Histone Lysine Methylation: Structures and Functions

组蛋白赖氨酸甲基化：结构和功能

基本信息

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
项目类别：
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

项目摘要

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）：表观遗传调节是一组新的且根本重要的基因控制机制，这些机制深刻影响染色质功能。组蛋白赖氨酸和精氨酸甲基化，脱甲基化以及这些甲基标记的检测是构成表观遗传调节的“组蛋白代码”的成分。表观遗传调节剂调节哺乳动物基因组的结构，功能和获取以调节转录。已经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。这些酶中的许多酶在同一多肽内包含不同的功能结构域，以创建（或去除）并与给定的甲基标记结合。迄今为止，这些染色质（DE）修饰酶的大多数可用结构知识都来自单个域的结构。为了更完整地了解表观遗传调节的机制，我们需要了解这些不同的功能领域如何单独和共同起作用。该建议的核心目标是通过确定跨越几个互补表观遗传调节剂的多个领域的结构来了解此类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”领域是否在同一组蛋白上作用，以及是否存在任何可能影响/调节其目标特异性的域间相互作用。重要的是，可以认可更广泛的主题，因为将同时研究几个不同的表观遗传调节剂。我在这里提出了四个旨在回答四个相关问题的新特定目标。（1）赖氨酸甲基化标记如何扩散？（2）现有的甲基标记如何阻止组蛋白中相邻残基的修饰？（3）抑制的组蛋白标记如何连接到DNA甲基化？（4）如何在核小体内去除局部抑制的局部甲基标记？公共卫生相关性：表观遗传调节是一组新的且根本重要的基因控制机制，这些基因控制机制深远影响染色质功能，这与大量人类疾病具有直接相关性。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，炎症以及最值得注意的是癌症有关。因此，针对这种新兴基因调节酶的结构和生化研究可能为开发高度选择性的治疗剂提供一种方法，这些方法有望完全新颖地治疗人类疾病的方法。在此建议中，我们将探讨组蛋白赖氨酸修饰，修饰和特定位置相互作用的动态调节（创建和去除）问题，以及通过几种不同的表观遗传调节剂进行修改之间的生化串扰。