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. Our lab is 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 reward-related learning and memory; and (3) how dysregulation of epigenetic factors contributes to the development of diseases such as diabetes, drug addiction, neurological diseases, and cancer. Our laboratory aims to apply this basic research to studying a broad spectrum of human diseases.
Over the past decade, we have 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 its capability to use a variety of state-of-the-art techniques, including single-cell live imaging, cell lineage tracing in the mouse preimplantation embryo, somatic cell nuclear transfer, stem cell reprogramming, high-throughput epigenetic modification analysis, research on cancer drug resistance, and mouse genetics. Current lines of investigation include: