Regulation of polycomb repressive complex 2 (PRC2) by nascent pre-mRNA during cell differentiation

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Each of our cells contains the same genome but the differentiation of specific cell types and maintenance of different cell identities requires that only certain genes are accessible. Defects in these processes underly developmental disorders, cause cancer, and contribute to ageing.Polycomb repressive complex 2 (PRC2) is essential for the differentiation of specific cell types. PRC2 modifies how DNA is packaged in chromatin to prevent access to genes specific for other cell types. During cell differentiation, PRC2 is displaced from genes important for the new cell identity and recruited to genes that become repressed. Knowledge of the mechanisms that underlie these dynamic changes in chromatin state is necessary to understand how cell differentiation is controlled and to correct these processes when they fail.We have discovered that the product of active genes, nascent pre-mRNA, directly regulates chromatin state by interacting with PRC2 and inhibiting the association of the complex with chromatin. We hypothesise that pre-mRNAs and G-tract sequence elements within them regulate the dynamic changes in chromatin state that are essential for cell differentiation. Our aim is to determine the role of pre-mRNA, G-tract RNA elements and PRC2 RNA binding activity in the temporal regulation of chromatin state during cell differentiation. We will first establish the dynamics of PRC2 removal from chromatin by G-tract RNA. We will then define the contribution of pre-mRNA and G-tract elements to the changes in PRC2 occupancy that occur during embryonic stem cell (ESC) differentiation. Finally, we will determine the importance of PRC2 RNA binding activity for changes in chromatin state during ESC differentiation.This study will reveal mechanisms underlying the changes in gene accessibility that are central to cell differentiation and provide tools by which this process can be modulated. In doing so, this work will establish pre-mRNA as a regulatory molecule that directly controls chromatin state.