Jinsong Zhang, Ph.D.
Pharmacological and Physiological Science
During cell differentiation, development and disease progression, certain genes are transcriptionally activated while others are repressed. These changes in gene transcription may result from altered binding of transcription factors to target genes, or from modification of DNA and histones following recruitment of corepressors or coactivators. My lab is generally interested in understanding the interplay of transcription factors, corepressors and coactivators in the regulation of chromatin and transcription, which ultimately leads to changes of gene expression in various cell differentiation, development and disease pathways.
Our studies focus on leukemia fusion proteins (that function as aberrant transcription factors), nuclear receptor corepressors, and histone deacetylases (HDACs). AML1-ETO is a leukemia fusion protein that is generated by t(8;21) chromosomal translocation and is responsible for nearly 15% of all acute myeloid leukemia cases. Although it has been recognized that AML1-ETO drives leukemogenesis by deregulating gene transcription, how AML1-ETO represses or activates transcription remains unclear. AML1-ETO directly binds to E-proteins and HDACs. Our studies have shown that E-proteins and HDACs are critically involved in AML1-ETO-dependent gene regulation pathways, and that the interaction of AML1-ETO and E-protein is a promising therapeutic target for t(8;21) leukemia.
HDACs play key roles in switching on and off gene transcription and are proven targets for cancer therapy. Among the 12 human HDACs, we are particularly interested in HDAC1 and HDAC3, which are members of the ubiquitously-expressed Class I HDACs. Whereas HDAC1 resides in Sin3A, NuRD and CoREST complexes, HDAC3 forms complexes with nuclear receptor corepressors N-CoR and SMRT, which in turn interact with TBL1 and GPS2. We are interested in understanding how HDAC3 is activated and stabilized by nuclear receptor corepressors. In addition, we have isolated a novel HDAC1 complex that may be important for endocrine resistance in breast cancer. Another ongoing study is to understand the role of GPS2 in regulating the activity of PPARg, a nuclear receptor that controls adipogenesis, inflammation and lipid metabolism.
Gow C-H*, Guo C*, Wang D*(* Co-first authors), Hu Q and Zhang J. (2013) Differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways. Nucleic Acids Research, 2014 Jan 7;42(1):137-52. doi: 10.1093/nar/gkt855. Epub 2013 Sep 24.
Chen W-Y, Zhang J, Geng H, Du Z, Nakadai T, Roeder RG. (2013) A TAF4 coactivator function for E proteins that involves enhanced TFIID binding. Genes & Development 27: 1596-1609.
Feng Y, Singleton D, Guo C, Gardner A, Pakala S, Kumar R, Jensen E, Zhang J and Khan S. (2013) DNA homologous recombination factor SFR1 physically and functionally interacts with estrogen receptor alpha. PLoS ONE 8(7): e68075. doi:10.1371/journal.pone.0068075
Benavidesa M, Chow-Tsanga L-F, Zhang J, Zhong H. (2013) The Novel Complex of Microspherule Protein Msp58 and Ubiquitin E3 Ligase EDD Regulates Cell Cycle Progression by Controlling Cyclins. BBA - Molecular Cell Research 1833(1):21-32.
Guo C, Gow CH, Li Y, Gardner A, Khan S, Zhang J. (2012) Regulated clearance of histone deacetylase 3 protects independent formation of nuclear receptor corepressor complexes. Journal of Biological Chemistry 287(15):12111-20.
Wang L, Gural A, Sun XJ, Zhao X, Perna F, Huang G, Hatlen MA, Vu L, Liu F, Xu H, Asai T, Xu H, Deblasio T, Menendez S, Voza F, Jiang Y, Cole PA, Zhang J, Melnick A, Roeder RG, Nimer SD. (2011) The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation. Science 333(6043):765-9.
Hu Q, Guo C, Li Y, Aronow BJ, Zhang J. (2011) LMO7 mediates cell-specific activation of the Rho-myocardin-related transcription factor-serum response factor pathway and plays an important role in breast cancer cell migration. Molecular and Cellular Biology 31(16):3223-40.
Olshavsky NA, Comstock CE, Schiewer MJ, Augello MA, Hyslop T, Sette C, Zhang J, Parysek LM, Knudsen KE. (2010) Identification of ASF/SF2 as a critical, allele-specific effector of the cyclin D1b oncogene. Cancer Research 70(10):3975-84.
Guo C, Hu Q, Yan C, Zhang J. (2009) Multivalent binding of the ETO corepressor to E proteins facilitates dual repression controls targeting chromatin and the basal transcription machinery. Molecular and Cellular Biology 29(10):2644-57.
Lee K, Liu Y, Mo JQ, Zhang J, Dong Z, Lu S. (2008) Vav3 oncogene activates estrogen receptor and its overexpression may be involved in human breast cancer. BMC Cancer 8:158.
Plevin MJ, Zhang J, Guo C, Roeder RG, Ikura M. (2006) The acute myeloid leukemia fusion protein AML1-ETO targets E proteins via a paired amphipathic helix-like TBP-associated factor homology domain. Proc Natl Acad Sci U S A 103(27):10242-7.
Zhang J, Kalkum M, Yamamura S, Chait BT, Roeder RG. (2004) E protein silencing by the leukemogenic AML1-ETO fusion protein. Science 305(5688):1286-9.
Hug BA, Lee SY, Kinsler EL, Zhang J, Lazar MA. (2002) Cooperative function of AML1-ETO corepressor recruitment domains in the expansion of primary bone marrow cells. Cancer Research 62(10):2906-12.
Zhang J, Kalkum M, Chait BT, Roeder RG. (2002) The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Molecular Cell 9(3):611-23.
Zhang J, Hug BA, Huang EY, Chen CW, Gelmetti V, Maccarana M, et al. (2001) Oligomerization of ETO is obligatory for corepressor interaction. Molecular and Cellular Biology 21(1):156-63.
Zhang J, Lazar MA. (2000) The mechanism of action of thyroid hormones. Annual Review of Physiology 62:439-66 (invited review).
Huang EY*, Zhang J*(* Co-first authors), Miska EA, Guenther MG, Kouzarides T, Lazar MA. (2000) Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway. Genes & Development 14(1):45-54.
Zhang J*, Hu X*(* Co-first authors), Lazar MA. (1999) A novel role for helix 12 of retinoid X receptor in regulating repression. Molecular and Cellular Biology 19(9):6448-57.
Gelmetti V*, Zhang J*(* Co-first authors), Fanelli M, Minucci S, Pelicci PG, Lazar MA. (1998) Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Molecular and Cellular Biology18(12):7185-91.
Zhang J, Guenther MG, Carthew RW, Lazar MA. (1998) Proteasomal regulation of nuclear receptor corepressor-mediated repression. Genes & Development 12(12):1775-80.
Zamir I, Zhang J, Lazar MA. (1997) Stoichiometric and steric principles governing repression by nuclear hormone receptors. Genes & Development 11(7):835-46.
Zhang J, Zamir I, Lazar MA. (1997) Differential recognition of liganded and unliganded thyroid hormone receptor by retinoid X receptor regulates transcriptional repression. Molecular and Cellular Biology 17(12):6887-97.
Reginato MJ, Zhang J, Lazar MA. (1996) DNA-independent and DNA-dependent mechanisms regulate the differential heterodimerization of the isoforms of the thyroid hormone receptor with retinoid X receptor. Journal of Biological Chemistry 271(45):28199-205.
Zhang J, Liu W. (1992) The mechanism of action of trichosanthin on eukaryotic ribosomes--RNA N-glycosidase activity of the cytotoxin. Nucleic Acids Research 20(6):1271-5.