Genetic Silencing in Germline Maintenance and Function

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DESCRIPTION (provided by applicant): The adult germ line has many disparate functions, including proliferation, meiotic synapsis and recombination, maternal and paternal mRNA and protein synthesis, and gametogenesis. It also has multiple obligations, including preventing mobile genetic elements (transposons) from inflicting heritable genetic damage, preventing differentiation of the germ cells into somatic cells, and establishing heritable states of transcriptional activity. All of these obligations are met, to some extent, by repressive mechanisms that act to silence or prevent inappropriate activities that are counter to these obligations. Germ cell repression utilizes a combination of post-transcriptional repression (e.g., RNAi-based) and transcriptional (e.g., chromatin based) mechanisms to achieve its goals. A major target of these mechanisms is the X chromosome, which is transcriptionally repressed during meiosis in both sexes in C. elegans, but is fully inactivated during male meiosis in both worms and mammals. Sex chromosome inactivation is mediated by a highly conserved process that targets unsynapsed chromatin during meiosis, and is likely an ancient genome defense mechanism. We understand some of the components of the mechanism, and plan to further dissect the mechanism and its regulation using C. elegans as a model system. In both mammals and worms, the male X is "imprinted" for preferentially inactivation in embryos, and this is likely a consequence of its meiotic silencing. Imprinted X inactivation is a dramatic example of genetic imprinting, and little is understood about imprint establishment. We will also use the genetic, molecular, biochemical, and cytological tools available in C. elegans to dissect the mechanism of male X imprinting. We have used the extensive tools available for this organism to build it into an excellent model organism for studying germ line repression, or silencing, and are now poised to dissect the role of chromatin in germ cell silencing, imprint establishment and genome defense mechanisms in this genetic model system. Epigenetic mechanisms operating in the germ line are essential for the establishment of imprinting and the prevention of heritable genetic mutations, both of which are crucial for normal human health and normal human development.