Polycomb Repressive Complex 1 Primes Non-Growing Oocytes for Growth and Early Embryogenesis [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, 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. 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.