Molecular Basis of Drosophila Homeotic Gene Regulation

果蝇同源基因调控的分子基础

• 批准号: 8729582
• 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/8729582
• 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侧重于理解在发育过程中维持稳定的基因表达状态的基础机制，以及它们的发展编程的逆转。果蝇同源基因仍然是对这些机制的新见解的首要来源。我们专注于PolyComb组（PCG）和Trithorax组（TRXG）蛋白，它们通过其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。现在，他们的活动与许多生物学过程有关，包括对转录程序的控制，干细胞维持和分化，再生，寿命等。现在已知怀疑PCG和TRXG蛋白功能或调节的干扰是癌症，慢性炎症，肥胖，糖尿病，代谢综合征等多种疾病状态的基础，而这些疾病似乎表现出了遗传性的“转变”作用。拟议工作的目的是：1）进一步研究TRX蛋白的新发现的活性，该活动将在维持活跃状态​​和拮抗polycomb沉默中发明新的启示； 2）研究CBP蛋白的一种新活性，该活性在功能上更加与TRX紧密整合，并提出了一种机制，通过CBP通过CBP影响H3K27乙酰化以拮抗PolyComb沉默； 3）研究多肉汤蛋白（PC）在活性染色质状态的负调节 /拮抗维持中的新作用。了解这些新因素在调节PolyComb沉默中的作用将为稳定染色质状态在发育过程中的表观遗传遗传的基础机制提供新的见解。