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 how epigenetic-mediated dynamic changes in chromatin structure affect gene expression, cell lineage commitment, stem cell pluripotency and self-renewal, and cancer development. Our long-term goal is to apply this basic research to studies of human diseases.
Studies in our lab focus on four different areas. The first is the relationship between ATP-dependent nucleosome remodeling and histone deacetylation. This area of study focuses on the nucleosome-remodeling and deacetylase complex NuRD, which we have demonstrated also plays an important role in methylated DNA silencing. We combine biochemical and mouse genetic approaches to understand the biological function of the NuRD complex and how it performs this function. Our recent studies have linked NuRD's function to erythropoiesis and the autoimmune disease lupus.
In our second area of study, we are identifying and characterizing novel enzymes capable of covalently modifying histones, including histone methyltransferases, demethylases, and histone ubiquitin E3 ligases. Of the histone methyltransferases that we have identified, we focus on EZH2 and hDOT1 because of their functions in stem cell and cancer biology. For example, the EZH2 complex silences important differentiation genes in ES cells and is linked to different types of solid cancers, and hDOT1 is linked to leukemia. We used a novel biochemical assay and have identified a large family of histone demethylases—the JmjC-domain–containing proteins. Using a loss-of-function approach, we have demonstrated that certain demethylases are important for spermatogenesis and cellular metabolism.
Our third area of focus involves the role of various epigenetic modifications in cell lineage commitment, maintenance, and stem cell biology. We are evaluating the effect of various epigenetic factors in induced pluripotent stem (iPS) cell generation and the therapeutic potential of iPS cells. Our goal is to develop an epigenetic-based therapy for human diseases.
Our fourth area of research involves identification and characterization of small chemical compounds that can modulate the enzymatic activities of the histone methyltransferases EZH2 and hDOT1. By performing high-throughput screening of chemical libraries, followed by in vitro and in vivo verification, we hope to identify compounds that inhibit the EZH2 and hDOT1 enzymatic activities. Our goal is to use this information to develop drugs for the treatment of cancer.
