Comprehensive analysis of epigenetic regulators in their native chromatin context

表观遗传调节因子在其天然染色质环境中的综合分析

• 批准号: 9037141
• 负责人: Mitzi I Kuroda
• 金额: $ 36.92万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-13 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9037141
• 关键词: Address; Affinity Chromatography; Binding; Biological Models; Biology; Chemicals; Chromatin; Complex; DNA; Development; Developmental Gene; Disease; Drosophila genus; Embryonic Development; Ensure; Epigenetic Process; Event; Excision; Funding; Future; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genome; Genomics; Grant; Histone Code; Human; In Vitro; Life Cycle Stages; Link; Location; Mammalian Cell; Mammals; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Organism; PRC1 Protein; Play; Polycomb; Proteins; RNA; RNA Interference; Regulatory Element; Reproducibility; Role; SAM Domain; Series; Sex Combs on Midleg; Specificity; Supporting Cell; System; Testing; Tissues; Transcription Coactivator; Transcriptional Activation; Variant; Work; base; cell type; chromatin protein; epigenetic regulation; fly; histone modification; improved; in vivo; inhibitor/antagonist; insight; knock-down; novel; novel strategies; programs; research study; success; transcriptome sequencing

PROJECT SUMMARY The genomes of higher organisms are highly annotated by specific chromosomal proteins and histone modifications along active genes, regulatory elements, or silent regions. An ongoing challenge is to decipher the rules that establish and maintain chromatin organization. In the upcoming funding period, we propose to focus on analysis of the Polycomb group (PcG) proteins, based on their central importance in development and disease, the intriguing hypotheses raised by our current results, and our ability to use new approaches to probe chromatin protein interactions with precision. Our studies will focus on the versatile Drosophila model, but due to the high conservation of this key regulatory system we can move between fly and human systems with ease. Our experiments will address two central problems in chromatin biology: understanding the targeting and spreading of chromatin domains, and probing the ability of chromatin factors to mark genes as future regulators of cell type specificity. In Aim 1, we will define the series of molecular interactions that coordinate canonical and variant PcG complexes. In Aim 2, we will analyze how H3K27me3 is propagated in cis, to create heritable repressive domains. In Aim 3, we will determine whether a bivalent state primes developmental genes in Drosophila. Success in our studies will be highly relevant to understanding normal and aberrant genome organization and function in development and disease.

项目概要 高等生物的基因组由特定的染色体蛋白高度注释， 沿活性基因、调控元件或沉默区域的组蛋白修饰。正在进行的 挑战是破译建立和维持染色质组织的规则。在即将到来的 资助期间，我们建议重点分析 Polycomb 组 (PcG) 蛋白质，基于 它们在发育和疾病中的核心重要性，我们当前提出的有趣假设 结果，以及我们使用新方法精确探测染色质蛋白质相互作用的能力。 我们的研究将集中在多功能果蝇模型上，但由于该密钥的高度保守性 我们可以轻松地在果蝇和人类系统之间移动的调节系统。我们的实验将 解决染色质生物学的两个核心问题：了解染色质的靶向和传播 染色质结构域，并探讨染色质因子将基因标记为未来调节因子的能力 细胞类型特异性。在目标 1 中，我们将定义一系列协调的分子相互作用 典型的和变体的 PcG 复合物。在目标 2 中，我们将分析 H3K27me3 如何在 cis，创建可遗传的压制领域。在目标 3 中，我们将确定二价态是否 启动果蝇的发育基因。我们学习的成功与否高度相关 了解发育和疾病中正常和异常的基因组组织和功能。