Serine metabolism ensures proper minor ZGA, regulating histone methylation and DNA integrity specifically male pronuclei of mouse zygotes

In such genome-wide epigenetic conversion, upstream regulation by metabolic pathways that supply essential substrates and cofactors is frequently observed in various cell types. However, the specific involvement of metabolic pathways in orchestrating epigenetic establishment within zygotes has remained largely unclear.

In this study, we elucidated that the serine-glycine one-carbon (SGOC) metabolic pathway, which synthesizes S-Adenosylmethionine (SAM), a critical methyl group donor, has an essential role in regulating histone methylation in zygotes. Inhibition of the SGOC pathway led to pronounced zygotic arrest accompanied by disrupted histone methylations, specifically in the male pronuclei (PN). Notably, both zygotic arrest and disrupted histone methylation were rescued by inhibiting minor ZGA, indicating that minor ZGA regulated by the SGOC pathway functions upstream of histone methylation in the male PNs.