Roles of Histone H3K27 demethylases in germ cell epigenetic development

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DESCRIPTION (provided by applicant): Histone posttranslational modifications regulate nucleosome structure and thus gene expression. Histone H3 Lysine 27 (H3K27) methylation is a global regulator of gene activation/repression and contributes to the epigenetic inheritance of defined transcriptional states across cell divisions. The establishment of a mature germline is characterized by several well-defined epigenetic changes throughout embryonic and adult germ cell development. I plan to study the role of Histone H3K27 demethylases in major events of germ cell developmental biology. I hypothesize that Utx and JmjdS H3K27 demethylases are required in the early mammalian embryo and will prove essential for reprogramming and differentiation events that are critical for development of mature gametes. To test this hypothesis, my proposal will utilize mouse genetic models to assess the global and cell specific impact of H3K27 demethylases in germ cell biology. While these studies focus on germ cell development, my findings will bring to light in vivo function of Utx and JmjdS in H3K27 demethylation, how these demethylases operate in mammalian organismal development, and how they regulate stem cell differentiation/pluripotency within the germ cell lineage. Epigenetics plays a major role in human disease, specifically in the form of imprinted and epigenetic gene disorders (such as Beckwith-Widemann, Prader-Willi, Angelmann, and Rett syndromes) or globally in large scale epigenetic changes of cancer. Overexpression of H3K27 methyl-transferases regulates cellular proliferation in prostate cancer, while loss of H3K27 trimethylation is associated with cellular senescence. Understanding how H3K27 demethylases regulate cell fate decisions within the germ cell lineage may be amendable to understanding the oncogenic nature of misregulated cellular differentiation events in cancer. The potential therapeautic implications of H3K27 demethylases towards these ends are limitless, but we must first have a basic understanding of how they regulate cellular fate decisions.