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

项目概要/摘要： 人类染色体用来压缩基因组DNA数千倍的长度，以适应在细胞内。 细胞的核，同时也允许过程，如基因表达。为了实现这一点， 基因组被组装成一个复杂的，多方面的复合体，称为染色质。大会 染色质首先涉及将短片段（~200 bp）包裹在由核心组成的蛋白质线轴周围， 组蛋白转化为核小体。巨大的，基因组大小的核小体串 通过核小体的自相互作用性质组装成大结构。的关键因素 这些大的凝聚结构的形成是核心组蛋白的“尾”域， 从核小体的主体突出以介导核小体间的相互作用。然而，在这方面， 尽管它们对于染色体的形成是必不可少的，但人们对它们是如何形成的却知之甚少。 组蛋白尾部结构域与相邻核小体接触。此外，这些相互作用代表了关键的 调节点，并通过表观遗传翻译后修饰，包括乙酰化， 以及其他染色质修饰剂。该项目将采用生物化学和生物物理技术， 定义核心组蛋白尾介导的核小体间相互作用的关键分子方面 结构域的模型系统，并阐明如何表观遗传修饰内的尾部结构域调节 这些互动。本建议中所述工作的具体目标是：1）确定相互间 核小体相互作用介导的核心组蛋白尾部结构域，以及如何翻译后 修饰将不活跃的染色质结构转变为适合模型中活跃基因的结构 染色质系统; 2）定义连接体组蛋白如何与核小体结合的方面， 阵列，受翻译后修饰的影响，并传达核心组蛋白尾部结构域;和 3)了解HMGN染色质结构因素如何影响H1结构不稳定 此外，我们将利用从上述工作中获得的经验教训来了解染色质浓缩物。 分子基础：一种新发现的连接组蛋白突变，导致称为 拉赫曼氏病这些结果将填补我们在理解如何 染色体被组装和调节以提供转录、复制、DNA修复和其他功能。 基因组相关的过程。

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.