Histone lactylation regulates early embryonic development through m6A methyltransferase METTL3 in goats

Histone lysine lactylation (Kla) is a novel epigenetic modification that plays a crucial role in cellular processes driven by glycolysis and lactate production. However, the mechanisms of histone lactylation and its interaction with m6A RNA methylation during early embryonic development remain underexplored. This study systematically investigated the effects of oxygen levels-atmospheric oxygen (atmosO₂; 20% O₂) and physiological oxygen (physO₂; 5% O₂)-on hallmark events during early embryonic development, revealing that lactylation modification regulates early goat embryonic development through the m6A methyltransferase-like 3 (METTL3). We observed that physO₂ conditions significantly promote embryonic development, with higher expression levels of METTL3, global histone lactylation, and histone H3 lysine 18 lactylation (H3K18la) compared to atmosO₂ exposure. Furthermore, the addition of lactate dehydrogenase inhibitors led to a decrease in global lactylation, which was accompanied by a significant reduction in METTL3 expression. Sequencing analysis of the METTL3 knockdown embryo revealed that the differentially expressed genes (DEGs) were primarily enriched in the ribosome, oxidative phosphorylation, thermogenesis, RNA degradation, and RNA polymerase pathways. These findings provide novel insights into the epigenetic regulatory mechanisms of histone lactylation during early embryonic development in livestock, highlighting potential molecular targets and strategies to enhance mammalian in vitro embryo production techniques.