of human diseases.
Studies in our lab focus on three different areas. One is the relationship between ATP-dependent nucleosome remodeling and histone deacetylation. This area of study focuses on the nucleosome remodeling and deacetylase complex NuRD which we have recently demonstrated also plays an important role in methylated DNA silencing. We use a combination of biochemical and mouse genetic approaches to understand its biological function and the underlying mechanism through identification of its target genes by a genome wide localization approach.
The second area of studies involve identification of novel histone methyltrasferases and understanding their biochemical and biological functions. Thus far, we have identified and characterized six novel histone methyltransferases including PRMT1, SET7, SET8, ESET, EZH2, and hDOT1. Our preliminary studies suggest that several of the enzymes are potentially involved in cancer. Our current study are focused on validating our primary observation and setting up assays for identification of inhibitors of these enzymes.
The third area of our study focus on the role of various epigenetic modifications in cell lineage commitment. We use T cell and ES cell as our model systems. Our general approach involve chromatin immunoprecipitation coupled with genomic microarry. Our goal is to identify a cell lineage specific "histone code" and then to address the role of the specific "histone code" in the cell lineage commitment process.
Recent Accomplishments and Honors
In the past several years, we have made significant contributions to the epigenetic and chromatin field. The important discoveries include: 1) First demonstration that histone modification, ATP-dependent nucleosome remodeling and methylated gene silencing are intimately related; 2) First demonstration that histone H4-R3 methylation by PRMT1 play an important role in nuclear receptor mediated gene activation; 3) Cloned the first H3-K4 methyltransferase and demonstrated the cross-talk between histone methylation and acetylation; 4) Demonstration that EZH2 complex mediated H3-K27 methylation play important roles in PcG silencing and X-inactivation. As a result of the above accomplishment, the PI received several awards including the Kimmel Scholar Award for Cancer Research and the Gertrude B. Elion Cancer Research Award.
Publications
Feng, Q. and Zhang, Y., (2001). The MeCP1 complex represses transcription through preferential binding, remodeling, and deacetylating methylated nucleosomes. Genes & Dev, 15: 827-832.
2. Wang, H-B., Huang, Z.-Q., Li, X., Feng, Q., Erdjument-Bromage, H., Strahl, B.D., Briggs, S., Allis, D.C., Wong, J., Tempst, P., and Zhang, Y. (2001). Methylation of histone H4 at arginine 3 facilitates transcriptional activation by nuclear hormone receptor Science 293, 853-857.
3. Wang, H-B., Cao, R., Xia, L., Erdjument-Bromage, H., Borchers, C., Tempst, P., and Zhang, Y. (2001). Purification and functional characterization of a histone H3-lysine 4-specific methyltransferase. Mol. Cell 8, 1207-1217.
4. Ng, H.-H., Feng, Q., Wang, H., Erdjument-Bromage, H., Tempst, P., Zhang, Y., and Struhl, K. (2002). Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association. Genes Dev 16, 1518-1527.
5. Cao, R., Wang, L., Wang, H., Xia, L., Erdjument-Bromage, H., Tempst, P., Jones, R.S., Zhang, Y. (2002). Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039-1043.
6. Plath, K., Fang, J., Mlynarczyk-Evans, S. K., Cao, R., Worringer, K. A., Wang, H., de la Cruz, C. C., Otte, A., Panning, B., Zhang, Y. (2003). Role of histone H3 lysine 27 methylation in X-inactivation. Science 300, 131-135.
7. Min, J., Feng, Q., Li, Z., Zhang, Y. Xu, R.-M. (2003). Structure of the catalytic domain of human Dot1L, a non-SET domain nucleosomal histone methyltransferase. Cell 112, 711-723.
8. Min, J., Zhang, Y. Xu, R.-M. (2003). Structural basis for specific binding of Polycomb chromodomain to histone H3 methylated at Lys 27. Genes Dev 17, 1823-1828.
9. Wang, H-B., An W. Cao, R., Xia, L., Erdjument-Bromage, H., Chatton, B., Tempst, P., Roeder, R. and Zhang, Y. (2003). mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression. Mol. Cell 12, 475-487.
E-mail: yi_zhang@med.unc.edu
Telephone: (919) 843-8225
FAX: (919) 966-9673
Address: Lineberger, Room 32-046, CB# 7295 Chapel Hill, NC
URL: www.med.unc.edu/~zhangyi/lab.htm
