Understanding the molecular mechanisms of Polycomb recruitment in ES cells and during cellular differentiation

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Polycomb group (PcG) proteins are chromatin modifiers that bind to DNA and induce gene silencing. PcG proteins control several essential biological processes including pluripotency in stem cells and embryonic development. The overarching goal of this proposal is to identify the molecular mechanism responsible for the recruitment of Polycomb Repressive Complex 2 (PRC2) to the chromatin in embryonic stem cells and during cellular differentiation. Differentiated cells and undifferentiated pluripotent stem cells in the same individual have the same genomic sequence, however, PRC2 binding sites varies. This suggests that the mechanisms driving PRC2 binding to different sites must be beyond the DNA sequence itself. We will first create an atlas of normal PRC2 binding sites in human ES cells, and in Hepatocyte (Endoderm) and Cardiomyocytes (Mesoderm) using in vitro differentiation. We will then use the newly defined atlas of developmental PRC2 binding to study the molecular mechanisms driving PRC2 recruitment. Overall, this work will allow us to explore novel hypotheses regarding the molecular mechanisms driving the fundamental process of PRC2 recruitment in pluripotent cells and how this changes during development. The long-term vision for our research program is to expand our epigenomic atlas through adding other differentiated cells and other chromatin modifiers and histone marks. The generation of this atlas will give us the opportunity to address ideas regarding the regulatory epigenome that previously we were not able to investigate, significantly improving our knowledge of the cellular differentiation and mammalian development processes. The work proposed here will have significant impacts on a number of biological fields including chromatin biology, stem cell biology and cellular differentiation.