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 遗传材料分离为主动转录（白染色质）和遗传性抑制 （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 电机和特定的染色质结合蛋白。拟议的工作旨在研究核心 这些染色质调节剂的机制可以更好地了解其活动的方式 受体内调节。使用多种生物物理方法，我们发现染色质 重塑ATPases利用了最小的染色质单元内的意外可塑性，A 核小体。塑料核小体表明染色质存在其他调节作用。 我们还发现了HP1蛋白中的相位分​​离行为，这是 异染色质。这些结果表明，异染色质的某些抑制功能可能 是由相位分离体中染色质的物理隔离引起的。在这里，我们将建立在这些基础上 提出以下问题的新发现： 1。染色质重塑电动机如何将ATP水解与核小体构象变化？ 2。不同类别的重塑器之间的机制有什么区别？ 3。相分离在异染色质调节中的作用是什么？