Jinsong Zhang, Ph.D.
Pharmacological and Physiological Science
Leukemia and Lymphoma Society Fellow (2000-2003)
Leukemia and Lymphoma Society Special Fellow (2003-2006)
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 (which 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.
- Study how genes are turned on and off spatially and temporarily, Dynamics of gene expression
- Cancer genomics and next-generation sequencing
- Structure biology
- Determine how key regulatory factors function in cancer and leukemia cells
Guo C, Li J, Steinauer N, Wong M, Wu B, Dickson A, Kalkum M, Zhang J. (2020) Histone deacetylase 3 preferentially binds and collaborates with transcription factor RUNX1 to repress AML1-ETO-dependent transcription in t(8;21) AML. Journal of Biological Chemistry 2020 Feb 18. pii: jbc.RA119.010707. doi: 10.1074/jbc.RA119.010707. [Epub ahead of print]
Yosten GL, Harada CM, Haddock CJ, Giancotti LA, Kolar GR, Patel R, Guo C, Chen Z,
Zhang J, Doyle TM, Dickenson AH, Samson WK, Salvemini D. (2020) GPR160 de-orphanization reveals
critical roles in neuropathic pain in rodents. J Clin Invest. 2020 Jan 30. pii: 133270. doi: 10.1172/JCI133270. [Epub ahead of print]
Carpenter KJ, Valfort AC, Steinauer N, Chatterjee A, Abuirqeba S, Majidi S, Sengupta M, Di Paolo RJ, Shornick LP, Zhang J, Flaveny CA. (2019) LXR-inverse agonism stimulates immune-mediated tumor destruction by enhancing CD8 T-cell activity in triple negative breast cancer. Sci Rep. 2019 Dec 20;9(1):19530. doi: 10.1038/s41598-019-56038-1.
Steinauer N, Guo C, Huang C, Wong M, Tu Y, Freter CE and Zhang J. (2019) Myeloid translocation gene CBFA2T3 directs a relapse gene program and determines patient-specific outcomes in AML. Blood Advances. 2019 3:1379-1393; doi: https://doi.org/10.1182/bloodadvances.2018028514
Butler AA, Zhang J, Price CA, Stevens JR, Graham JL, Stanhope KL, King S, Krauss RM, Bremer AA and Havel PJ. (2019) Low plasma adropin concentrations increase risks of weight gain and metabolic dysregulation in response to a high-sugar diet in male nonhuman primates. Journal of Biological Chemistry. First Published on April 15, 2019 doi: 10.1074/jbc.RA119.007528 jbc.RA119.007528.
Roby D, Ruiz F, Niehoff M, Kermath B, Voorhees J, Zhang J, Morley J, Musiek E, Farr S. Burris T. (2019) Pharmacological Activation of the Nuclear Receptor REV-ERB Reverses Cognitive Deficits and Reduces Amyloid-beta Burden in a Mouse Model of Alzheimer’s Disease. PLoS One. 2019 Apr 11;14(4):e0215004. doi: 10.1371/journal.pone.0215004. eCollection 2019.
Griffin P, Dimitry JM, Sheehan PW, Lananna BV, Guo C, Robinette ML, Hayes ME, Cedeño MR, Nadarajah CJ, Ezerskiy LA, Colonna M, Zhang J, Bauer AQ, Burris TP, Musiek ES. (2019) Circadian clock protein Rev-erbα regulates neuroinflammation. Proc Natl Acad Sci U S A. 2019 Feb 21. pii: 201812405. doi: 10.1073/pnas.1812405116. [Epub ahead of print]
Cui N, Zhang J, Huang H, Lu L. (2018) Epigenetic regulator ARID1A and stem cell transcription factor
SOX9 in the maintenance of pancreatic ductal cell differentiation state and development
of IPMN and PDAC. Translational Cancer Research. 7(S7):S748-S751. doi:10.21037/tcr.2018.07.25
Ghoshal S, Stevens JR, Billon C, Girardet C, Sitaula S, Leon AS, Rao DC, Skinner JS, Rankinen T, Bouchard C, Nuñez MV, Stanhope KL, Howatt DA, Daugherty A, Zhang J , Schuelke M, Weiss EP, Coffey AR, Bennett BJ, Sethupathy P, Burris TP, Havel PJ, Butler AA. (2018) Adropin: An endocrine link between the biological clock and cholesterol homeostasis. Molecular Metabolism. 8:51-64
Zhang L, Liu Y, Wang M, Wu Z, Li N, Zhang J, Yang C. (2017) EZH2-, CHD4-, and IDH-linked epigenetic perturbation and its association
with survival in glioma patients. J Mol Cell Biol. 2017 Dec 1;9(6):477-488. doi: 10.1093/jmcb/mjx056.
