The role of retrotransposons in female reproductive aging

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Project Summary Nearly 40% mammalian genome originates from retrotransposons. Most mammalian retrotransposons are strictly silenced in development and physiology, yet induction of specific retrotransposons can be observed in normal oocytes and preimplantation embryos. Interestingly, a subset of retrotransposons confer a gene regulatory role, at least in part, by acting as alternative promoters, exons and polyadenylation signals to regulate proximal protein-coding genes. Such retrotransposon-dependent gene regulation frequently alter gene structure and/or gene expression, and have been shown in our preliminary studies to play important developmental functions in oocyte biology and preimplantation development. Female reproductive aging presents an excellent experimental system to probe the functional importance of retrotransposons in aging. Unlike somatic tissues which strongly repress retrotransposon expression, oocytes and preimplantation embryos exhibit a strong induction of specific retrotransposons, possibly due to extensive epigenetic reprogramming during these unique developmental stages. Our preliminary studies show that aged oocytes exhibit expression alteration of specific retrotransposons, as well as RT:gene isoforms. Interestingly, the IAPEy4 family, which is retrotransposition-competent, is strongly induced in aged oocytes. IAPEy4 induction could lead to DNA damage and innate immune response in aged oocytes, as a result of its retrotransposition. In addition, the MII oocyte specific MTC-Dicer1 isoform is strongly repressed in aged oocytes. The MTC-Dicer1 encodes an N-terminally truncated Dicer isoform that governs the transposon surveillance through post-transcriptional silencing by RNAi. These findings suggest that altered retrotransposon expression and retrotransposon mediated gene regulation in aged oocytes could functionally promote reproductive aging. Using genomics, mouse genetics, cell and molecular biology, we proposed to investigate the importance of retrotransposons in female reproductive aging. We will 1) profile retrotransposons and retrotransposon-dependent gene regulation in young and old oocytes and somatic granulosa cells; 2) Investigate the importance of aberrant retrotransposon induction and retrotransposition during reproductive aging; 3) investigate the importance of retrotransposon mediated gene regulation in reproductive aging. Taken together, the proposed studies will provide new insights into the cellular and molecular mechanisms that govern female reproductive aging, and will add a new dimension to our understanding of retrotransposon functions in development and disease.