Structural Basis of Gene Regulation by Polycomb Repressive Complex 2

Polycomb 抑制复合物 2 基因调控的结构基础

基本信息

批准号：
9219491
负责人：
Xin Liu
金额：
$ 31.02万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9219491
关键词：
Address Allosteric Regulation Alpha Cell Binding Biochemical Biochemistry Biology Catalysis Catalytic Domain Cell physiology Cells Chemicals Chromatin Chromatin Structure Complex Crystallization Cues Data Development Disease Enzymatic Biochemistry Epigenetic Process Epitopes Family Feedback Fermentation Future Gene Activation Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Transcription Goals Heterochromatin Histone H3 Histones Human Knowledge Ligation Link Lysine Macromolecular Complexes Maintenance Malignant Neoplasms Mediating Methyltransferase Molecular Conformation Multienzyme Complexes Mutation Normal Cell Nuclear Protein Nucleosomes Phosphorylation Play Polycomb Process Proteins Publishing Reaction Recruitment Activity Regulation Research Resolution Role Series Structure Subgroup Tail Therapeutic Untranslated RNA Yeasts base cancer cell cell growth regulation cell type cofactor developmental disease disease phenotype enzyme activity experimental study gene repression human disease insight macromolecular assembly mutant novel overexpression reconstitution structural biology targeted treatment

项目摘要

Project Summary: Polycomb repressive complex 2 (PRC2) mediates trimethylation of histone H3 lysine 27 (H3K27me3), a hallmark for gene silencing and facultative heterochromatin formation. PRC2 consists of four core subunits, including the catalytic subunit Ezh2, Eed, Suz12, and Rbbp4, which together respond to a myriad of developmental cues. PRC2 catalysis on chromatin substrate has been known to be subjected to several layers of regulation, including chromatin context-dependent control of the enzyme activity of PRC2, auxiliary nuclear protein factor-mediated recruitment of PRC2 to chromatin, and Ezh2 phosphorylation-dependent regulation of Ezh2 activity in the canonical gene repression and the non-canonical gene activation processes. Dysregulation of PRC2 and in particular mutation of Ezh2 are broadly linked to human disease including cancer and developmental disorder. Indeed, many regulatory mechanisms of PRC2 to be studied in depth in our proposed experiments are associated with disease phenotypes. In this regard, our research may identify novel mechanism-based targets and avenues for future therapeutics. Our long-term objective is to elucidate the structural mechanisms whereby PRC2 regulates gene expression during development by controlling chromatin structure and transcriptional state. Specifically, in this research, we will address the following three key questions concerning PRC2 catalysis and regulation. (1) What are the catalytic mechanism of PRC2, including cofactor binding, substrate recognition, and allosteric regulation? (2) How is PRC2 recruited to chromatin by auxiliary nuclear protein factors, including Aebp2, Phf19, and Jarid2? (3) How are the gene repression and activation function of Ezh2 mechanistically connected and regulated, in particular by Ezh2 phosphorylation? Using a combined structural biology, biochemistry, and chemical biology approach and in particular benefiting from our established expertise and strength in structural biology, we will be focused on several PRC2-centered multi-subunit macromolecular complexes to address each of these key questions.

项目概要： Polycomb 抑制复合物 2 (PRC2) 介导组蛋白 H3 赖氨酸 27 (H3K27me3) 的三甲基化，基因沉默和兼性异染色质形成的标志。 PRC2由四个核心亚基组成，包括催化亚基 Ezh2、Eed、Suz12 和 Rbbp4，它们共同响应无数的发展线索。 PRC2 对染色质底物的催化作用已知会受到多种影响调控层，包括对 PRC2 酶活性的染色质环境依赖性控制，辅助核蛋白因子介导的 PRC2 向染色质的募集，以及 Ezh2 磷酸化依赖性 Ezh2 活性在经典基因抑制和非经典基因激活过程中的调节。 PRC2 的失调，特别是 Ezh2 的突变与人类疾病广泛相关，包括癌症和发育障碍。事实上，PRC2的许多调控机制有待深入研究我们提出的实验与疾病表型相关。在这方面，我们的研究可能会确定未来治疗的新的基于机制的目标和途径。我们的长期目标是阐明 PRC2 调节基因的结构机制通过控制染色质结构和转录状态来在发育过程中表达。具体来说，在这个研究中，我们将解决以下有关 PRC2 催化和调控的三个关键问题。 (1) PRC2的催化机制是什么，包括辅因子结合、底物识别和变构规定？ (2) PRC2如何被辅助核蛋白因子（包括Aebp2）募集至染色质， Phf19 和 Jarid2？ (3) Ezh2基因抑制和激活功能的机制如何连接和调节，特别是通过 Ezh2 磷酸化？利用组合结构生物学，生物化学和化学生物学方法，特别受益于我们既定的专业知识和凭借结构生物学的优势，我们将重点关注几个以PRC2为中心的多亚基大分子综合体来解决这些关键问题。