Ldha positively regulates the lactylation of Hdac1 to hinder the 2-cell state of embryonic stem cells [RNA-seq]

Protein lactylation is a process that is fueled by lactate, generated by the enzyme lactate dehydrogenase (Ldh) from pyruvate. Despite prior research, the precise role of protein lactylation in controlling the identity of mouse embryonic stem cells (ESCs) is still not fully understood. We observed that inhibiting or eliminating Ldha causes a reduction in global protein lactylation in ESCs, and RNA-seq analysis suggests that Ldha inhibition induces a 2-cell-like cell (2CLC) signature in ESCs. To probe the underlying mechanisms, we performed quantitative lactylation proteomics analysis, we discovered that Hdac1, a gene with significant regulatory roles during the 2-cell stage (2C), undergoes lactylation modification. Additionally, we observed that treatment with an Ldh (lactate dehydrogenase) inhibitor can decrease the lactylation levels of Hdac1. Mechanistically, we discovered that Ldha positively regulates the lactylation of Hdac1, promoting its direct binding to zygotic genome activation (ZGA) gene promoters and has stronger deacetylase activity. This leads to the removal of acetyl groups from H3K27 on these loci, effectively suppressing the expression of 2C genes. Our study presents novel evidence supporting protein lactylation's potential as a means of inhibiting the generation of 2CLCs and modulating acetylation activity.