Molecular Basis of Gene Regulation by Polycomb Repressive Complex 2

Polycomb 抑制复合物 2 基因调控的分子基础

• 批准号: 10373974
• 负责人: Xin Liu
• 金额: $ 61.15万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10373974
• 关键词: Address; Award; BRCA1 gene; Binding; Biochemical; Biological Process; Catalysis; Catalytic Domain; Cell Differentiation process; Cell Proliferation; Cell division; Cell physiology; Cells; Chromatin; Clinical; Complex; CpG Islands; DNA Damage; DNA Methylation; Development; Disease; EZH2 gene; Epigenetic Process; Gene Expression Regulation; Gene Silencing; Genome; Genomic Imprinting; Goals; Histone H3; Human; Link; Lysine; Maintenance; Malignant Neoplasms; Mediating; Molecular; Molecular Analysis; Mutation; Polycomb; Research; Role; Signal Pathway; Signal Transduction; Stem cell pluripotency; Structure; X Inactivation; cell type; developmental disease; epigenetic memory; imprint; molecular assembly/self assembly; paralogous gene; reconstitution; recruit; repaired; response; stem cell differentiation

Project Summary: Polycomb Repressive Complex 2 (PRC2) maintains an epigenetic memory of cell identity and controls many fundamental cellular processes, such as stem cell pluripotency maintenance, stem cell differentiation, X- chromosome inactivation, imprinting, and so on. Dysregulation of PRC2 function is associated with a wide spectrum of cancers and developmental disorders. On the molecular level, PRC2 mediates histone H3 lysine 27 trimethylation (H3K27me3), hallmark of gene silencing. Cell type and developmental state-specific PRC2 function largely depends on the dynamic interactome of the complex. PRC2 displays tremendous compositional complexity, which correlates with pleiotropic roles of PRC2 in cell development. The core PRC2 complex consists of EZH1/2, EED, SUZ12 and RBBP4/7. The mammalian paralogs EZH1 and EZH2 are the catalytic subunit of PRC2. The enzymatic activity and chromatin targeting of PRC2 are impacted by a diverse array of accessory subunits, including AEBP2, JARID2, PHF1, MTF2, PHF19 and EPOP, which form two classes of mutually exclusive PRC2 holo complexes. Besides these mostly dedicated accessory subunits, PRC2 also dynamically associates with a plethora of other cellular factors to mediate crosstalk with important cell signaling pathways, for example BRCA1 in DNA damage response and repair, DNMTs in DNA methylation and genomic imprinting, and CTCF in genome structure and organization. While biologically and clinically important PRC2 function has been widely appreciated, the underlying molecular mechanisms are largely lacking. Due to their size and complexity, biochemical reconstitution and structural analysis of the molecular assemblies of PRC2 present a formidable challenge; only recently have we and others started to reveal the structural basis of catalysis, chromatin binding and disease mutation of PRC2. The overarching theme of this MIRA award is focused on the structure and function of PRC2 and aims to understand how they are regulated to control cell proliferation and differentiation. The proposed study will close gaps of understanding in the field by addressing the following three specific questions. (1) How the enzymatic activity of PRC2 is regulated in various cellular contexts? (2) How is PRC2 specifically recruited to CpG island chromatin? (3) How are the structural mechanisms of PRC2 connected to gene regulation during some central biological processes, such as stem cell differentiation and epigenetic memory maintenance during cell division?

项目概要： Polycomb 抑制复合物 2 (PRC2) 维持细胞身份和控制的表观遗传记忆 许多基本的细胞过程，例如干细胞多能性维持、干细胞分化、X- 染色体失活、印记等。 PRC2 功能失调与广泛的 一系列癌症和发育障碍。在分子水平上，PRC2 介导组蛋白 H3 赖氨酸 27 三甲基化 (H3K27me3)，基因沉默的标志。细胞类型和发育状态特异性 PRC2 功能很大程度上取决于复合物的动态相互作用组。 PRC2显示出巨大的 成分复杂性，与 PRC2 在细胞发育中的多效性作用相关。核心PRC2 复合体由 EZH1/2、EED、SUZ12 和 RBBP4/7 组成。哺乳动物旁系同源物 EZH1 和 EZH2 是 PRC2的催化亚基。 PRC2 的酶活性和染色质靶向受到多种因素的影响 一系列辅助亚基，包括 AEBP2、JARID2、PHF1、MTF2、PHF19 和 EPOP，形成两个 相互排斥的 PRC2 全息复合体的类别。除了这些主要专用的辅助子单元之外， PRC2 还与大量其他细胞因子动态关联，以介导与重要细胞的串扰。 细胞信号通路，例如 DNA 损伤反应和修复中的 BRCA1、DNA 甲基化中的 DNMT 和基因组印记，以及基因组结构和组织中的 CTCF。 虽然在生物学和临床上重要的 PRC2 功能已得到广泛认可，但潜在的 很大程度上缺乏分子机制。由于其大小和复杂性，生化重建和 PRC2 分子组装体的结构分析提出了巨大的挑战；直到最近我们才 等人开始揭示 PRC2 的催化、染色质结合和疾病突变的结构基础。 MIRA 奖的总体主题集中在 PRC2 的结构和功能上，旨在 了解它们如何被调节以控制细胞增殖和分化。拟议的研究将 通过解决以下三个具体问题来缩小该领域的理解差距。 (1) 如何 PRC2 的酶活性在各种细胞环境中受到调节？ (2) PRC2具体是如何招募的 CpG岛染色质？ (3) PRC2的结构机制如何与基因调控相关 一些核心生物过程，例如干细胞分化和表观遗传记忆维持 细胞分裂期间？