The lysine deacetylase activity of HDAC1/2 is required to safeguard zygotic genome activation in mice and cattle

The genome is transcriptionally inert at fertilization and must be activated through a remarkable developmental process called zygotic genome activation (ZGA). Epigenetic reprogramming contributes significantly to the dynamic gene expression during ZGA, however the mechanism has yet to be resolved. Here, we find histone deacetylase 1 and 2 (HDAC1/2) can regulate ZGA through the lysine deacetylase activity. Notably, in mouse embryos, overexpression of HDAC1/2 dominant negative mutant leads to a developmental arrest at 2-cell stage. RNA-seq reveals that 64% of down-regulated genes are ZGA genes and 49% of up-regulated genes are developmental genes. Inhibition of the deacetylase activity of HDAC1/2 causes a failure of histone deacetylation at multiple sites including H4K5, H4K16, H3K14, H3K18, and H3K27. ChIP-seq analysis exhibits an increase and decrease of H3K27ac enrichment at promoters of up- and down-regulated genes, respectively. Moreover, HDAC1 mutants prohibited the removal of H3K4me3 via impeding KDM5s. Importantly, the developmental block can be greatly rescued through Kdm5b injection and expression of the majority of dysregulated genes partially corrected. Similar functional significance of HDAC1/2 is conserved in cattle embryos. Overall, we propose that HDAC1/2 is indispensable for ZGA via creating correct transcriptional repressive and active states in mouse and bovine embryos.