Chief Molecular Biology, Massachusetts General Hospital

SVP, Chief Academic Officer Massachusetts General Hospital

Professor of Genetics Harvard Medical School

Associate Member Broad Institute

adenosine triphosphatases; chromatin; chromatin assembly and disassembly; chromosomal proteins non-histone; drosophila proteins; epigenetics; eukeukaryotic protein complexes; histones; nucleosomes; polycomb proteins; transcription factors

The Kingston Lab seeks to understand the mechanisms eukaryotic protein complexes use to regulate the epigenetic status of chromatin both in vitro and in vivo, with much of our focus on structural alterations to chromatin. We isolate chromatin-modifying complexes involved in the stable and heritable repression and activation of master regulatory genes, test them using functional assays, and assess the mechanistic hypotheses generated in cell culture and mouse systems.

In eukaryotes, DNA is dynamically regulated by higher order packaging of the DNA into chromatin. The fundamental unit of chromatin is the nucleosome - DNA wrapped around a core of histone proteins. These nucleosomes can be compacted into a closed structure or they can be remodeled into an open and accessible structure. Changing the chromatin conformation alters the ability of the transcriptional machinery to gain access and can thus alter gene expression. How is this dynamic regulation achieved? One prime mechanism for chromatin regulation is modification of the chromatin by protein complexes that are encoded by genes that were initially identified as being essential for the epigenetic regulation of development. Two major classes that we work on are the normally repressive complexes encoded by the Polycomb-Group and the activating complexes encoded the trithorax-Group.

The general goal of our group is to determine how these complexes function during development of specific cell lineages in mammals. We have deconstructed the functional core of the Polycomb Group complexes of the PRC1 family in mammals and have identified key domains in these proteins. We have used similar approaches in the SWI/SNF (BAF) family of ATP-dependent remodeling complexes. We are now elucidating the effects of these complexes on long-range chromatin interactions, their impacts on chromatin compaction, and the potential for phase separation to play a role in memory of the Polycomb repressed state.