ATP-dependent and independent mechanisms of regulating chromatin states

调节染色质状态的 ATP 依赖性和非依赖性机制

• 批准号: 10394727
• 负责人: GEETA J NARLIKAR
• 金额: $ 79.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394727
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; Behavior; Binding Proteins; Breast cancer metastasis; Cell Maintenance; Cells; Chromatin; Chromatin Remodeling Factor; Euchromatin; Gene Silencing; Genetic Materials; Heritability; Heterochromatin; Link; Malignant Neoplasms; Mediating; Molecular Conformation; Motor; Mutation; Nucleosomes; Phase; Proteins; Reaction; Regulation; Role; Testing; Therapeutic Intervention; Work; biophysical techniques; chromatin remodeling; driver mutation; in vivo; segregation

Abstract The segregation of genetic material into actively transcribed (euchromatin) and heritably repressed (heterochromatin) chromatin states is essential for the maintenance of cell identity. These chromatin states are maintained and rearranged by the combined action of ATP-dependent chromatin remodeling motors and specific chromatin binding proteins. The proposed work is aimed at studying the core mechanisms of these chromatin regulators to achieve a better understanding of how their activities are regulated in vivo. Using a variety of biophysical approaches we have found that chromatin remodeling ATPases take advantage of unexpected plasticity within the smallest unit of chromatin, a nucleosome. A plastic nucleosome suggests the presence of additional regulatory roles for chromatin. We have also uncovered phase-separation behavior in HP1 proteins, which are core components of heterochromatin. These results suggest that some of the repressive functions of heterochromatin may arise from physical sequestration of chromatin in phase-separated bodies. Here we will build on these new discoveries to ask the following questions: 1. How do chromatin remodeling motors couple ATP hydrolysis to changes in nucleosome conformation? 2. What are the differences in mechanism between remodelers from different classes? 3. What is the role of phase-separation in heterochromatin regulation?

抽象的 遗传物质分为主动转录（常染色质）和遗传抑制 （异染色质）染色质状态对于维持细胞身份至关重要。这些染色质 通过 ATP 依赖性染色质重塑的联合作用来维持和重新排列状态 马达和特定染色质结合蛋白。拟议的工作旨在研究核心 这些染色质调节因子的机制，以更好地了解它们的活动如何 体内调节。使用各种生物物理方法，我们发现染色质 重塑 ATP 酶利用染色质最小单位内意想不到的可塑性， 核小体。塑料核小体表明染色质存在额外的调节作用。 我们还发现了 HP1 蛋白的相分离行为，HP1 蛋白是 异染色质。这些结果表明异染色质的一些抑制功能可能 由相分离体中染色质的物理隔离产生。在这里我们将在这些基础上 新发现提出以下问题： 1. 染色质重塑马达如何将 ATP 水解与核小体构象的变化耦合起来？ 2. 不同阶层的改造者机制有何差异？ 3. 相分离在异染色质调控中的作用是什么？