H2A.Z levels control the timing of major events at the maternal-zygotic transition

Across animals, early embryonic events are temporally tightly coordinated but the underlying mechanisms remain incompletely understood. In Drosophila, both global and nuclear levels of the histone variant H2Av rise progressively during the maternal-zygotic transition (MZT), but whether this increase is functionally important is unknown. We find that increased H2Av dosage expedites specific MZT events: the transition from nuclear cycle (NC) 13 to 14 occurs prematurely as does the turnover of thousands of maternal transcripts; in addition, a subset of genes is precociously expressed in the zygote. Reduced H2Av dosage has reciprocal effects. Comparable transcriptional shifts are observed in zebrafish embryos overexpressing the H2Av ortholog H2A.Z, suggesting H2Av/H2A.Z dosage as a conserved timer of early development. We also examined mutants with impaired H2Av sequestration on lipid droplets which exhibit increased nuclear H2Av levels but reduced cytoplasmic levels. Unexpectedly, nuclear H2Av abundance influences the timing of NC 13 but is not the main driver of transcriptome remodeling. In summary, we find that H2Av/H2A.Z levels are critical timers of early embryogenesis and that H2Av can act in part via a non-nuclear mechanism. Author summaryIn animals, the earliest stages of embryogenesis are initially driven by proteins and RNAs that the mother provides via the egg; later development is controlled by the embryos own genes. The switch from maternal to zygotic control is called the maternal-zygotic transition (MZT). This conserved process involves degradation of maternal mRNAs, activation of zygotic genes, cell cycle lengthening, and morphological remodeling. All these events require precise control, but how they are coordinated remains incompletely understood. Here we show that the levels of a specific histone, H2A.Z, provide a timer for the MZT. In Drosophila, H2A.Z levels - both in the embryo overall and in nuclei - increase during the MZT. When we ectopically increased H2A.Z levels, specific MZT events occurred prematurely. Reducing H2A.Z levels had the opposite effect. Using mutant flies in which H2A.Z levels are ectopically increased in the nucleus but reduced in the embryo as a whole, we uncovered both nuclear and non-nuclear roles for H2A.Z in the establishment of developmental timing. Moreover, we observed similar outcomes in genetically manipulated zebrafish embryos. Our results are consistent with an ancient mechanism in which H2A.Z abundance functions as a timer of early embryogenesis.