Epigenetic modifications, particularly DNA methylation and covalent histone modifications, play an important role in regulating chromatin dynamics and therefore have a significant impact on gene expression. The Zhang lab has been interested in (1) how epigenetic modification-mediated dynamic changes in chromatin structure affect gene expression, embryonic development, cell lineage commitment, stem cell pluripotency/self-renewal; (2) epigenetic mechanism of drug addiction; and (3) how dysregulation of epigenetic factors contributes to the development of diseases such as diabetes, neurological diseases, and cancer. The long-term goal of the lab is to apply this basic research to studies of human diseases.
Over the past decade, the Zhang lab has worked on a number of projects that span many aspects of epigenetics and chromatin modifications, including identification and characterization of (1) the ATP-dependent nucleosome-remodeling and histone deacetylase complex NuRD; (2) various histone methyltransferases, such as EZH2, hDOT1, ESET, SET7, SET8, and PRMT1; (3) various histone demethylases, such as the JmjC family proteins, JHDM1A, JHDM2A, JHDM3A, RBP2, PLU-1, JMJD3, UTX, and Lid; (4) histone H2A ubiquitin E3 ligase PRC1, and (5) the DNA demethylation-related factors such as the Ten Eleven Translocation (Tet) family of 5-methylcytosine dioxygenases. The general approach to these projects involves biochemical purification and functional characterization of these enzymes in vitro and in cell culture, followed by biological characterization in mouse models. The proof-of-concept studies have uncovered a link between several of these enzymes and various diseases such as metabolic syndrome and cancer. This link is the basis for the establishment of Epizyme, a company focusing on the development of epigenetic-based drugs for cancer.
Built upon our strength in protein biochemistry, the lab has expanded the capacity of performing a wide range of state-of-the-art techniques, including single-cell live imaging, cell lineage tracing in the mouse preimplantation embryo, pancreatic β-cell differentiation, iPS cell generation and differentiation, stem cell reprogramming, bone marrow and pancreatic cell transplantation, high-throughput epigenetic modification analysis, and mouse genetics. Current lines of investigation include:
Dynamic DNA methylation and the underlying mechanisms;
Epigenetic and chromatin changes and their molecular basis of early development;
Epigenetic basis of cell lineage specification, particularly the formation of ICM and trophectoderm cell lineage;
Epigenetic mechanism of iPS cell generation and its application in pancreatic beta cell generation;
Role of lncRNAs in epigenetic and chromatin regulation;
How the information gained from these investigation can be used in the development of treatment for human diseases, such as diabetes and cancer.
Research Background
We’re honored that Dr. Zhang has been elected to the National Academy of Medicine for 2023 for his fundamental contributions to the epigenetics field, through systematic identification and characterization of chromatin modifying enzymes, including EZH2, JmjC, and Tet. Dr. Zhang’s proof-of-principle work on EZH2 inhibitors led to the founding of Epizyme and an approved drug, tazemetostat, for epithelioid sarcoma and follicular lymphoma.
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Dr. Zhang received his BS from China Agriculture University in 1984, his Ph.D from Florida State University in 1995. His postdoctoral training was at the Robert Wood Johnson Medical School of UMDNJ where he identified and characterized the Sin3 and the NuRD histone deacetylase complexes. He became an independent investigator at the Lineberger Comprehensive Cancer Center of the University of North Carolina at Chapel Hill in 1999, a Howard Hughes Investigator in 2005, and the Kenan Distinguished Professor in 2009.
Dr. Zhang moved to Boston Children’s Hospital and Harvard Medical School as the Fred Rosen Professor of Pediatrics at Boston Children’s Hospital and Professor of Genetics at Harvard Medical School in 2012. Dr. Zhang has received a number of honors and awards, including the Gertrude B. Elion Cancer Research Award from AACR, the Kimmel Scholar Award from the Kimmel Foundation for Cancer Research, and the Senior Investigator Award of the Chinese Biological Investigators’ Society.