Steinauer N, Guo C and Zhang J. (2017). Emerging roles of MTG16 in cell-fate control of hematopoietic stem cells and cancer. Stem Cells international. Article ID 6301385, 12 pages. https://doi.org/10.1155/2017/6301385.
Lin S, Ptasinska A, Chen X, Shretha1 M, Assi SA, Aronow B, Zhang J, Weirauch MT, Bonifer C, and Mulloy JC. (2017) FOXO1 is an oncogenic mediator in AML1-ETO leukemia. Blood. 2017 130:1213-1222; doi: https://doi.org/10.1182/blood-2016-11-750976.
Welch RD, Guo C, Sengupta M, Carpenter KJ, Stephens NA, Arnett SA, Meyers MJ, Sparks LM, Smith SR, Zhang J, Burris TP and Flaveny CA. (2017) Rev-Erb directs myogenesis via transcriptional co-regulation of the muscle-specific NF-Y cistrome. Molecular Metabolism. https://doi.org/10.1016/j.molmet.2017.05.001.
Zhang J, Gow C-H, Khan S, Liu Y and Yang C. (2017) Transcriptional and Genomic Control of Stem Cells in Development and Cancer. Stem Cells International. 2017;2017:2513598. Epub 2017/07/22. doi: 10.1155/2017/2513598. PubMed PMID: 28729878; PMCID: PMC5495003.
Sitaula S, Zhang J, Ruiz F and Burris TP. (2017) Rev-erb Regulation of Cholesterologenesis. Biochem Pharmacology 2017 Feb 14. pii: S0006-2952(17)30083-7. doi: 10.1016/j.bcp.2017.02.006. [Epub ahead of print]
Li, J, Guo, C, Steinauer, N and Zhang J (2016). New insights into transcriptional and leukemogenic mechanisms of AML1-ETO and E2A fusion proteins. Frontiers in Biology 2016;11(4):285-304. Epub 2017/03/07. doi: 10.1007/s11515-016-1415-1. PubMed PMID: 28261265; PMCID: PMC5336278.
Guo C, Li Y, Zha J, Gow C-H, Wong M, Yan C, Liu H-Q, Wang Y, Burris TP and Zhang J. (2015) The optimal corepressor function of nuclear receptor corepressor (NCoR) for peroxisome proliferator-activated receptor requires G-protein pathway suppressor 2. Journal of Biological Chemistry 290(6):3666-79.
Wong MM, Guo C, and Zhang J. (2014) Nuclear receptor corepressor complexes in cancer: mechanism, function and regulation (invited review). American Journal of Clinical and Experimental Urology 2(3):169-187.
Gow C-H*, Guo C*, Wang D* (* Co-first authors), Hu Q, Zhang J.(2014) Differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways. Nucleic Acids Research 42(1):137-52. doi: 10.1093/nar/gkt855.
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, Yeh M. (1994) Cloning, sequencing and analyzing of the heavy chain V region genes of human polyreactive antibodies. Cell Research 4:31-46.
Zhang J, Liu W. (1994) Progress in topography of ribosomal RNA and RNA N-glycosidase research (II) (review). Progress in Biochemistry and Biophysics 21:113-117.
Zhang J, Liu W. (1994) Progress in topography of ribosomal RNA and RNA N-glycosidase research (I) (review). Progress in Biochemistry and Biophysics 21:23-7.
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.