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SF424(R&R) Biographical Sketch Format Page BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FOUR PAGES. NAME POSITION TITLE Cheng, Xiaodong eRA COMMONS USER NAME (credential, e.g., agency login) Professor of Biochemistry xcheng EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.) DEGREE INSTITUTION AND LOCATION MM/YY FIELD OF STUDY (if applicable) Fudan University, Shanghai, China B.Sc. 1982 Physics State University of New York at Stony Brook Ph.D. 1989 Protein Crystallography A. Personal Statement. I have studied the biological methylation for the last 20 years. It was in Cold Spring Harbor laboratory where I began a fruitful research collaboration with Dr. Richard J. Roberts that led to the discovery of DNA base flipping by HhaI methyltransferase (1994). I moved to Emory in 1997 and my current work focuses on structural and functional linkage of DNA and histone methylation. My group determined the first structure of a protein arginine methyltransferase (2000), the first structure of a histone lysine methyltransferase (2002), established a switch mechanism of Phe/Tyr (phenylalanine/tyrosine) in controlling the product specificity, i.e. the degree of lysine methylation by mono-, di- or tri-methyl groups (2003), and illustrated the transition from nonspecific to specific DNA interaction along the substrate recognition pathway by a DNA methyltransferase (2005). In collaboration with a group of scientists, my group used structural and biochemical analyses that provide insights into the long-standing question of how imprinted genes are targeted for DNA methylation and discovered the mechanistic linkage of unmethylated H3 lysine 4 to de novo DNA methylation (2007). Recently, my group demonstrated that an ankyrin repeat domain bind selectively to mono- and dimethylated lysine 9 of histone H3 (2008), a recognition of hemi-methylated CpG by SRA domain using a base-flipping mechanism (2008), a structural basis for inhibition of G9a histone H3 lysine 9 methyltransferase by a small molecule inhibitor (2009), and a role of Jumonji proteins in reciprocal methylation of H3K4 and H3K9 (2010). B. Positions. 6/1/1990 – 3/31/1997 Cold Spring Harbor Laboratory: Robertson Postdoctoral Research Fellow (1990-1991) Staff Investigator (1992-1993) Senior Staff Investigator and W.M. Keck Foundation endowed professor (1994-1997) 4/1/1997 – present Emory University School of Medicine: Professor of Biochemistry and Georgia Research Alliance Eminent Scholar Adjunct professor of Chemistry and Physics Honors Albert E. Levy Awards for Excellence in Scientific Research (2008) Grant Reviewer: NIH MSFC Study section (Ad hoc Feb. 2008); NIEHS Special Emphasis Panel of Environmental Influences on Epigenetic Regulation (2006); NCI molecular oncology 3 cluster Review Committee (2006); American Cancer Society: Genetic Mechanisms in Cancer Committee member (2005); NCI site visit team for the review of the Laboratory of Immunobiology (2003); NCI initial review group (2001); NIH BBCB Study Section Member (1997-2001); Army Breast Cancer Research Program (1995-1996). Meeting Organizer and Session Chair FASEB Summer Methylation meetings: co-organizer with Mark Bedford (2008); Session chairperson (2010, 2006, 2004, 2001); Cold Spring Harbor Laboratory Banbury Center conference on “DNA base flipping: how and why”, 7-10 April 1996 (Co-organizer with R.S. Lloyd). Emory University Committee member Emory University School of Medicine: Faculty Committee on Appointments and Promotions (2010-); Chairperson of Biochemistry Structural Biology Faculty Search Committee (2006); Member of Chair search committee for Radiology Department (2003-2004); Faculty Committee on Appointments and Promotions (1999-2001). Board member Editorial Board of Epigenetics (2006-); Editorial Board of Nucleic Acids Research (2002-) Board member and treasurer of Epigenetic Society (formerly DNA Methylation Society) (2005-) Book Editorship AdoMet-dependent Methytransferases: Structures and Functions. World Scientific Publishing Co., 1999 (Co-editors: X. Cheng and R.M. Blumenthal) C. Selected peer-reviewed publications (15 of 116 publications) http://www.biochem.emory.edu/labs/xcheng/ Most Recent: 1. Horton, J.R., Upadhyay, A.K., Qi, H.H., Zhang, X., Shi, Y., Cheng, X. (2010) Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases. Nat Struct Mol Biol. 17: 38-43. 