The Role of Histone Chaperones in Histone Acetylation and Nucleosome Dynamics

组蛋白伴侣在组蛋白乙酰化和核小体动力学中的作用

• 批准号: 10393781
• 负责人: Andrew Joseph Andrews
• 金额: $ 1.02万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393781
• 关键词: Acetylation; Biochemical; Cell Nucleus; Chromatin; Chromatin Structure; DNA; Enzyme Inhibition; Enzymes; Epigenetic Process; Equilibrium; Eukaryotic Cell; Gene Expression Regulation; Genetic Materials; Genetic Transcription; Genome; Histone Acetylation; Histones; Knowledge; Link; Lysine; Methodological Studies; Modification; Molecular; Molecular Chaperones; Nucleosomes; Positioning Attribute; Proteins; Regulation; Role; Site; Specificity; Structure; Work; drug modification; histone acetyltransferase; histone modification; histone-binding proteins; human disease; insight; new therapeutic target; protein complex; success; virtual

Project Summary There is a fundamental paradox within the nucleus of every eukaryotic cell: The genetic material must be organized and compacted yet remain accessible for readout by transcription machinery. Two of the many factors that retain this balance are histones and histone binding proteins. Histones are ultimately responsible for compacting the chromosomal DNA almost 500,000-fold to fit into the nucleus. While genome accessibility is regulated in part by the actions of histone acetyltransferases (KATs), histone chaperones interact directly with histones and can assemble and/or disassemble them on DNA. KATs covalently modify the histones and therefore, have the potential to alter chromatin structure. Exciting new evidence structurally and functionally link KATs and histone chaperones. However, virtually nothing is known about the mechanisms by which these proteins cooperate to manage compaction and genome accessibility. We have demonstrated the ability of histone chaperones (Asf1), to recognize the acetylation state of histones and work together to modify the specificity of KATs. We are proposing that these chaperones function to maintain the proper acetyl-profiles of chromatin by regulating both which lysines get acetylated and their incorporation in to chromatin. A biochemical and molecular understanding of how specificity and selectivity is achieved is currently a major challenge in the chromatin field. This project will employ and expand on new methodologies for studying complex protein-protein networks needed to regulate chromatin dynamics and post-translational specificity.

项目摘要 在每个真核细胞的细胞核中都有一个根本的悖论：遗传物质必须是 组织和压缩，但仍可由转录机器读出。众多因素中的两个 保持这种平衡的是组蛋白和组蛋白结合蛋白。组蛋白最终要对 将染色体DNA压缩近500,000倍以适应细胞核。虽然基因组可获得性是 部分受组蛋白乙酰转移酶(KATS)调节，组蛋白伴侣蛋白直接与 组蛋白，并可以在DNA上组装和/或分解它们。KATS共价修饰组蛋白和 因此，有可能改变染色质结构。令人振奋的新证据在结构和功能上的联系 猫咪和组蛋白伴侣。然而，人们对这些机制几乎一无所知。 蛋白质相互协作来管理紧凑和基因组的可及性。我们已经证明了 组蛋白伴侣蛋白(ASF1)，识别组蛋白的乙酰化状态，并共同修饰 KATS的专一性。我们提出，这些伴侣的功能是维持正确的乙酰基轮廓。 通过调节哪些赖氨酸被乙酰化以及它们与染色质的结合来调节染色质。一种生化 而分子理解如何实现特异性和选择性目前是一个重大挑战 染色质区域。该项目将采用并扩展研究复杂蛋白质的新方法。 需要网络来调节染色质的动态和翻译后的特异性。