Intergenerationally Maintained Histone H4 Lysine 16 Acetylation Is Instructive for Future Gene Activation

Before zygotic genome activation (ZGA), the quiescent genome undergoes reprogramming to transition into the transcriptionally active state. However, the mechanisms underlying euchromatin establishment during early embryogenesis remain poorly understood. Here, we show that histone H4 lysine 16 acetylation (H4K16ac) is maintained from oocytes to fertilized embryos in Drosophila and mammals. H4K16ac forms large domains that control nucleosome accessibility of promoters prior to ZGA in flies. Maternal depletion of MOF acetyltransferase leading to H4K16ac loss causes aberrant RNA Pol II recruitment, compromises the 3D organization of the active genomic compartments during ZGA, and causes downregulation of post-zygotically expressed genes. Germline depletion of histone deacetylases revealed that other acetyl marks cannot compensate for H4K16ac loss in the oocyte. Moreover, zygotic re-expression of MOF was neither able to restore embryonic viability nor onset of X chromosome dosage compensation. Thus, maternal H4K16ac provides an instructive function to the offspring, priming future gene activation. [Display omitted] •Evolutionarily conserved H4K16ac transmission from the maternal germline•Maternal MOF and H4K16ac prime gene activation in a sex-independent manner•Zygotic MOF fails to rescue embryonic lethality caused by maternal MOF loss•X chromosome dosage compensation onset in males relies on maternal H4K16ac The developmental events following gamete fusion are guided by maternally provided mRNAs and proteins prior to zygotic genome activation. Samata et al. show that H4K16ac transmission from the maternal germline poises genes for future activation.