Epigenomic Roadmap of Ovarian Reserve Development: Polycomb-Mediated Programming and Reprogramming [CUT&Tag]
Ovarian reserve defines the female reproductive lifespan, which in humans spans decades due to the robust maintenance of meiotic arrest in non-growing oocytes residing in primordial follicles. Dynamic epigenomic reprogramming and programming occur during mammalian germline and early embryonic development. However, the chromatin-based mechanisms that underlie the establishment and maintenance of ovarian reserves are poorly defined. Here, we report a comprehensive epigenomic landscape of mouse perinatal oocytes and unravel Polycomb-based mechanisms underlying ovarian reserve development. By quantitatively profiling key histone modifications, including the Polycomb-mediated repressive marks H2AK119ub and H3K27me3, and the active marks H3K4me3 and H3K27ac, we identified two major epigenomic transitions: one for ovarian reserve formation from meiotic prophase I to dictyate-arrested non-growing oocytes, and another for ovarian reserve activation from non-growing to growing oocytes. Combining conditional loss-of-function mouse models for Polycomb Repressive Complex 1 or 2 (PRC1/2), we show that PRC1-H2AK119ub and PRC2-H3K27me3 undergo differential dynamics during perinatal oogenesis and have distinct biological functions in ovarian reserve formation and maintenance. Notably, PRC1-H2AK119ub presets the epigenetic states in non-growing oocytes and provides a blueprint for the PRC2-H3K27me3 profile, which is globally reprogrammed as oocytes exit the ovarian reserve and grow. We also demonstrated how coordinated changes of key histone modifications at promoters drive the two major transcriptome transitions during ovarian reserve formation and activation. Importantly, Polycomb complexes play crucial roles in shaping both promoter bivalency and enhancer landscape in the ovarian reserve. Our study determines a comprehensive epigenomic roadmap of perinatal oogenesis, shedding light on how the ovarian reserve is formed, maintained, and activated, emphasizing a critical window of epigenetic programming during female germline development. Overall design: Chromatin profiling analysis of quantitative CUT&Tag data for (1) WT perinatal oocytes; (2) PRC1ctrl and PRC1cKO non-growing oocytes and early growing oocytes; (3) PRC2ctrl and PRC2cKO non-growing oocytes.