|Yujun George Zheng|
Biochemistry, Organic Chemistry
B.S. (1995): Peking University
M.S. (1998) : Peking University
Ph.D. (2002) : University of Miami
Postdoctoral Associate (2002-2006) : Johns Hopkins University School of Medicine
Dr. Yujun George Zheng
Department of Chemistry
Georgia State University
P.O. Box 3965
Atlanta, Georgia 30302-3965
Department Office Phone: 404-413-5500
Georgia State University Research Initiation Award, 2008
Georgia Cancer Coalition Distinguished Cancer Scientist, 2007
Keck Foundation Fellowship, Johns Hopkins University, 2004-2006
Award of Academic Excellence, University of Miami, 2002
Chemical biology; organic synthesis; combinatorial chemistry; histone modifications (acetylation, methylation, ubiquination/sumoylation); epigenetic regulation of cancer; organic reactions in aqueous media; enzymology; medicinal chemistry; protein chemistry (synthesis and engineering); diagnostic sensors.
In the post-genomic research era, there has been a rapid shift in focus from simply collecting and archiving genomic data to dissecting and interpreting complex genomic/proteomic functions and networks. Particular attention is applied to understand how variations in genetic instructions result in human disease and to discover novel therapies based on genomic information. We are concerned about key problems in the rapidly evolving field of epigenetics that describes inheritable changes in gene expression patterns that are not due to changes in DNA sequence. Such epigenetic regulations are important mechanisms that organisms use to change gene expression patterns and directly correlate with disease occurrence. As a matter of fact, recent data have shown that epigenetic processes play key roles in transforming a normal cell into malignant tumor cell and epigenetic abnormality presents a useful biomarker for cancer diagnosis and also a molecular target for cancer treatment. Therefore, identification of chromatin remodeling factors such as histone modifying enzymes and understanding of their mechanism, specificity, and function undoubtedly represent a forefront in the post-genomic research arena. In short term, research in my laboratory is aimed at revealing molecular and cellular functions of important enzymes involved in epigenetic regulation of human disease processes especially cancer. We adopt a chemical biology approach, which combines organic synthesis, molecular biology, biochemistry, cellular biology, biophysics and bioinformatics. The research endeavors of my laboratory revolve around a set of key projects.
Chromatin plays essential roles in all DNA regulated processes such as replication, recombination, repair, and transcription. Chromatin modifications and remodeling is critical in regulating many cellular processes and alteration of functions of chromatin modifying enzymes such as histone acetyltransferse leads to different diseases especially cancer. Aberrant silencing of tumor suppressor genes is often achieved by methylation and deacetylation of histones at promoters. Gene DNA hypermethylation and histone hypoacetylation are attractive targets for treatment of epigenetic diseases. The principle underlying this type of epigenetic therapy is that reversal of epigenetic silencing will reinstate cellular caner defense mechanisms. The research in our laboratory focuses on the molecular basis of posttranslational modifications of histone and nonhistone proteins that contribute to the epigenetic regulation of gene expression, particularly the biochemical and cellular mechanisms of those epigenetic factors linked to cancer initiation and progression. One of such projects is to characterize the HAT activity of MYST family histone acetyltransferases such as MOF, TIP60, and MORF and study their regulations.
It has been apparent that cancer is as much a genetic as an epigenetic pathology. Epigenetic alterations contribute to the expansion of aberrant cellular colones during tumorigenesis. The clearest example of cancer-associated epigenetic alteration is the hypermethylation of DNA in gene-regulatory regions which is associated with repressive histone modifications (H3-K9 methylation and hypoacetylation). Such altered chromatin state can bring about the silencing and hence loss-of-function of tumor suppressor genes. This has led to the notion of epigenetic therapy as a mode to reverse the transformed state of tumor cells. The HAT activity represents a potential novel target for a couple of cancer diseases. Aberrant acetylation by mistargeted HATs plays a causative role in leukemogenesis. In acute myeloid leukemia (AML), the gene for HAT CBP is translocated and fused either to the Monocytic Leukemia Zinc finger (MOZ) gene, or to MLL (A homeotic regulator, mixed lineage leukemia). The translocation-derived fusion proteins cause aberrant gene expression through improper targeting to genes that are not the normal targets of either protein. Evidences for the involvement of acetylases in cancer also come from the observation that p300 and PCAF play an important role in MyoD dependent cell cycle arrest. The binding of the onco-protein E1A to p300/CBP and TIP60 is necessary for the former to regulate transcription, suppress differentiation and induce the immortalization of the cell cultures, resulting in tumorigenesis. Recent reports have shown that TIP60 interacts with and activates several other oncogenes such as c-Myc and E2F. Therefore, small organic compounds activating or inhibiting specific HATs may have great therapeutic values. One focus of our work is the development of potent and selective inhibitors of histone modification enzymes especially HATs. We are using several lines of experimental work to discover small molecules that selectively regulate the HAT activity of several histone acetylases including MOF, p300/CBP, GCN5/PCAF, and others.
