H2A.Z regulates transcription, oocyte maturation and female fertility in mouse [RNA-seq]

Histone variants differ from canonical histones in their ability to be incorporated into chromatin independently of S-phase. H2A.Z is an evolutionarily conserved histone variant that plays critical roles in transcription regulation. However, its roles during mammalian oogenesis, a unique developmental stage marked by dynamic transcription activity without DNA replication, remain elusive. In this study, we demonstrated that oocyte-specific depletion of H2A.Z results in profound epigenetic and transcriptional alterations, impeding oocyte meiosis II resumption in mice, causing female infertility. Mechanistically, H2A.Z in mouse oocytes is enriched at active promoters and enhancers. Interestingly, H2A.Z is depleted from CG-rich silenced promoters in fully-grown oocytes (FGOs), unlike that in growing oocytes, early embryos and mESCs. In FGOs, the presence of H2A.Z correlates with H3K27ac, except in regions with DNA methylation and H3K36me3. Depletion of H2A.Z leads to partial loss of H3K27ac at both promoters and enhancers, correlated with impaired gene expression. Consistent with a role in gene activation, H2A.Z in FGOs is widely acetylated at the promoters and enhancers. Together, our findings uncover an essential role of H2A.Z in oocyte maturation and activation of cis-regulatory elements.