Curtis Beck Rose Hills
Active Chromatin Marks Modulate the Activity of the Crucial Epigenetic Silencer PRC2
In mammals, Polycomb Repressive Complex 2 (PRC2) plays a crucial role in maintaining the gene-expression patterns that enforce cell differentiation during embryonic development. Mutations in the core components of PRC2 or its associated cofactors result in early embryonic lethality. PRC2 represses transcription by mono-, di- and tri-methylating histone H3 at lysine 27 of nucleosomes, the smallest structural unit of chromatin. The molecular basis and mechanistic insight into the modulation of methyltransferase activity of PRC2 by the presence of other histone modifications remains poorly understood. Previous biochemical studies of PRC2 activity in the context of various histone modifications have given conflicting results. This project will carry out enzymatic assays to measure the kinetics of PRC2 activity using nucleosome substrates carrying different histone modifications. Furthermore, to investigate the underlying molecular mechanisms behind the trends we observe in our biochemical assays, we will use cryo-electron microscopy to directly visualize the interactions between PRC2 and the same nucleosome substrates. This project aims to understand how the presence of active chromatin marks limits the spread of PRC2s own transcriptionally repressive product.