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: 10623899
• 负责人: GEETA J NARLIKAR
• 金额: $ 79.49万
• 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 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623899
• 关键词: Behavior; Binding Proteins; Biological; Biophysics; Cells; Chromatin; Defect; Development; Enzymes; Euchromatin; Future; Genome; Goals; Heritability; Heterochromatin; Malignant Neoplasms; Motor; Nucleosomes; Phase; Proteins; Regulation; Repression; Role; Testing; Therapeutic Intervention; Tube; Work; biophysical properties; biophysical techniques; chromatin remodeling; in vivo; reconstitution

Abstract Chromatin provides a means to compartmentalize the genome into active (euchromatin) and heritably repressed (heterochromatin) states. Changes in these states accompany changes in cellular differentiation and are essential for stabilizing cellular identity. Both types of chromatin states are maintained and rearranged by the combined action of diverse ATP-dependent chromatin remodeling motors and specific chromatin binding proteins. The proposed work is aimed at studying the core mechanisms of some of the major chromatin regulators to achieve a better understanding of how their activities are regulated in vivo. Using a variety of biophysical approaches, we have uncovered that ATP-dependent remodelers use sophisticated auto- inhibition based mechanisms. We have also uncovered hexasomes as the preferred substrate for one type of conserved remodeler. These findings provide a biophysical basis for further probing why different remodelers have different biological roles. We had previously discovered phase-separation behavior by HP1 proteins, the core components of heterochromatin. Since then, we have uncovered that phase-separated heterochromatin reconstituted in a test-tube possesses several of the biophysical properties attributed to heterochromatin in cells. Here we will build on these new discoveries to ask the following questions: 1. Why are their differences in mechanism between remodelers from different classes? 2. How does action of remodelers at the nucleosome scale impact chromatin at bigger scales? 3. What is the role of phase-separation in heterochromatin regulation?

摘要 染色质提供了一种将基因组划分为活性（常染色质）和遗传抑制的手段 （异染色质）状态。这些状态的变化伴随着细胞分化的变化， 对稳定细胞身份至关重要这两种类型的染色质状态都是由 多种ATP依赖性染色质重塑马达和特异性染色质结合的联合作用 proteins.拟议的工作旨在研究一些主要的核心机制， 染色质调节剂，以更好地了解它们的活动是如何在体内调节。使用 各种生物物理方法，我们已经发现，ATP依赖性重塑使用复杂的自动， 抑制机制。我们还发现了六酶体作为一种类型的蛋白酶的优选底物。 保守的重塑者这些发现为进一步探索为什么不同的重塑提供了生物物理学基础。 具有不同的生物学作用。我们之前已经发现了HP1蛋白的相分离行为， 异染色质的核心成分。从那时起，我们发现了相分离的异染色质 在试管中重构的异染色质具有归因于细胞中异染色质的几种生物物理性质。 在这里，我们将在这些新发现的基础上提出以下问题： 1.为什么不同职业的重塑者在机制上存在差异？ 2.核小体尺度上的重塑分子如何影响更大尺度上的染色质？ 3.异染色质调控中相分离的作用是什么？