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?

摘要 将遗传物质分离成转录活跃的（常染色质）和遗传抑制的 （异染色质）染色质状态对于维持细胞身份是必不可少的。这些染色质 通过ATP依赖性染色质重塑的联合作用， 马达和特异性染色质结合蛋白。拟议的工作旨在研究核心 这些染色质调节剂的机制，以更好地了解他们的活动是如何 在体内调节。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， 核小体可塑性核小体表明染色质的额外调节作用的存在。 我们还发现了HP1蛋白的相分离行为，这是蛋白质的核心组成部分。 异染色质这些结果表明，异染色质的某些抑制功能可能 由相分离体中染色质的物理隔离引起。我们将在此基础上 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偶联？ 2.不同职业的重塑者在机制上有什么不同？ 3.异染色质调控中相分离的作用是什么？