Research Project
8366901
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.