2. Chang, Y., Zhang, X., Horton, J.R., Upadhyay, A.K., Spannhoff, A., Liu, J., Snyder, J.P., Bedford, M.T., Cheng, X. (2009) Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nature Struct. Mol. Biol. 16: 312-317. 3. Hashimoto, H., Horton, J.R., Zhang, X., Bostick, M., Jacobsen, S., Cheng, X. (2008) The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature 455: 826-829. 4. Collins, R.E., Northrop, J.P., Horton, J.R., Lee, D.Y., Zhang, X., Stallcup, M.R., Cheng, X. (2008) The ankyrin repeats of G9a and GLP histone methyltransferases are mono- and di-methyl-lysine binding modules. Nature Struct. Mol. Biol. 15: 245-250. 5. Jia, D., Jurkowska, R., Zhang, X,. Jeltsch, A., Cheng, X. (2007) Structure of Dnmt3a bound Dnmt3L suggests a model for de novo DNA methylation. Nature 449: 248-251. 6. Lan F, Collins RE, del Cegli R, Alpatov R, Horton JR, Shi X, Gozani O, Cheng X, Shi Y (2007) Recognition of un-methylated H3K4 by the BHC80 PHD finger links BHC80 to LSD1 mediated gene repression. Nature 448, 718-722 7. Ooi S, Qiu C, Bernstein E, Li K, Jia D, Yang Z, Erdjument-Bromage H, Tempst P, Lin SP, Allis CD, Cheng X, Bestor TH (2007) DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448, 714-7 8. Zhang X, Yang Z, Khan SI, Horton JR, Tamaru H, Selker EU, Cheng X (2003) Structural basis for the product specificity of histone lysine methyltransferases. Molecular Cell 12, 177-185 9. Zhang X, Tamaru H, Khan SI, Horton JR, Keefe LJ, Selker EU, Cheng X (2002) Structure of the Neurospora SET domain protein DIM-5, a histone H3 lysine methyltransferase. Cell 111, 117-127 10. Zhang X, Zhou L, Cheng X (2000) Crystal structure of the conserved core of the protein arginine methyltransferase PRMT3. EMBO J. 19, 3509-3519 Additional publications of importance to the field: 1. Cheng, X., Kumar, S., Posfai, J., Pflugrath, J.W., Roberts, R.J. (1993) Crystal structure of the HhaI DNA methyltransferase complexed with S-adenosyl-L-methionine. Cell 74: 299-307. 2. Klimasauskas, S., Kumar, S., Roberts, R.J., Cheng, X. (1994) HhaI methyltransferase flips its target base out of the DNA helix. Cell 76: 357-369. 3. O’Gara, M., Horton, J.R., Roberts, R.J., Cheng, X. (1998) Structures of HhaI methyltransferase complexed with substrates containing mismatches at the target base. Nature Struct. Biol. 5: 872-877. 4. Yang, Z., Horton, J.R., Zhou, L., Zhang, X.J., Dong. A., Zhang, X., Schlagman, S.L., Kossykh, V., Hattman. S., Cheng X (2003) Structure of the bacteriophage T4 DNA adenine methyltransferase. Nature Struct. Biol. 10: 849-855. 5. Horton, J.R., Liebert, K., Hattman, S., Jeltsch, A., Cheng, X. (2005) Transition from nonspecific to specific DNA interaction along the substrate recognition pathway of Dam methyltransferase. Cell 121: 349-361. D. Research Support. Current Active Grant Support 2R01-GM068680-05 Cheng (PI) 06/01/09-05/31/13 Title: Histone Lysine Methylation The major goals of this project are to determine the histone methylation crosstalk mechanisms by linked protein modules between a methyl writer and a methyl reader (aims 1 and 2); between two readers (aim 3); and between a methyl reader and an eraser (aim 4). Role: PI 5R56-DK082678-02 Cheng (PI) Jeltsch and Shinkai (Co-PI) 09/30/08-08/31/10 Title: Identification and characterization of novel epigenetic marks of non-histone proteins by SPOT peptide arrays The major goal of this project is to use of SPOT peptide arrays to identify novel epigenetic methyl marks of non-histone proteins. This award is part of the Roadmap Epigenome Program and will end on 08/31/2010. Role: PI 1RC1-GM092035-01 YOON and CHENG (multi-PI) 04/01/10–03/31/12 Generation of Induced Pluripotent Stem Cells with Novel Small Molecule Regulator Pending Grant Support 2R01-GM49245-17A1 Cheng (PI) 07/01/10-06/30/14 Title: DNA Methylation: Structures, Functions, and Regulation The major goal of this project is to continue the investigation of functional role of posttranslational modifications of mammalian DNA methyltransferases (Dnmts) in epigenetic regulation of gene expression, using a combination of biochemical assays, X-ray crystallography, and in vivo assays. Role: PI .
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