ILLUMINATION OF CHROMATIN REGULATION VIA CHEMICAL CONTROLLED PROXIMITY

通过化学控制的接近来阐明染色质调控

• 批准号: 10550480
• 负责人: Nathaniel A. Hathaway
• 金额: $ 37.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10550480
• 关键词: Area; Binding Proteins; Cells; Chemicals; Chromatin; Chromatin Structure; Enzymes; Gene Expression; Gene Expression Regulation; Goals; Grant; Heterochromatin; Human Development; Learning; Lighting; Malignant Neoplasms; Methylation; Pathway interactions; Regulation; Regulatory Pathway; Research; Site; Technology; Time; Visualization; Work; developmental disease; drug discovery; gene repression; genetic regulatory protein; heterochromatin-specific nonhistone chromosomal protein HP-1; human disease; inhibitor; mammalian genome; nervous system disorder; programs; recruit; small molecule

Project Summary The overarching goal of this project is to understand at a mechanistic level the chromatin regulatory pathways governing gene expression. To achieve this objective, we use chemically controlled proximity to allow for temporal and special control over specific chromatin regulatory enzymes. Our research group has made contributions to understanding the interplay between the heterochromatin protein 1 gene repression pathway and other chromatin regulators. In addition, we have a drug discovery program that has identified inhibitors of heterochromatin gene repression. We also have developed bifunctional molecules that work with catalytically inactive dCas9 to recruit endogenous chromatin regulatory enzymes to any site across the mammalian genome. Three main goals of this research program are: 1. Explore how heterochromatin gene repression is governed by two distinct H3K9 methylation binding proteins, 2. Develop approaches to visualize dynamic heterochromatin gene repression in real time at the single cell level 3. Study chromatin dynamics in real time with bifunctional compounds to recruit endogenous enzymes to specific loci. Over the course of this grant our research group will continue to advance our understanding of the mechanisms of heterochromatin gene repression using unique chemically based technologies. We also will further advance areas we have pioneered developing bifunctional small molecules to explore the capture and retargeting of endogenous chromatin regulators as an approach to understanding mammalian genome regulation.

项目概要 该项目的总体目标是从机械层面了解染色质 控制基因表达的调控途径。为了实现这一目标，我们使用 化学控制的接近度允许对特定的时间和特殊的控制 染色质调节酶。我们的研究小组做出了贡献 了解异染色质蛋白 1 基因抑制之间的相互作用 途径和其他染色质调节因子。此外，我们还有一个药物发现计划 已经鉴定出异染色质基因抑制的抑制剂。我们还开发了 双功能分子与催化失活的 dCas9 一起招募内源性 染色质调节酶位于哺乳动物基因组的任何位点。三个主要 该研究计划的目标是： 1. 探索异染色质基因抑制是如何进行的 由两种不同的 H3K9 甲基化结合蛋白控制，2. 开发方法 在单细胞水平上实时可视化动态异染色质基因抑制 3. 使用双功能化合物实时研究染色质动力学以招募内源性 酶作用于特定位点。在这笔资助的过程中，我们的研究小组将继续 促进我们对异染色质基因抑制机制的理解 独特的化学技术。我们还将进一步推进我们已有的领域 率先开发双功能小分子以探索捕获和重定向 内源染色质调节因子作为理解哺乳动物的一种方法 基因组调控。