Chromatin Structure and Dynamics

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The long-term objective of this project is to understand the function of chromatin in the nucleus, with a particular emphasis on the molecular biology of chromatin structure and dynamics. Specific Aim 1 investigates chromatin assembly, a fundamental biological process that is required for the replication and maintenance of our chromosomes. Two key enzymes that .mediate chromatin assembly are the ACF and CHD1 motor proteins. The proposed studies are designed to examine directly the mechanisms by which nucleosomes are assembled by ACF and CHD1. Specific Aim 2 examines the function of human HARP, a protein that is closely related to the ATPase subunits of chromatin assembly and remodeling factors, which include ACF and CHD1. Mutations in HARP are responsible for Schimke immuno-osseous dysplasia (SIOD), which typically leads to death in early childhood. The proposed experiments are a systematic analysis of the function of HARP in vivo and in vitro, and will provide new knowledge that should advance the potential treatment of SIOD. Specific Aim 3 addresses the function of the four human HMGN proteins, which are abundant nonhistone chromosomal proteins that bind specifically to nucleosomes at two high-affinity binding sites. The proposed studies will identify and characterize the interactions of each of the HMGN proteins over 30 Mb of the human genome, and investigate the molecular basis for the phenomena observed in vivo. Given their abundance and nucleosome-binding activity, the HMGN proteins are likely to have a significant impact upon chromatin structure and activity. These studies should lead to a better understanding of chromatin, and should therefore provide new insights into the molecular basis and potential treatment of human diseases, such as many forms of cancer, that involve abnormalities in chromatin structure and DNA-directed processes in chromatin. Importantly, the analysis of HARP should reveal key aspects of the molecular events that lead to SIOD.