Histone Lysine Methylation: Structures and Functions

组蛋白赖氨酸甲基化：结构和功能

• 批准号: 8124458
• 负责人: Xiaodong Cheng
• 金额: $ 9.87万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124458
• 关键词: Address; Ankyrin Repeat; Ankyrins; Architecture; Arginine; Base Excision Repairs; Binding; Biochemical; Catalytic Domain; Cell division; Chromatin; Complex; Cytosine; DNA; DNA Binding; DNA Damage; DNA Methylation; DNA biosynthesis; Data; Detection; Enzymes; Epigenetic Process; Fingers; Gene Expression; Genes; Genetic Transcription; Goals; HIV; Histone Code; Histone H3; Histones; Human; In Vitro; Individual; Inflammation; Kinetics; Knowledge; Link; Lysine; Maintenance; Malignant Neoplasms; Measures; Metabolic Diseases; Methylation; Modeling; Modification; Mono-S; Mus; N-terminal; Neurodegenerative Disorders; Nucleosomes; Null Lymphocytes; Peptides; Play; Positioning Attribute; Predisposition; Proteins; Reader; Recruitment Activity; Regulation; Regulator Genes; Repression; Role; SET Domain; Signal Transduction; Site; Specificity; Spottings; Structure; Substrate Specificity; Tail; Therapeutic Agents; Transcriptional Activation; Ubiquitin; Viral Genes; Work; arginyllysine; base; chromatin modification; demethylation; design; flexibility; gene repression; human disease; in vivo; mammalian genome; method development; methyl group; novel strategies; polypeptide; prevent; public health relevance; spatial relationship

DESCRIPTION (provided by applicant): Epigenetic regulation is a newly appreciated and fundamentally important set of gene control mechanisms that profoundly influences chromatin function. Histone lysine and arginine methylation, demethylation, and the detection of these methyl marks are components of a "histone code" that underlies epigenetic regulation. Epigenetic regulators modulate the structure, function, and access of the mammalian genome to regulate transcription. Hundreds of epigenetic effectors have been identified, many of which are enzymes that catalyze reversible chromatin modifications. Many of these enzymes contain distinct functional domains, within the same polypeptide, for both creating (or removing) and binding to a given methyl mark. To date, most if not all available structural knowledge of these chromatin (de)modifying enzymes comes from the structures of individual domains. To approach a more complete understanding of the mechanisms of epigenetic regulation, we need to understand how these different functional domains work, both individually and in concert. The central goal of this proposal is to understand the interactions and spatial relationships between such domains by determining structures spanning multiple domains of several complementary epigenetic regulators. Such information will help us to address whether the "writer" and "reader" domains act on the same histone, and whether there are any inter-domain interactions that can influence/regulate their target specificity. Importantly, broader themes may be recognized because several distinct epigenetic regulators will be studied in parallel. I propose here four new specific aims that are designed to answer four related questions. (1) How does a lysine methylation mark for repression spread? (2) How does an existing methyl mark prevent the modification of neighboring residues in histones? (3) How are the histone marks of repression connected to DNA methylation? (4) How are the local methyl marks of repression removed within a nucleosome? PUBLIC HEALTH RELEVANCE: Epigenetic regulation is a newly appreciated and fundamentally important set of gene control mechanisms that profoundly influences chromatin function, which has direct relevance to a large number of human diseases. An increasing number of chromatin modifying and de-modifying enzymes have been associated with neurodegenerative disorders, metabolic diseases, inflammation, and, most notably, cancer. Thus, structural and biochemical studies directed against this emerging class of gene regulatory enzymes may provide a method for the development of highly selective therapeutic agents that promise entirely novel approaches for the treatment of human diseases. In this proposal, we will explore questions of dynamic regulation (creating and removing) of histone lysine modifications, modification- and position-specific interactions, and biochemical crosstalk between modifications by several distinct epigenetic regulators.

描述（由申请人提供）：表观遗传调控是一组新近被认识的、极其重要的基因控制机制，它深刻地影响染色质功能。组蛋白赖氨酸和精氨酸甲基化、去甲基化以及这些甲基标记的检测是表观遗传调控的“组蛋白密码”的组成部分。表观遗传调节因子通过调节哺乳动物基因组的结构、功能和通路来调节转录。已鉴定出数百种表观遗传效应子，其中许多是催化可逆染色质修饰的酶。许多这些酶在同一多肽内含有不同的功能域，用于创建（或去除）和结合给定的甲基标记。迄今为止，这些染色质（去）修饰酶的大多数（如果不是全部）可用结构知识都来自各个域的结构。为了更全面地理解表观遗传调控机制，我们需要了解这些不同的功能域如何单独和协同发挥作用。该提案的中心目标是通过确定跨越多个互补表观遗传调节因子的多个域的结构来了解这些域之间的相互作用和空间关系。这些信息将帮助我们解决“作者”和“读者”域是否作用于相同的组蛋白，以及是否存在任何可以影响/调节其目标特异性的域间相互作用。重要的是，由于将同时研究几种不同的表观遗传调节因子，因此可能会认识到更广泛的主题。我在此提出四个新的具体目标，旨在回答四个相关问题。 (1) 赖氨酸甲基化抑制标记如何传播？ (2) 现有的甲基标记如何阻止组蛋白中邻近残基的修饰？ (3) 组蛋白抑制标记如何与 DNA 甲基化相关？ (4) 核小体内的局部甲基抑制标记是如何去除的？公共健康相关性：表观遗传调控是一套新近被认识的、极其重要的基因控制机制，它深刻影响染色质功能，与大量人类疾病直接相关。越来越多的染色质修饰和去修饰酶与神经退行性疾病、代谢疾病、炎症，尤其是癌症有关。因此，针对这一新兴基因调控酶类的结构和生化研究可能提供一种开发高选择性治疗剂的方法，从而有望为治疗人类疾病提供全新的方法。在本提案中，我们将探讨组蛋白赖氨酸修饰的动态调节（创建和去除）、修饰和位置特异性相互作用以及几种不同表观遗传调节因子修饰之间的生化串扰的问题。