An experimental plan is proposed to investigate the genetics, biochemistry, and cell biology of a previously uncharacterized class of plant methylcytosine binding proteins. Mutation in the VIM1 (Variant in Methylation 1) gene encoding one member of this family was uncovered in a screen for natural variation affecting cytosine methylation in Arabidopsis thaliana.
Four specific aims are outlined, including 1) completion of genetic analysis of vim1, vim paralogs and genetic modifiers;2) characterization of the methylcytosine-DNA binding specificty of VIM1, VIM paralogs, and VIM1-like mammalian homologs;3) investigation of VIMVs role in chromatin modification;and 4) evaluation of the role of mammalian VIM1-like proteins in cytosine methyation and epigenetic regulation. The proposed experimental plan will exploit the tools and approaches available in one of the premier experimental genetic systems, which has been the source of much of our knowledge of epigenetic regulation. This knowledge promises to translate to mammalian systems, based on the strong record of past application of Arabidopsis work to mammalian epigenetics. In addition, mammalian proteins that are structurally and functionally related to VIM proteins have been implicated in carcinogenesis. Several subaims of the proposal directly address the role of these proteins in epigenetic regulation in mammalian cells.
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