Roles of Chromatin Protein HIM-17 in Chromosome Structure and Function

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DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to understand how chromosome and chromatin structures control essential cellular processes. Changes in chromosome and chromatin structures can affect the ability of DNA and chromatin binding proteins to associate with their sites of action, thereby providing a mechanism by which to regulate transcription, signaling, and genome-stability pathways. To further our understanding of these chromosome-based control mechanisms, the current application will focus on the C. elegans protein HIM-17, a chromatin-associated protein that is proposed to function as a global chromatin organizer. HIM-17 is required for proper segregation of meiotic chromosomes, a process whose failure leads to aneuploid offspring, one of the leading causes of miscarriages and birth defects in humans. HIM-17 also functions in maintaining the correct balance between proliferation and differentiation of germ cells. Failure to maintain this balance can result in the formation and growth of tumors. Finally, HIM-17 is required for normal acquisition of covalent modifications of germline chromatin. The experiments proposed will investigate the mechanisms by which HIM-17 interacts with chromatin to control these essential cellular processes. The specific aims are: 1) To assess candidate HIM-17-associated proteins for roles in genome stability, chromatin methylation, and regulating the balance between germ cell proliferation and differentiation, 2) To investigate relationships between HIM-17, histone methyltransferase MET-2, and chromatin methylation in germ cells, 3) To investigate the role of HIM-17 as a tumor suppressor protein, and 4) To conduct screens to identify gene products that collaborate with or antagonize HIM-17.