Histone lactylation maintains bovine early embryo development via regulating embryonic genome activation

BACKGROUND: Early embryo loss is an important factor affecting the reproductive capacity of cattle. Recent studies have revealed that during the process of embryonic genome activation (EGA), epigenetic modification, such as histone lactylation remodeling, is crucial for early embryonic development. However, the effects of histone lactylation on early embryonic development in bovines and the related mechanisms remain unknown. In this study, in vitro fertilized embryos were utilized to investigate the effects of histone lactylation on EGA and early embryo development in cattle. RESULTS: Histone lactylation, including pan-lysine lactylation, histone H3 lysine 9 lactylation, and histone H3 lysine 18 lactylation, occurred mainly in the nucleus and significantly decreased from the 8-cell stage to the morula stage and increased from the morula stage to the blastocyst stage. Decreased or increased levels of histone lactylation induced by GSKA or sodium lactate supplementation inhibited early bovine embryo development and blastocyst lineage differentiation. Furthermore, single-cell RNA sequencing data and 5-ethynyluridine staining revealed that a reduction in histone lactylation levels altered the expression of genes associated with DNA transcription and RNA polymerase activity, thereby impairing EGA. Importantly, β-nicotinamide mononucleotide rescued the inhibitory effects of GSKA supplementation on bovine EGA and early embryonic development. CONCLUSIONS: Histone lactylation maintains early bovine embryo development by regulating EGA. Our findings provide a theoretical reference for addressing early embryo loss and thereby increasing the reproductive capacity of cattle.