Molecular mechanisms of the core and linker histone tail domains that drive chromatin condensation

驱动染色质浓缩的核心和连接组蛋白尾域的分子机制

• 批准号: 10628745
• 负责人: Jeffrey J Hayes
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-10 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628745
• 关键词: Acetylation; Affect; Architecture; Binding; Biochemical; Biological Models; Cell Nucleus; Cell physiology; Chromatin; Chromatin Modeling; Chromatin Remodeling Factor; Chromatin Structure; Chromosomes; Communication; Complex; DNA; DNA Repair; Disease; Elements; Epigenetic Process; Eukaryotic Cell; Gene Expression; Genes; Genetic Diseases; Genetic Transcription; Genome; Genomic DNA; Goals; HMGN Proteins; Histones; Human Chromosomes; Human Genome; Knowledge; Learning; Length; Mediating; Modification; Molecular; Mutation; Nature; Nucleosomes; Physical condensation; Post-Translational Protein Processing; Process; Proteins; Regulation; Structure; System; Tail; Work; biophysical techniques

Project Summary/Abstract: Human chromosomes serve to compact the genomic DNA several thousand times its length to fit within the cell’s nucleus, while also allowing for processes such as and gene expression. To accomplish this, the genome is assembled into a complicated, multifaceted complex known as chromatin. The assembly of chromatin first involves wrapping short (~200 bp) segments around spools of protein comprised of core histone into structures known as nucleosomes. Immensely long, genome-sized strings of nucleosomes are assembled into large structures via to the self-interacting nature of nucleosomes. The key elements in formation of these large condensed structures are the ‘tail’ domains of the core histone proteins, which protrude out from the main body of nucleosomes to mediate inter-nucleosome interactions. However, despite their essential nature to the formation of chromosomes, little is actually known about how the histone tail domains contact neighboring nucleosomes. Moreover, these interactions represent critical points for regulation, and are modified by epigenetic posttranslational modifications, including acetylation, as well as other chromatin modifiers. This project will employ biochemical and biophysical techniques to define critical molecular aspects of the inter-nucleosome interactions mediated by the core histone tail domains in model systems, and elucidate how epigenetic modifications within the tail domains regulate these interactions. The specific goals of the work described in this proposal are to: 1) define inter- nucleosome interactions mediated by the core histone tail domains, and how posttranslational modifications transition inactive chromatin structures to those hospitable to active genes in a model chromatin system; 2) define aspects of how linker histones bind to nucleosomes, and oligonucleosome arrays, are affected by posttranslational modifications, and communicate the core histone tail domains; and 3) understand how the HMGN chromatin architectural factors influence H1 structure to destabilize chromatin condensates In addition, we will use lessons learned from the above work to understand the molecular basis a newly identified mutation in a linker histone that causes the genetic disorder known as Rahman’s disease. These results will fill in key knowledge gaps in our understanding of how chromosomes are assembled, and regulated to provide for transcription, replication, DNA repair, and other genome-related processes.

项目摘要/摘要： 人类染色体可将基因组DNA隔离到其长度为薄薄的基因组DNA。 细胞的核，同时还允许诸如基因表达的过程。 基因组被组装成一个复杂的多方面组合，称为染色质 染色质首先涉及在核心蛋白质组成的线轴周围包裹短（〜200 bp）段 组成的结构被称为核小体。 通过核小体的自我相互作用组装成大型结构。 大型结构的形成是核心核心组蛋白蛋白的“尾巴”域， 从核小体的主体伸出，介导核体间相互作用。 尽管它们是染色体形成的本质，但实际上对这个主题知之甚少 组蛋白的尾巴接触相邻的核小体，这些相互作用代表关键 调节点，并通过表观遗传后的翻译后修饰（包括乙酰化）修饰 以及其他染色质修饰符。 定义由核心组​​蛋白尾巴介导的核间相互作用的关键分子方面 模型系统中的域，并阐明尾部域内的表观遗传修饰如何调节 该提案中没有的工作的具体目标是：1）定义 由核心组蛋白尾域介导的核小体相互作用，以及翻译后如何 修改过渡过渡过渡非活性染色质结构到模型中热情好客的活性基因 染色质系统； 2）定义连接器组蛋白与核小体的结合方面 阵列是由翻译后修饰所影响的，并传达了核心组蛋白尾巴域； 3）了解HMGN染色质架构因子如何影响H1结构不稳定 染色质凝结此外，我们还将使用上述工作中的教训来了解您 分子基础在接头组蛋白中新发现的突变，导致遗传疾病被称为遗传疾病 拉赫曼氏病。 染色体组装并规范以提供转录，复制，DNA修复和其他 基因组相关的过程。