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Functional interaction of histone H1 with the core nucleosome

组蛋白 H1 与核心核小体的功能相互作用

基本信息

批准号：
8366901
负责人：
SCOTT G HOLMES
金额：
$ 37.42万
依托单位：
WESLEYAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2017-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Functional interaction of histone H1 with the core nucleosome The packaging of DNA by chromatin plays a fundamental role in all dynamic DNA transactions, including replication, repair, recombination, and transcription. Intense scrutiny of the many roles of chromatin over the preceding decades has defined crucial and specific roles for chromatin altering factors in all facets of these processes. In particular, defects in histone modifying enzymes have been implicated in many diseases, and drugs that influence the activity of these enzymes are being used to treat specific cancers, while others are in clinical trials for additional indications. Most of the progress in understanding chromatin biology has been focused on the core nucleosome, comprised of histones H2A, H2B, H3, and H4. Linker histones, exemplified by histone H1, bind to the core nucleosome and the linker DNA between nucleosomes. Histone H1 is broadly associated with chromatin and has essential functions in mammalian cells, but a clear description of its functions has lagged behind that of the core nucleosome histones. Much of the basic knowledge about nucleosome function stems from studies first conducted on budding yeast cells. We propose to take advantage of the many tools available in yeast to comprehensively examine H1's functional interaction with the nucleosome. We will eliminate the gene for histone H1 in a large panel of yeast strains (~400 distinct strains) that bear viable histone H3 or H4 mutations. We will subject these strains to a variety of phenotypic assays, and then perform statistical analyses to detect patterns of responses that suggest unique and specific H1 functions, as well as H1-H3/H4 interactions. Wesleyan University combines the mission of a highly selective undergraduate liberal arts college with the resources and graduate program of a university. In addition to addressing significant research questions, this project will offer excellent training opportunities for both graduate and undergraduate students. PUBLIC HEALTH RELEVANCE: Our research seeks to determine fundamental mechanisms by which an organism's DNA is organized into chromosomes. This packaging influences all aspects of DNA's function, particularly its ability to express genes in their proper patterns and levels. Inappropriate gene expression underlies a large number of disease states.

描述（由申请人提供）：组蛋白H1与核心核小体的功能相互作用染色质对DNA的包装在所有动态DNA处理中起着重要作用，包括复制、修复、重组和转录。在过去的几十年里，对染色质的许多作用的深入研究已经确定了染色质改变因子在这些过程的各个方面的关键和具体作用。特别是，组蛋白修饰酶的缺陷与许多疾病有关，影响这些酶活性的药物正被用于治疗特定癌症，而其他药物正在临床试验中用于其他适应症。在了解染色质生物学方面的大部分进展都集中在核心核小体上，包括组蛋白H2 A，H2 B，H3和H4。以组蛋白H1为例的接头组蛋白与核心核小体和核小体之间的接头DNA结合。组蛋白H1与染色质广泛相关，在哺乳动物细胞中具有重要功能，但对其功能的明确描述落后于核心核小体组蛋白。许多关于核小体功能的基础知识都来自于对芽殖酵母细胞的研究。我们建议利用酵母中的许多工具来全面研究H1与核小体的功能相互作用。我们将在大量酵母菌株（约400种不同的菌株）中消除组蛋白H1基因。携带活的组蛋白H3或H4突变的细胞。我们将对这些菌株进行各种表型测定，然后进行统计分析，以检测表明独特和特异性H1功能以及H1-H3/H4相互作用的反应模式。卫斯理大学结合了一个高度选择性的本科文科学院的使命与大学的资源和研究生课程。除了解决重大的研究问题，该项目将为研究生和本科生提供良好的培训机会。公共卫生相关性：我们的研究旨在确定生物体DNA组织成染色体的基本机制。这种包装影响DNA功能的各个方面，特别是它以适当的模式和水平表达基因的能力。不适当的基因表达是大量疾病状态的基础。