Persistent pervasive transcription in RNA exosome depleted oocytes results in loss of female fertility

Maturing mammalian oocytes are transcriptionally inactive and attendant RNA degradation determines the maternal transcriptome for embryonic development1. Perturbing oocyte RNA degradation can result in failure of meiosis, fertilization, or zygotic gene activation1-5. We recently reported that conditional depletion of EXOSC10, an RNA exosome associated RNase, blocks oocyte growth-to-maturation transition by interfering with ribosomal RNA processing and meiotic checkpoint genes3. Here we have established oocyte-specific knockout mice of a second RNA exosome associated RNase, Dis3. Mutant females (Dis3cKO) exhibit significantly reduced fertility because oocytes arrest at early maturation. DIS3 depletion allows persistent pervasive transcription, which blocks transcription termination and sequesters RNA polymerase II in intergenic regions. In addition, Dis3cKO oocytes gain H3K27me3 at pre-defined loci6 due to insufficient demethylases KDM6A/B. Oocyte double knockout of Dis3 and Exosc10 causes much earlier growth defects for similar persistence of pervasive transcription, suggesting the RNA exosome complex plays a critical role to ensure transcriptome integrity during oocyte development.