Research Abstract

Professor of Pathology at Harvard Medical School, Early Career Scientist at Howard Hughes Medical Institute and Senior Associate Member at the Broad Institute. Laboratory in the Richard B. Simches Research Building at Massachusetts General Hospital, part of Experimental Pathology and the Center of Systems Biology with research focused on chromatin and epigenetic regulation in normal and malignant stem cells. The laboratory applies high-throughput genomic technologies to study the role of chromatin in the regulation of cell fates, functional phenotypes and drug sensitivity. The group has introduced new technologies for mapping chromatin structure genome-wide and for locus-specific editing of chromatin modifications. Notable biological findings include the identification of alternative types of large-scale chromatin structures, or ‘domains’, that maintain gene activity, gene repression or gene potential under specific cellular contexts. For example, in differentiated cells, chromatin domains marked by either ‘active’ or ‘repressive’ histone modifications maintain expression or repression of key developmental genes. However, in pluripotent ES cells, ‘bivalent’ domains enriched for both active and repressive modifications keep developmental genes poised for subsequent activation. Current projects in the lab are focused on understanding the structures, functions and mechanisms of bivalent' domains and other chromatin states in developing stem cells. Towards this end we are deploying new technologies for profiling chromatin at single molecule and single cell resolution, and for global and locus-specific perturbation of chromatin structure. Analogous approaches are now being applied to characterize aberrant chromatin states and regulatory circuits that underlie malignant phenotypes and drug resistance in tumor models, including glioblastoma, leukemia and other cancers.