Structure and Mechanism of Protein Modules in Chromatin Biology

染色质生物学中蛋白质模块的结构和机制

• 批准号: 8465196
• 负责人: Ming-Ming Zhou
• 金额: $ 27.2万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465196
• 关键词: Address; Binding; Biological; Biological Process; Biology; Bromodomain; Cells; Chromatin; Chromosome Pairing; Code; DNA; Development; Disease; Enzymes; Epigenetic Process; Gene Activation; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genetic Transcription; Genomics; Goals; Grant; Health; Histone Acetylation; Histone Code; Histone H4; Histones; Human; Human Biology; Human Genome; Inherited; Instruction; Knowledge; Language; Lead; Learning; Letters; Ligands; Lysine; Malignant Neoplasms; Methylation; Modeling; Modification; Molecular; Molecular Models; N-terminal; Nature; Outcome; PHD Finger; Pattern; Play; Post-Translational Protein Processing; Proteins; Reporting; Research; Role; Site; Specific qualifier value; Structure; Tertiary Protein Structure; Testing; Transcriptional Activation; Work; arginyllysine; base; chromatin modification; chromatin protein; combinatorial; complex biological systems; genome-wide; histone modification; histone-binding proteins; molecular modeling; phrases; programs; stem cell differentiation

DESCRIPTION (provided by applicant): Genomic DNA of a human cell is packaged in 23 pairs of chromosomes that are collectively called chromatin. Chromatin is not a storage space. Rather it functions as a fundamental regulator that governs global dynamic changes of gene expression. Site-specific modifications of histones - the DNA packing proteins in chromatin - play an essential role in controlling of the capacity of the human genome to store, release and inherit biological information. Studies of histone modifications previously led to the formation of the histone code hypothesis stating that patterns of histone modifications constitute a code that specifies transcriptional outcomes. While this hypothesis has played an important role in propelling the chromatin biology field in the past decade, mounting evidence argues that histone modifications exert context-dependent functions rather than a code. However, we still have very limited knowledge of how histone modifications work in concert to direct gene expression. The goal of our research in epigenetics is to understand how chromatin modifications lead to regulatory capability of chromatin that directs both gene silencing and "on demand" expression in an orderly manner. Over the past years, we have elucidated the structure and mechanism of histone modifying enzymes and histone binding protein domains. Built on the lessons learned from our own studies, as well as from those of other leading research labs in the field, we postulate that gene expression (or silencing) in chromatin proceeds with an instruction that is programmed with a set of molecular activities of the conserved functional units that are present in participating proteins, and that these basic molecular functions including chromatin modifying activities and modification-directed molecular interactions constitute alphabets of a chromatin language of gene expression. In this project, we will test and develop mechanistic models predicted by this hypothesis through the study of the structure and mechanism of tandem chromatin protein modules in the functional context of gene transcription. To tackle this highly dynamic and complex biological system, we use an integrated structural/chromatin biology approach. The specific aims of this project are to: (1) characterize the basic mechanisms of acetylated and methylated histone recognition in gene expression; (2) investigate molecular interplay of different histone modifications; and (3) define the histone crosstalk by the tandem chromatin modules in gene transcription.

描述（由申请人提供）：人类细胞的基因组DNA包装在统称为染色质的23对染色体中。染色质不是存储空间。相反，它的功能是作为一个基本的调节器，管理全球动态变化的基因表达。组蛋白（染色质中的DNA包装蛋白）的位点特异性修饰在控制人类基因组储存、释放和继承生物信息的能力中起着至关重要的作用。以前对组蛋白修饰的研究导致了 组蛋白密码假说，认为组蛋白修饰的模式构成了一个指定转录结果的密码。虽然这一假说在过去十年中在推动染色质生物学领域发挥了重要作用，但越来越多的证据表明，组蛋白修饰发挥的是上下文依赖的功能，而不是密码。然而，我们仍然有非常有限的知识组蛋白修饰如何协同工作，以指导基因表达。我们在表观遗传学研究的目标是了解染色质修饰如何导致染色质的调控能力，指导基因沉默和“按需”表达以有序的方式。在过去的几年里，我们已经阐明了组蛋白修饰酶和组蛋白结合蛋白结构域的结构和机制。基于我们自己的研究以及该领域其他领先研究实验室的研究经验，我们假设基因表达在染色质中的表达（或沉默）以一种指令进行，该指令用参与蛋白质中存在的保守功能单元的一组分子活性编程，并且这些基本分子功能包括染色质修饰活性和修饰指导的分子相互作用构成基因表达的染色质语言的字母表。在这个项目中，我们将通过研究串联染色质蛋白模块在基因转录的功能背景下的结构和机制来测试和开发这一假设所预测的机制模型。为了解决这个高度动态和复杂的生物系统，我们使用集成的结构/染色质生物学方法。本项目的具体目标是：（1）表征基因表达中乙酰化和甲基化组蛋白识别的基本机制;（2）研究不同组蛋白修饰的分子相互作用;（3）定义基因转录中串联染色质模块的组蛋白串扰。