Molecular Basis of Drosophila Homeotic Gene Regulation

果蝇同源基因调控的分子基础

• 批准号: 8439457
• 负责人: Peter J. Harte
• 金额: $ 46.11万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439457
• 关键词: Accounting; Acetylation; Acetyltransferase; Affect; Affinity; Alanine; Binding; Biological Process; Bromodomain; CREB-binding protein; Calorimetry; Cell Differentiation process; Cell Maintenance; Cells; ChIP-seq; Chromatin; Chromosomes; Chronic; Development; Diabetes Mellitus; Disease; Drosophila genus; Enhancers; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genes; Genome; Genomics; Goals; Histones; Homeobox Genes; Human; In Vitro; Individual; Inflammation; Lead; Light; Longevity; Lysine; Maintenance; Malignant Neoplasms; Metabolic syndrome; Metabolism; Modification; Molecular; Mutation; Natural regeneration; Obesity; PHD Finger; PRC1 Protein; Pattern; Phenotype; Play; Pluripotent Stem Cells; Polycomb; Positioning Attribute; Protein Binding; Proteins; RNA Interference; Recombinants; Recruitment Activity; Regulation; Research; Role; SET Domain; Salivary Glands; Site; Source; Specificity; Stem cells; Testing; Titrations; Transcriptional Regulation; Transgenic Organisms; Work; base; cancer stem cell; enzyme activity; genome-wide; in vivo; inhibitor/antagonist; insight; interest; mutant; overexpression; programs; protein function; public health relevance; research study; stem cell biology

DESCRIPTION (provided by applicant): The experiments described in this proposal are focused on understanding the mechanisms underlying the maintenance of stable heritable states of gene expression during development, as well as their developmentally programmed reversal. The Drosophila homeotic genes remain a preeminent source of new insights into these mechanisms. We focus on the Polycomb Group (PcG) and Trithorax Group (TrxG) proteins, which regulate chromatin states associated respectively with transcriptionally silent and active states through their chromatin modifying and remodeling enzyme activities. Their activities are now implicated in many biological processes, including genome-wide control of transcriptional programs, stem cell maintenance and differentiation, regeneration, longevity and others. Disturbances in the function or regulation of PcG and TrxG proteins are now known suspected to underlie a wide variety of disease states from cancer, chronic inflammation, obesity, diabetes, metabolic syndrome and others, some of which appear to manifest heritable "transgenerational" effects. The aims of proposed work are: 1) to further investigate a newly discovered activity of the TRX protein that will shed new light on its function in a maintaining active states and antagonizing Polycomb silencing; 2) to investigate a new activity of the CBP protein which functionally integrates it even more intimately with TRX and suggests a mechanism by which TRX affects H3K27 acetylation by CBP to antagonize Polycomb silencing; 3) to investigate a newly discovered role of the Polycomb protein (PC) in negatively modulating / antagonizing maintenance of active chromatin states. Understanding the role of these new factors in regulating Polycomb silencing will provide new insights into the mechanisms underlying the epigenetic inheritance of stable chromatin states during development.

描述（由申请人提供）：本提案中描述的实验重点是了解发育过程中维持基因表达稳定可遗传状态的机制，以及它们的发育程序逆转。果蝇同源基因仍然是这些机制新见解的重要来源。我们重点关注 Polycomb Group (PcG) 和 Trithorax Group (TrxG) 蛋白，它们通过染色质修饰和重塑酶活性分别调节与转录沉默和活性状态相关的染色质状态。它们的活动现在涉及许多生物过程，包括转录程序的全基因组控制、干细胞维持和分化、再生、长寿等。现在已知，PcG 和 TrxG 蛋白的功能或调节紊乱可能是癌症、慢性炎症、肥胖、糖尿病、代谢综合征等多种疾病状态的基础，其中一些疾病似乎表现出可遗传的“跨代”效应。拟议工作的目的是：1）进一步研究新发现的 TRX 蛋白活性，这将为其维持活性状态和拮抗 Polycomb 沉默的功能提供新的线索； 2) 研究CBP蛋白的新活性，该活性在功能上将其与TRX更紧密地整合，并提出TRX通过CBP影响H3K27乙酰化以拮抗Polycomb沉默的机制； 3）研究新发现的Polycomb蛋白（PC）在负调节/拮抗活性染色质状态维持中的作用。了解这些新因素在调节 Polycomb 沉默中的作用将为了解发育过程中稳定染色质状态的表观遗传机制提供新的见解。