Cytoplasmic rivalry between parental pronuclei governs zygote epigenetic fate

Mouse zygotes rely on a cytoplasm-forced competition between the two separate parental pronuclei to limit their size and preserve key epigenetic marks (H3K4me3, H3K27me3, H3K27ac). In one-pronucleus biparental zygotes, this competition is absent, the pronucleus enlarges, epigenetic regulation becomes dysregulated, and development to term is reduced. The defects can be partially rescued by introducing a competing pronucleus, reducing cytoplasm, or using drugs (TSA) or KDM5b knockdown to restore epigenetic marks, linking pronuclear volume control to developmental potential. The findings have implications for assisted reproduction where 1PN zygotes are used, underscoring that far from being a mere fertilization artifact, pronuclear separation actively shapes embryonic viability.