Newly Evolved Endogenous Retroviruses Prime the Ovarian Reserve for Activation [ATAC-seq]

Female mammals are born with a finite pool of non-growing oocytes (NGOs) housed in primordial follicles, forming 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 across perinatal oogenesis in mice, we captured the full oocyte transcriptome. We show that NGOs establish extensive accessible chromatin at gene regulatory elements—including promoters and enhancers—with formation of many regions driven by newly evolved endogenous retroviruses. In NGOs, epigenetic priming for follicular activation involves pre-loading RNA polymerase II and transcription factors TCF3 and TCF12 at these sites, counteracted by repression via Polycomb Repressive Complex 1-mediated H2AK119 ubiquitylation. This transposable element (TE)-mediated epigenetic priming underlies the ovarian reserve’s long-term maintenance and poises oocytes for activation. Our findings establish the ovarian reserve as an actively primed population, with newly evolved TEs orchestrating genome-wide transcriptional activation.