Cytoplasmic competition between separate parental pronuclei in zygotes

Embryogenesis begins with a zygote, a single cell with two pronuclei that separately enclose maternal and paternal chromosomes. The functional significance of the separation of parental chromosomes into distinct pronuclei remains unexplored, despite the fact that one-pronuclear biparental zygotes are used clinically. Here, using a combination of mouse zygote manipulation, quantitative imaging and theoretical approaches, we show a cytoplasm-mediated competition mechanism between separate parental pronuclei. This mechanism limits pronuclear volume and prevents the loss of epigenetic marks, including maternally inherited trimethylated histones. One-pronuclear biparental zygotes lack this mechanism, resulting in a reduced rate of development to term. This low developmental potential can be rescued by competition-based or drug-based restoration of epigenetic marks. In human zygotes, epigenetic loss correlates with pronuclear volume. This study provides insight into strategies to improve the clinical use of one-pronuclear biparental zygotes. Overall design: Single two-cell embryos derived from 1PN, 2PN and parthenote were analyzed by RNA-seq. 1PN, 2PN and P1PN zygotes were analyzed by ChIL-seq.