The role of histone tails in chromatin structure and gene regulation

项目摘要/摘要： 染色质的动态调节对于基因的正常表达至关重要，失调会导致疾病 包括癌症和代谢紊乱。染色质的基本亚基是核小体，它是由 DNA 包裹的组蛋白核心。非结构化组蛋白末端，称为组蛋白尾部， 从这个核心突出，是染色质调控的关键角色。翻译后掺入组蛋白 修饰（PTM，组蛋白残基的化学或蛋白质修饰）和组蛋白变体（带有 替代典型组蛋白的不同序列）是染色质调节的两个主要机制， 它们部分通过组蛋白尾发挥作用。尽管在理解染色质方面取得了巨大进步 尽管我们对染色质结构、基因调控和组蛋白的了解仍然存在巨大差距 语言。实验室的长期目标是定义染色质景观（复杂的分子 核小体内部和核小体之间的相互作用及其遗传和表观遗传因素）是基因的基础 表达，从而可以纠正导致人类疾病的失调。目标是开发一个 对核小体内组蛋白尾部的构象和动力学的分子水平理解 以及它们的桥接相互作用（总而言之，组蛋白尾部景观）以及它们如何转化为 染色质结构和可及性。这包括确定组蛋白尾部景观如何受到干扰 组蛋白翻译后修饰和组蛋白变体以及这些景观如何相互关联 彼此以及其他核小体成分的相互作用。在这个为期五年的 MIRA 提案中，重点将放在：1) 确定赖氨酸酰化如何差异调节组蛋白尾部景观以促进代谢 连锁差异基因调控，2）着丝粒 H3 变体在调节中的变体特异性作用 有丝分裂期间的染色质结构和染色体稳定性。溶液核磁共振波谱与其他波谱的配对 正如此处提出的，生物物理方法和相分离研究对于破译这种高度 动态和异构系统。了解组蛋白 PTM 的结构和动态效应 基因表达和染色质结构调节控制的变异将导致显着增强 帮助我们理解基因调控和表观遗传相关疾病的基本机制。

Project Summary/Abstract: The dynamic regulation of chromatin is critical for proper gene expression, and dysregulation leads to diseases including cancer and metabolic disorders. The basic subunit of chromatin is the nucleosome, which is formed by a histone protein core around which DNA wraps. The unstructured histone termini, referred to as histone tails, protrude from this core and are key players in chromatin regulation. Incorporation of histone post-translational modifications (PTMs, chemical or protein modification of histone residues) and histone variants (histones with distinct sequences that substitute for canonical histones) are two major mechanisms of chromatin regulation, and they act in part through the histone tails. Despite great strides being made in understanding the chromatin landscape, large gaps remain in our knowledge of chromatin structure, gene regulation, and the histone language. The long-term goal of the laboratory is to define the chromatin landscape (the complex molecular interactions within and between nucleosomes along with their genetic and epigenetic factors) that underlies gene expression so that dysregulation that causes human disease can be corrected. The objective is to develop a molecular-level understanding of the conformation and dynamics of the histone tails within the nucleosome along with their bridging interactions (altogether, the histone tail landscape) and how these translate to the level of chromatin structure and accessibility. This includes determining how histone tail landscapes are perturbed by histone post-translational modifications and histone variants and how these landscapes are interconnected with each other and those of other nucleosome components. In this five-year MIRA proposal, the focus will be on: 1) determining how lysine acylations differentially regulate the histone tail landscape to contribute to metabolically- linked differential gene regulation, and 2) the variant-specific role of the centromeric H3 variant in regulating chromatin structure during mitosis and chromosome stability. A pairing of solution NMR spectroscopy with other biophysical approaches and phase separation studies, as proposed here, is essential to decipher this highly dynamic and heterogeneous system. Understanding the structural and dynamic effects of histone PTMs and variants on regulatory control of gene expression and chromatin structure will lead to a significant enhancement in our understanding of fundamental mechanisms of gene regulation and epigenetically-linked diseases.