Chemistry and biology are previously viewed as discrete academic disciplines, yet the two are increasingly integrated. Moreover, the two disciplines are undergoing remarkable converging transformations. The new challenge demands today's scientists to think bravely at the interface and across disciplines. Opportunities exist for chemical biologists to make connections and have insights that are difficult to obtain otherwise with single-sided chemistry or biology experience. Scientists of chemistry background not only appreciate the biological context of their research questions and more importantly, they resolve biological problems with powerful chemical biology tools and create new directions. In the aspect of chemical biology, the general themes of our research are to use chemical approaches in combination with classical genetics to resolve critical disease-associated biomedical problems, as well as to investigate the growing bio-oriented challenges and opportunities in chemistry. One of the research efforts of our laboratory is on development of site-specific tag-free labeling method to profile acetylase activity in proteomics scale. We use chemical, biochemical, and cellular methods to study protein acetylase function in human disease. Such projects include synthesis of novel chemical probes for each of the primary acetylase families and in vivo study of acetylase activity. Technically, we will on first stage use three benign chemical methods to perform labeling reactions in biological systems: click chemistry, Staudinger ligation, and Expressed Protein Ligation (EPL). With progress, we will improve these reactions by introducing modifications thus make them more amenable for use in ambient environment. In the meantime, efforts will be put on exploring new chemoselective organic reactions that can overcome current problems and challenges.
Biochemical probes with high sensitivity and selectivity take essential roles in the quantitative understanding of biological processes. Labeling of proteins with fluorescent probes or affinity reagents has greatly facilitated elucidating the studies of protein structure, dynamics and protein-protein interactions. Traditional methods of protein labeling are inadequate for in vivo studies because they require expression, purification of the protein, chemical labeling, and reintroduction into cells by invasive methods such as microinjection. These limitations have spawned efforts to non-invasively and site-specifically label proteins in living cells. Currently we focus our efforts on the design of efficacious reporter platforms to study the cellular activity of histone modification enzymes and to aid our therapeutic discovery program. Posttranslational covalent modifications on histone and nonhistone proteins lead to conformational changes in biomacromolecules which subsequently influence fluorescence properties. We are interested in reporters for several histone modification enzyme classes including acetyltransferases, methyltransferases, and ubiquitin ligases. These reporters will be used directly to study epigenetic mechanism that cells use to signal special cellular pathway such as DNA damage repair, apoptosis, and tumorigenesis. It is also one of our research aims to develop “smart” labels that not only probe the dynamic and spatial localization of proteins, but also reveal the conformation, interaction, and activities of intracellular macromolecules especially enzymes. We also work on the design of fluorescent nanosensors for biological study and medical diagnostics. Nanoparticles such as quantum dots, dendrimers, and modular proteins have the same size with biomacromolecules and present abundant functionalities on surface which render them ideal nanoplatforms for effective transduction of molecular recognition events into detectable signals (via energy or electron transfer). Such nanoprobes are directed to the sensing of important molecular targets which include carbohydrates, neurotransmitters, cancer markers and pathogens.
