Ovarian reserve formation and maintenance

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ABSTRACT The goal of this study is to understand how epigenetic states in oocytes that reside in primordial follicles contribute to maintenance of the ovarian reserve in women. The ovarian reserve defines female reproductive lifespan, which in humans spans decades due to maintenance of meiotic arrest in oocytes residing in primordial follicles. The quality and quantity of oocytes are critical determinants for ovarian functions, and exhaustion of primordial follicles triggers menopause. However, our understanding how the ovarian reserve is generated and maintained is currently limited due to the inability to perform molecular analysis. In our unpublished study, we developed a protocol to isolate the pool of non-growing oocytes that enabled molecular analyses. We found that the Polycomb Repressive Complex 1 establishes repressive chromatin states in perinatal mouse oocytes that directly suppress the gene expression program of meiotic prophase-I and thereby enable the transition to dictyate arrest. Based on these findings, we propose that the chromatin state is established during perinatal oogenesis that enables ovarian reserve formation and then maintained in adult and aged ovaries. In Aim 1, we will perform a comprehensive chromatin profiling of the initial pools of non- growing oocytes from juvenile ovaries and the ovarian reserve maintained in adulthood. Aim 1 will establish an epigenome data resource of the ovarian reserve. In Aim2, we designed a candidate-based approach to define the regulatory mechanism of chromatin states in the ovarian reserve. We will determine the function of CHD4, a chromatin remodeler, in maintaining the ovarian reserve. Aim 2 will provide the foundation to investigate the chromatin-based maintenance mechanisms of the ovarian reserve. The proposed research will significantly advance the field by providing molecular insights how the epigenome of the ovarian reserve is established and maintained.