Publications
Clusterin drives myeloid bias in aged hematopoietic stem cells by regulating mitochondrial function. Nat Aging. 2025 Aug; 5(8):1510-1527. View Abstract
Publisher Correction: A subset of dopamine receptor-expressing neurons in the nucleus accumbens controls feeding and energy homeostasis. Nat Metab. 2025 Apr; 7(4):856. View Abstract
A subset of dopamine receptor-expressing neurons in the nucleus accumbens controls feeding and energy homeostasis. Nat Metab. 2024 Aug; 6(8):1616-1631. View Abstract
Spatial transcriptomics reveals the distinct organization of mouse prefrontal cortex and neuronal subtypes regulating chronic pain. Nat Neurosci. 2023 11; 26(11):1880-1893. View Abstract
Loss of Slc38a4 imprinting is a major cause of mouse placenta hyperplasia in somatic cell nuclear transferred embryos at late gestation. Cell Rep. 2022 02 22; 38(8):110407. View Abstract
eccDNAs are apoptotic products with high innate immunostimulatory activity. Nature. 2021 11; 599(7884):308-314. View Abstract
Decoding molecular and cellular heterogeneity of mouse nucleus accumbens. Nat Neurosci. 2021 12; 24(12):1757-1771. View Abstract
Author Correction: Distinct dynamics and functions of H2AK119ub1 and H3K27me3 in mouse preimplantation embryos. Nat Genet. 2021 Jun; 53(6):936. View Abstract
Distinct dynamics and functions of H2AK119ub1 and H3K27me3 in mouse preimplantation embryos. Nat Genet. 2021 04; 53(4):551-563. View Abstract
Role of Mammalian DNA Methyltransferases in Development. Annu Rev Biochem. 2020 06 20; 89:135-158. View Abstract
Cell type-specific transcriptional programs in mouse prefrontal cortex during adolescence and addiction. Nat Commun. 2019 09 13; 10(1):4169. View Abstract
Myc and Dnmt1 impede the pluripotent to totipotent state transition in embryonic stem cells. Nat Cell Biol. 2019 07; 21(7):835-844. View Abstract
In vivo nuclear capture and molecular profiling identifies Gmeb1 as a transcriptional regulator essential for dopamine neuron function. Nat Commun. 2019 06 07; 10(1):2508. View Abstract
Loss of H3K27me3 Imprinting in Somatic Cell Nuclear Transfer Embryos Disrupts Post-Implantation Development. Cell Stem Cell. 2018 09 06; 23(3):343-354.e5. View Abstract
Reprogramming of Chromatin Accessibility in Somatic Cell Nuclear Transfer Is DNA Replication Independent. Cell Rep. 2018 05 15; 23(7):1939-1947. View Abstract
Establishing Chromatin Regulatory Landscape during Mouse Preimplantation Development. Cell. 2016 Jun 02; 165(6):1375-1388. View Abstract
Histone Demethylase Expression Enhances Human Somatic Cell Nuclear Transfer Efficiency and Promotes Derivation of Pluripotent Stem Cells. Cell Stem Cell. 2015 Dec 03; 17(6):758-766. View Abstract
Haploinsufficiency, but not defective paternal 5mC oxidation, accounts for the developmental defects of maternal Tet3 knockouts. Cell Rep. 2015 Feb 03; 10(4):463-70. View Abstract
Embryonic development following somatic cell nuclear transfer impeded by persisting histone methylation. Cell. 2014 Nov 06; 159(4):884-95. View Abstract
Tet3 and DNA replication mediate demethylation of both the maternal and paternal genomes in mouse zygotes. Cell Stem Cell. 2014 Oct 02; 15(4):459-471. View Abstract
Mechanisms of epigenetic memory and addiction. EMBO J. 2014 May 16; 33(10):1091-103. View Abstract
Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell. 2014 Jan 16; 156(1-2):45-68. View Abstract
