Polycomb Repressive-Deubiquitinase Complex Safeguards Oocyte Epigenome and Female Fertility by Restraining Polycomb Activity [RNA-Seq]

Polycomb group proteins are essential for oogenesis, yet mechanisms underlying the non-canonical Polycomb landscapes in oocytes remain unclear. Here we report BAP1, a core component of the Polycomb Repressive-Deubiquitinase (PR-DUB) complex, as a key negative regulator of Polycomb activity during oogenesis. BAP1 restricts pervasive H2AK119ub1 accumulation in oocytes and protects oocyte-specific broad H3K27ac, particularly within gene-poor regions, from ectopic H3K27me3 deposition. While PR-DUB has been linked to gene repression, in oocytes BAP1 primarily promotes transcription and contributes minimally to Polycomb-mediated silencing. BAP1-deficient oocytes cannot support preimplantation development due to impaired maternal-to-zygotic transition and defective embryonic enhancer activation. Notably, aberrant H3K27me3 landscape established in BAP1-null oocytes persists into early embryos. Together, these findings reveal a critical role for PR-DUB in safeguarding the oocyte epigenome by protecting euchromatin from ectopic Polycomb activity, rather than enforcing transcriptional repression. This study is to investigate how loss of BAP1 may impact transcriptome and chromatin states of mouse oocytes and early embryos. Total RNA-seq and H2AK119ub1/H3K27me3/H3K27ac CUT&RUN were performed for control (Bap1 flox/flox) and conditional KO (Gdf9-iCre, Bap1 flox/flox) fully grown oocytes. The control and conditional KO oocytes were fertilized with wild type sperm, resulting control and maternal KO embryos. Total RNA-seq were performed for control and maternal KO embryos at late 1-cell, early 2-cell, and late 2-cell stages. H3K27me3/H3K27ac CUT&RUN were performed for both groups at late 2-cell stage.