Transcriptional repression by Polycomb Repressive Complex 2

Polycomb 抑制复合物 2 的转录抑制

基本信息

批准号：
10336265
负责人：
Zachary Lewis
金额：
$ 7.01万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10336265
关键词：
Address Animals Bioinformatics Biological Models Chromatin Complex Data Set Development Diagnosis Environment Enzymes Eukaryota Fission Yeast Fungi Model Future Gene Deletion Gene Expression Regulation Genes Genetic Genetic Diseases Genetic Transcription Genome Genomic approach Goals Heterochromatin Histones Human Knowledge Lysine Maintenance Malignant Neoplasms Mediating Methyltransferase Molecular Multienzyme Complexes Mutate Mutation Neurospora Neurospora crassa Other Genetics Plants Play Polycomb Proteins Proteomics Regulation Repression Saccharomyces cerevisiae Structure System Weaver Syndrome Work X Inactivation Yeasts cancer genetics cancer type chromatin modification chromatin remodeling fungus gene repression genetic regulatory protein histone methyltransferase human disease improved insight link protein novel prevent stem cells tool transcriptome sequencing

项目摘要

Project Summary The long-term goals of this project are to understand assembly of repressed chromatin states and to elucidate mechanisms of gene repression in these specialized chromatin environments. Polycomb Group (PcG) proteins interact to form enzyme complexes that modify chromatin and assemble repressed chromatin states in animals, plants, and most fungi. Polycomb Repressive Complex 2 (PRC2) is a highly conserved histone lysine-27 methyltransferase complex that is essential for multicellular development and plays key roles in maintenance of stem cell identify, X-chromosome inactivation, and gene regulation. Mutations that alter PRC2 function are responsible for human Weaver syndrome and multiple cancers. Despite its importance, we lack a clear understanding of the mechanisms that control PRC2 and repress transcription of PRC2 target genes. Preliminary studies with the model fungus Neurospora crassa have begun to address these critical gaps in knowledge. Neurospora is a powerful experimental system that shares key features with higher eukaryotes. Namely, components of PRC2 are structurally and functionally conserved, while they are lacking in both major yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe. A targeted RNA-sequencing screen of over 400 N. crassa gene deletion strains that lack known or predicted chromatin-associated or chromatin regulatory proteins uncovered new genes required for PcG repression and are beginning to yield mechanistic insights into their functions. Application of genetic, molecular, proteomic, and genomic approaches will capitalize on these novel findings, and bioinformatic analyses will interrogate this unique RNA-seq data set to: 1) determine how a conserved ATP-dependent chromatin remodeling enzyme controls PRC2 and gene repression at PcG-repressed domains, 2) define mechanisms by which constitutive heterochromatin components regulate PRC2, and 3) define a comprehensive PcG chromatin network in a simple model system. Successful completion of the proposed aims will uncover general principles and mechanisms governing assembly and function of PcG-repressed chromatin domains. Because the first two newly identified components of PcG-mediated silencing are conserved, findings from the proposed studies will serve as a framework for future studies in higher eukaryotes, including humans. In addition, because PcG proteins are linked to cancer and other genetic diseases, understanding the regulation and function of these key chromatin regulators will ultimately improve diagnosis and treatment of human disease.

项目概要该项目的长期目标是了解抑制染色质状态的组装并阐明这些特殊染色质环境中基因抑制的机制。宝利康集团 (PcG) 蛋白相互作用形成酶复合物，修饰染色质并组装受抑制的染色质动物、植物和大多数真菌中的状态。 Polycomb 抑制复合物 2 (PRC2) 是一种高度保守的组蛋白赖氨酸 27 甲基转移酶复合物对于多细胞发育至关重要并发挥关键作用在维持干细胞识别、X 染色体失活和基因调控中发挥作用。突变 PRC2 功能的改变是导致人类韦弗综合征和多种癌症的原因。尽管其重要性，我们对控制 PRC2 和抑制转录的机制缺乏清晰的了解 PRC2 靶基因。对模式真菌粗糙脉孢菌的初步研究已经开始解决这些知识上的关键差距。 Neurospora 是一个强大的实验系统，具有共同的关键特征与高等真核生物。也就是说，PRC2 的组成部分在结构和功能上是保守的，而它们缺乏两种主要酵母：酿酒酵母和粟酒裂殖酵母。一个对 400 多种缺乏已知或预测的粗糙脉孢菌基因缺失菌株进行靶向 RNA 测序筛选染色质相关蛋白或染色质调节蛋白发现了 PcG 抑制所需的新基因并开始对其功能产生机械性的见解。应用遗传、分子、蛋白质组学和基因组学方法将利用这些新发现，生物信息学分析将询问这个独特的 RNA-seq 数据集以：1) 确定保守的 ATP 依赖性染色质如何重塑酶控制 PRC2 和 PcG 抑制域的基因抑制，2) 定义机制组成型异染色质成分通过其调节 PRC2，以及 3) 定义全面的 PcG 简单模型系统中的染色质网络。成功完成拟议目标将揭示控制 PcG 抑制的染色质结构域的组装和功能的一般原则和机制。由于 PcG 介导的沉默的前两个新发现的成分是保守的，因此研究结果拟议的研究将作为未来对包括人类在内的高等真核生物研究的框架。此外，由于 PcG 蛋白与癌症和其他遗传性疾病有关，因此了解这些关键染色质调节因子的调节和功能最终将改善疾病的诊断和治疗人类疾病。