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

我们的每个细胞都含有相同的基因组，但特定细胞类型的分化和不同细胞特性的保持需要只有某些基因是可访问的。这些过程中的缺陷会导致发育障碍，导致癌症，并导致衰老。多梳抑制复合体2(PRC2)对于特定类型的细胞分化是必不可少的。PRC2改变了DNA在染色质中的包装方式，以防止访问其他类型细胞特有的基因。在细胞分化过程中，PrC2被从对新的细胞身份重要的基因中移位，并被招募到被抑制的基因中。了解这些染色质状态动态变化的机制对于了解细胞分化是如何控制的并在它们失败时纠正这些过程是必要的。我们已经发现，活性基因的产物新生前mRNA通过与PRC2相互作用并抑制该复合体与染色质的结合来直接调节染色质状态。我们假设它们内部的前mRNAs和G-tra序列元件调节染色质状态的动态变化，这是细胞分化所必需的。我们的目的是确定在细胞分化过程中染色质状态的时间调节中，前mRNA、G-tra RNA元件和PRC2 RNA结合活性所起的作用。我们将首先建立G-Track RNA从染色质中去除PRC2的动力学。然后，我们将确定在胚胎干细胞(ESC)分化过程中，前信使核糖核酸和G-tra元件对PRC2占有率变化的贡献。最后，我们将确定PRC2 RNA结合活性对ESC分化过程中染色质状态变化的重要性。这项研究将揭示对细胞分化至关重要的基因可及性变化的机制，并提供调节这一过程的工具。通过这样做，这项工作将建立Pre-mRNA作为直接控制染色质状态的调节分子。

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.