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Molecular Mechanisms Underlying the Regulation of Local Chromatin Structure

局部染色质结构调控的分子机制

基本信息

批准号：
10661627
负责人：
Sheena D'Arcy
金额：
$ 38.25万
依托单位：
UNIVERSITY OF TEXAS DALLAS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-06-30
项目状态：
已结题

项目摘要

PROPOSAL SUMMARY The packaging of genomic DNA into repeating nucleosome units plays a pivotal role in the regulation of essential biological process including DNA transcription, DNA replication, and DNA repair. Cells must assemble and disassemble nucleosomes to read the information stored in the DNA sequence in a temporally and spatially regulated way. As such, cells have evolved several mechanisms that precisely regulate nucleosome dynamics and influence the local structure of chromatin. These mechanisms include: (1) the incorporation of histone variants into the nucleosome, (2) post-translational modification of histones, (3) histone chaperone activity, (4) ATP-dependent nucleosome remodeling, and (5) nucleosome-binding proteins. We currently do not know how these mechanisms act synergistically, nor how they influence intrinsic nucleosome dynamics. The research proposed in this MIRA application will focus on the quantification of nucleosome dynamics and the molecular basis of its regulation. We will develop a high-throughput assay for the quantification of nucleosome dynamics that will be applied to nucleosome assembly intermediates, mono-nucleosomes and multi- nucleosome arrays. This assay revolves around hydrogen-deuterium exchange analysis chromatin substrates in varied biologically-relevant states. We will also characterize the molecular mechanisms underpinning concerted activity of histone chaperones and histone acetyltransferases. Systems of interest at Rtt109, Vps75 and Asf1; as well as Nap1, CBP/p300 and linker histone H1. Varied approaches will be employed including biochemistry, high-resolution structural characterization, and in vivo complex analysis. The proposed work will impact translational studies motivated to develop anti-fungal therapeutics and identify new avenues for targeting of anti-cancer treatments.

建议书摘要基因组DNA包装成重复的核小体单位在调节基本的生物学过程，包括DNA转录、DNA复制和DNA修复。细胞必须组装在一起以及分解核小体以在时间和空间上读取存储在DNA序列中的信息规范的方式。因此，细胞进化出几种精确调节核小体动态的机制。并影响染色质的局部结构。这些机制包括：(1)组蛋白的掺入变异体进入核小体，(2)组蛋白翻译后修饰，(3)组蛋白伴侣活性，(4) 依赖于ATP的核小体重塑，以及(5)核小体结合蛋白。我们目前还不知道如何这些机制是协同作用的，也不知道它们如何影响内在的核小体动力学。在这个Mira应用中提出的研究将集中在核小体动力学的量化上以及其调控的分子基础。我们将开发一种高通量的定量分析方法核小体动力学将应用于核小体组装中间体、单核小体和多核小体。核小体阵列。这项分析围绕着氢-重离子交换分析染色质底物。在不同的生物相关状态下。我们还将描述支撑分子机制的特征。组蛋白伴侣和组蛋白乙酰转移酶的协同活性。感兴趣的系统在Rtt109，Vps75 和ASF1，以及NAP1、CBP/p300和连接子组蛋白H1。我们会采用不同的方法，包括生物化学、高分辨率结构表征和体内络合物分析。拟议的工作将旨在开发抗真菌治疗药物和确定靶向的新途径的IMPACT翻译研究抗癌治疗。