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Mechanism and Function of Epigenetic Modifications

Research Summary

Yi Zhang is interested in how epigenetic modification-mediated dynamic changes in chromatin structure affect gene expression, cell lineage commitment, stem cell pluripotency and self-renewal, and the development and treatment of human diseases.

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. My lab is interested in how epigenetic modification-mediated dynamic changes in chromatin structure affect gene expression, cell lineage commitment, stem cell pluripotency, and stem cell self-renewal as well as epigenetic mechanism of drug addiction. I am also interested in how misregulation of epigenetic factors contributes to the development of diseases such as diabetes, neurological diseases, and cancer. My long-term goal is to apply what we have learned in basic research to the studies of human diseases.

Over the past decade, my lab has worked on a number of projects that span many aspects of epigenetics and chromatin modifications, including (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 Ten Eleven Translocation (Tet) family of 5-methylcytosine dioxygenases. The general approach to these projects involved 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 was the basis for the establishment of Epizyme, a company focusing on the development of epigenetic-based drugs for cancer.

Building upon our strength in protein biochemistry, my lab has recently broadened our research interests to include the epigenetic mechanisms in embryonic development, stem cell reprogramming, β-cel regeneration, and drug addiction.

Current lines of investigation include the following:

  1. Dynamic DNA methylation and the underlying mechanisms
  2. Epigenetic and chromatin changes and their molecular basis in preimplantation embryos
  3. Epigenetic mechanism of induced pluripotent stem (iPS) cell generation and its application in pancreatic β-cell generation
  4. Role of long noncoding RNAs in epigenetic and chromatin regulation
  5. Epigenetic mechanisms of drug addiction and cancer
  6. The use of the information gained from these investigations for the development of treatments for human diseases, such as diabetes, cancer, and drug addiction

To address questions in these areas, we have expanded our ability to perform a wide range of state-of-the-art biological 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.

Grants from the National Institutes of Health provided partial support for these projects.

As of May 30, 2012

Scientist Profile

Investigator
Boston Children's Hospital
Biochemistry, Genetics