Molecular Basis of Gene Regulation by Polycomb Repressive Complex 2

项目概要： Polycomb抑制复合物2（PRC 2）维持细胞身份和对照的表观遗传记忆 许多基本的细胞过程，如干细胞多能性维持、干细胞分化、X- PRC 2功能的失调与广泛的染色体失活、印记等有关。 一系列癌症和发育障碍。在分子水平上，PRC 2介导组蛋白H3赖氨酸 27三甲基化（H3 K27 me 3），基因沉默的标志。细胞类型和发育状态特异性PRC 2 功能在很大程度上取决于复合物的动态相互作用。PRC 2显示出巨大的 组成的复杂性，这与PRC 2在细胞发育中的多效性作用相关。核心PRC 2 复合物由EZH 12、EED、SUZ 12和RBBP 4/7组成。哺乳动物旁系同源物EZH 1和EZH 2是哺乳动物的旁系同源物。 PRC 2的催化亚基。PRC 2的酶活性和染色质靶向受到多种生物学活性的影响。 AEBP 2、JARID 2、PHF 1、MTF 2、PHF 19和EPOP等一系列辅助亚基，形成两个 互斥PRC 2全息复合体的类。除了这些主要专用的辅助子单元之外， PRC 2还动态地与过多的其他细胞因子相关联，以介导与重要的细胞因子的串扰。 细胞信号通路，例如DNA损伤反应和修复中的BRCA 1，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。 虽然生物学和临床上重要的PRC 2功能已被广泛认可，但潜在的PRC 2功能可能是一个潜在的问题。 很大程度上缺乏分子机制。由于它们的大小和复杂性，生化重建和 PRC 2分子组装的结构分析提出了一个艰巨的挑战;直到最近，我们才 等开始揭示PRC 2的催化、染色质结合和疾病突变的结构基础。 这个MIRA奖的首要主题是集中在PRC 2的结构和功能，旨在 了解它们是如何被调节以控制细胞增殖和分化的。拟定的研究将 通过解决以下三个具体问题，弥合实地的认识差距。(1)如何 PRC 2的酶活性在各种细胞环境中受到调节？(2)PRC 2是如何专门招募 CpG岛染色质？(3)PRC 2的结构机制是如何与基因调控相联系的？ 一些重要的生物学过程，如干细胞分化和表观遗传记忆维持 在细胞分裂？

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?