N. Xie, E. N. Elangwe, S. Asher, Y. G. Zheng, 2008, submitted. “A dual-mode fluorescence strategy for screening HAT modulators”
J. Wu, Y. G. Zheng, Analytical Biochemistry, 2008, in press. “Fluorescent reporters of the histone acetyltransferases”
J. Wu, Z. Chen, M. Goodman, Y. Zheng. Medicinal Research Reviews, 2008, in press. “Chemical regulation of epigenetic modifications and opportunities of new cancer therapy”
Z. Chen, Y. Zheng. Heterocyclic Communications, 2007, 13, 343-346. “Synthesis of a coumarin-histone conjugate for HAT fluorescent assay”
Y. Zheng, K. Balasubramanyam, M. Cebrat, D. Buck, A. Zelent, R. M. Alani, P. A. Cole. Journal of the American Chemical Society, 2005, 127, 17182-17183. “Synthesis and Evaluation of a Potent and Selective Cell Permeable p300 Histone Acetyltransferase Inhibitor”
Y. Zheng, F. Mamdani, D. Toptygin, L. Brand, J. T. Stivers, P. A. Cole. Biochemistry, 2005, 44, 10501-10509. “Fluorescence analysis of a dynamic loop in the PCAF/GCN5 histone acetyltransferase”
Y. Zheng, P. R. Thompson, M. Cebrat, L. Wang, M. K. Devlin, R. M. Alani, P. A. Cole. Methods in Enzymology, 2004, 376 (B), 188-199. “Selective HAT Inhibitors as Mechanistic Tools for Protein Acetylation”
Y. Zheng, J. Orbulescu, X. Ji, F. M. Andreopoulos, S. M. Pham, R. M. Leblanc. Journal of the American Chemical Society, 2003, 125, 2680-2686. “Development of Fluorescent Film Sensors for the Detection of Divalent Copper”
Y. Zheng, X. Cao, V. K., F.M. Andreopoulos, S. M. Pham, R. M. Leblanc. Analytical Chemistry, 2003, 75, 1706-1712. “Peptidyl Fluorescent Chemosensors for the Detection of Divalent Copper”
Y. Zheng, K. M. Gattás-Asfura, C. Li, F.M. Andreopoulos, S. M. Pham, R. M. Leblanc. Journal of Physical Chemistry B, 2003, 107, 483-488. “Design of a Membrane Fluorescent Sensor Based on Photocrosslinked PEG Hydrogel”
Y. Zheng, K. M. Gattás-Asfura, V. Konka, R. M. Leblanc. Chemical Communications, 2002, 2350-2351. “A Dansylated Peptide for the Selective Detection of Copper Ions”
Y. Zheng, M. Micic, S. V. Mello, M. Mabrouki, F.M. Andreopoulos, V. Konka, S. M. Pham, R. M. Leblanc. Macromolecules, 2002, 35, 5228-5234. “Formation of PEG-Based Hydrogel Via the Photodimerization of Anthracene Groups”
Y. Zheng, Q. Huo, P. Kele, F.M. Andreopoulos, S. M. Pham, R. M. Leblanc. Organic Letters, 2001, 3, 3277-3280. “A New Fluorescent Chemosensor for Cu2+ Ions Based on the Tripeptide Glycyl-Histidyl-Lysine”
Y. Zheng, F.M. Andreopoulos, M. Micic, Q. Huo, S. M. Pham, R. M. Leblanc. Advanced Functional Materials, 2001, 11, 37-40. “A Novel Photoscissile PEG-based Hydrogel”
K. M. Gattás-Asfura, Y. Zheng, X. Cao, V. Konka, F.M. Andreopoulos, S. M. Pham, R. M. Leblanc. Journal of Physical Chemistry B, 2003, 107, 10464-10469. “Immobilization of Quantum Dots With Photo-Cross-Linked PEG Hydrogel”
M. Micic, Y. Zheng, V. Moy, X. Zhang, F.M. Andreopoulos, R. M. Leblanc. Colloid and Surface: B Biointerface, 2003, 27, 147-158. “Comparative Studies of Surface Topography and Mechanical Properties of a Novel Photoswitchable PEG-NC Based Hydrogel”
M. Micic, J. Orbulescu, K. Radotic, M. Jeremic, G. Sui, Y. Zheng, R. M. Leblanc. Biophysical Chemistry, 2002, 99, 55-62. “ZL-DHP Lignin Model Compound at the Air-Water Interface”
Q. Huo, G. Sui, Y. Zheng, P. Kele, T. Hasegawa, J. Nishijo, J. Umemura, R. M. Leblanc. Chemistry: A European Journal, 2001, 7, 4796-4804. “Metal Complexation with Langmuir Monolayer of Mixed Peptide Lipids”