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: 10158528
• 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/10158528
• 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