Functional interaction of histone H1 with the core nucleosome

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交易中起着基本作用，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严格审查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特定作用。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的癌症，而其他药物正处于临床试验中，以寻找其他适应症。大多数对染色质生物学的理解都集中在核心核小体上，核小体由组蛋白H2A、H2B、H3和H4组成。连接组蛋白，如组蛋白H1，结合核心核小体和核小体之间的连接DNA。组蛋白H1与染色质广泛相关，在哺乳动物细胞中具有基本功能，但对其功能的明确描述落后于核心核小体组蛋白。关于核小体功能的许多基本知识都源于最初对出芽酵母细胞进行的研究。我们建议利用酵母中可用的许多工具来全面检查H1与核小体的功能相互作用。我们将在一组酵母菌株（约400个不同的菌株）中去除组蛋白H1基因

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.