Lactate regulates major zygotic genome activation by H3K18 lactylation in mammals [RNA-seq]

Lactate is present at a high level in the microenvironment of mammalian preimplantation embryos in vivo and in vitro. However, its role in preimplantation development is unclear. Here, we report that lactate is highly enriched in the nuclei of early embryos when major zygotic genome activation (ZGA) occurs in humans and mice. The inhibition of its production and uptake results in developmental arrest at the 2-cell stage, major ZGA failure, and loss of lactate-derived H3K18lac, and the abnormal phenotypes could be recapitulated by overexpression of H3K18R mutation and rescued by addition of Lac-CoA. By profiling the landscape of H3K18lac in human and mouse preimplantation embryos, we show that H3K18lac is enriched on the promoter regions of most major ZGA genes and corelates with their expressions. Taken together, we demonstrate the important role for lactate in major ZGA via H3K18lac, showing a conserved metabolic mechanism underlies preimplantation development of mammalian embryos. Overall design: RNA-seq libraries were prepared as described previously. Briefly, 5 embryos were used per group, and three replicates were performed for each group. Embryos were washed three times in 0.5% BSA-PBS solution. cDNA was amplified using the Phusion Hot Start II High-Fidelity PCR Master Mix (Thermo Fisher). Library preparation was performed using the NEBNext Ultra II DNA Library Prep Kit (New England Biolabs) according to the manufacturer's instructions. Libraries were sequenced using the NovaSeq 6000 (Illumina, San Diego, CA) according to the manufacturer's instructions.