The role of histone tails in chromatin structure and gene regulation

项目概要/摘要： 染色质的动态调节对于基因的正常表达至关重要，而调节异常会导致疾病 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。非结构化的组蛋白末端，称为组蛋白尾部， 从这个核心突出，是染色质调节的关键参与者。组蛋白翻译后掺入 修饰（PTM，组蛋白残基的化学或蛋白质修饰）和组蛋白变体（具有 取代典型组蛋白的不同序列）是染色质调节的两种主要机制， 它们部分通过组蛋白的尾部起作用。尽管在了解染色质方面取得了很大的进步， 尽管如此，我们对染色质结构、基因调控和组蛋白的认识仍存在很大差距， 语言实验室的长期目标是确定染色质景观（复杂的分子结构）， 核小体内和核小体之间的相互作用（沿着它们的遗传和表观遗传因素）是基因 表达，以便可以纠正导致人类疾病的失调。目标是发展一个 在分子水平上理解核小体内组蛋白尾部的构象和动力学， 与他们的桥接相互作用（总的来说，组蛋白尾部景观），以及这些如何转化为水平， 染色质结构和可接近性。这包括确定组蛋白尾部景观是如何被 组蛋白翻译后修饰和组蛋白变体，以及这些景观如何与 以及其他核小体组分的那些。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- 连锁的差异基因调控，和2）着丝粒H3变异体在调控中的变异特异性作用 有丝分裂过程中的染色质结构和染色体稳定性。溶液NMR光谱与其他光谱的配对 生物物理方法和相分离研究，如这里所提出的，是必不可少的破译这一高度 动态异构系统。理解组蛋白PTM的结构和动力学效应， 基因表达和染色质结构的调节控制的变体将导致显着增强 在我们对基因调控和表观遗传相关疾病的基本机制的理解中。

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.