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bioRxiv · 10.1101/2025.07.06.663377

An Epigenomic Roadmap Primes Non-Growing Oocytes for Maturation and Early Embryogenesis

Hu, M.·Munakata, Y.·Yeh, Y.-H.·Wang, H.·Hunter, N.·Schultz, R. M.·Namekawa, S. H.
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Abstract

Female reproductive lifespan is defined by long-lived, non-growing oocytes (NGOs) that comprise the ovarian reserve. NGOs are assumed to acquire the epigenetic marks that will define the early embryo only after they exit the ovarian reserve and become activated for growth. Contrary to this dogma, we show that mouse NGOs possess abundant histone modifications that both underlie maintenance of the ovarian reserve and prime the epigenome of growing oocytes for early embryogenesis. As NGOs are established around birth, Polycomb Repressive Complex 1 (PRC1) mediates abundant H2AK119 ubiquitylation and reprograms the H3K27 acetylation landscape, which is essential to maintain the ovarian reserve. Importantly, the PRC1-driven epigenetic state of NGOs provides a blueprint for subsequent generation of a PRC2-catalyzed H3K27 trimethylation profile in growing oocytes that is characterized by broad domains and DNA methylation-independent imprints that are transmitted to the embryo. Thus, Polycomb complexes play pivotal roles in priming the NGO epigenome for oocyte maturation and early embryogenesis. HighlightsNon-growing oocytes have rich epigenetic landscapes to prime subsequent development Reprogramming of H3K27ac by PRC1 is required to maintain non-growing oocytes PRC1-catalyzed H2AK119ub provides a blueprint for PRC2-H3K27me3 in growing oocytes In non-growing oocytes, PRC1 primes DNA methylation-independent H3K27me3-imprinting

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Hu, M., Munakata, Y., Yeh, Y.-H., Wang, H., Hunter, N., Schultz, R. M., Namekawa, S. H.. 2025-07-06. An Epigenomic Roadmap Primes Non-Growing Oocytes for Maturation and Early Embryogenesis. https://doi.org/10.1101/2025.07.06.663377

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