Interspecific hybrids reveal a deeply conserved nuclear role of EIF1A-family proteins in zygotic genome activation

Zygotic genome activation (ZGA) launches inaugural gene expression and autonomous development of the embryo. Yet, conserved regulators of ZGA among different mammals remain poorly defined. Here, we generated interspecific hybrid embryos to place distant mammalian genomes in a shared maternal cytoplasm. These hybrids undergo cleavage and transcriptional activation from divergent parental genomes. Comparative transcriptomics identifies a core set of zygotic genes reproducibly activated across different hybrid contexts, including the Eif1a-like family. Depletion of EIF1A-like proteins disrupts ZGA and preimplantation development in mouse, pig and cattle embryos. Although best known for translation initiation, these proteins contain a conserved nuclear localization signal and translocate to the nucleus at the onset of major ZGA. Further studies revealed that they occupy promoters of nearly all ZGA genes and MERVL/MT2 retrotransposons, required for local chromatin accessibility. These findings uncover a conserved nuclear licensing function for EIF1A-family proteins in zygotic genome activation among divergent mammalian embryos.