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?

抽象的 染色质提供了将基因组划分为活性（白染色质）的手段，并遭到抑制 （异染色质）状态。这些状态的变化伴随细胞分化的变化，并且 稳定细胞身份必不可少的。两种类型的染色质状态均由 各种ATP依赖性染色质重塑电动机和特定染色质结合的组合作用 蛋白质。拟议的工作旨在研究一些主要的核心机制 染色质调节剂可以更好地了解其活动如何在体内调节。使用 多种生物物理方法，我们发现ATP依赖性重塑使用复杂的自动 基于抑制的机制。我们还发现了己糖体是一种类型的首选底物 保守的改建器。这些发现为进一步探讨了为什么不同的重塑剂提供了生物物理基础 具有不同的生物学作用。我们以前曾通过HP1蛋白发现了相分离行为， 异染色质的核心成分。从那以后，我们发现了相位分离的异染色质 在试管中重构具有归因于细胞中异染色质的几种生物物理特性。 在这里，我们将基于这些新发现来提出以下问题： 1。为什么它们在不同类别的重塑器之间的机制差异？ 2。重塑器在核小体尺度上的作用如何影响较大尺度的染色质？ 3。相分离在异染色质调节中的作用是什么？