Newly Evolved Endogenous Retroviruses Prime the Ovarian Reserve for Activation

Female mammals are born with a finite pool of non-growing oocytes (NGOs) housed in primordial follicles, which form the ovarian reserve that determines reproductive lifespan. Mechanisms underlying the reserve's long-term maintenance and subsequent follicular activation remain elusive. Using total RNA sequencing and de novo transcriptome assembly, we first captured the comprehensive oocyte transcriptome across perinatal oogenesis in mice. We show that NGOs establish accessible chromatin at gene regulatory elements-including promoters and enhancers-partly driven by newly evolved endogenous retroviruses (ERVs). In NGOs, epigenetic priming for follicular activation involves prior loading of transcription factors TCF3 and TCF12 and non-phosphorylated form of RNA polymerase II at these sites. This primed state is counteracted by repression via Polycomb Repressive Complex 1-mediated H2AK119 ubiquitylation. We propose that ERV-mediated epigenetic priming underlies the ovarian reserve's long-term maintenance and establishes a transcriptionally competent yet repressive configuration that enables rapid gene activation upon oocyte growth.