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

细胞分化过程中新生前体 mRNA 对多梳抑制复合物 2 (PRC2) 的调节

• 批准号: BB/W008750/1
• 负责人: Richard Jenner
• 金额: $ 86.61万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW008750%2F1
• 关键词: Regulation; polycomb; repressive; complex; PRC2

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.

我们的每个细胞都包含相同的基因组，但特定细胞类型的分化和不同细胞身份的维持需要只有某些基因是可访问的。多梳抑制复合物2（PRC 2）是特定细胞类型分化所必需的。PRC 2改变DNA在染色质中的包装方式，以防止其他细胞类型的特异性基因进入。在细胞分化过程中，PRC 2从对新细胞身份重要的基因中被取代，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以及当它们失败时纠正这些过程是必要的。我们发现活性基因的产物新生前mRNA通过与PRC 2相互作用并抑制复合物与染色质的结合来直接调节染色质状态。我们假设，前mRNA和它们内部的G-道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。我们的目的是确定前mRNA，G-tract RNA元件和PRC 2 RNA结合活性在细胞分化过程中染色质状态的时间调节中的作用。我们将首先建立PRC 2从染色质中去除的动力学G-道RNA。然后，我们将定义前mRNA和G-道元素的PRC 2占用的胚胎干细胞（ESC）分化过程中发生的变化的贡献。最后，我们将确定PRC 2 RNA结合活性对ESC分化过程中染色质状态变化的重要性，这项研究将揭示基因可及性变化的潜在机制，这些变化对细胞分化至关重要，并提供调控这一过程的工具。在这样做的过程中，这项工作将建立前mRNA作为直接控制染色质状态的调节分子。

项目成果

Apparent RNA bridging between PRC2 and chromatin is an artefact of non-specific chromatin precipitation upon RNA degradation

PRC2 和染色质之间的明显 RNA 桥是 RNA 降解时非特异性染色质沉淀的产物

• DOI: 10.1101/2023.08.16.553503
• 发表时间: 2023
• 作者: Hickman A