Polycomb Repressive-Deubiquitinase Complex Safeguards Oocyte Epigenome and Female Fertility by Restraining Polycomb Activity

Abstract

Mouse oocytes exhibit a unique chromatin landscape characterized by broad H3K27ac and H3K27me3 domains, demarcating euchromatin and facultative heterochromatin, respectively. However, the mechanisms underlying this non-canonical landscape remain elusive. 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-dependent transcriptional activation is essential for oocyte developmental competence and female fertility. BAP1 loss disrupts the maternal-to-zygotic transition and impairs embryonic enhancer activation, ultimately compromising preimplantation development. Notably, while H3K27ac patterns are reset after fertilization, the aberrant H3K27me3 landscape established in BAP1-deficient oocytes persists in 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.