Control of epigenomic landscape and development of fetal male germ cells through L-serine metabolism

Sex-specific metabolic characteristics emerge in the mouse germline after reaching the genital ridges around embryonic day 10.5, coinciding with the initiation of sexual differentiation. However, the impact of such metabolic characteristics on the development of male and female germ cells remains unclear. In this study, we observed the specific upregulation in male fetal germ cells of D-3-phosphoglycerate dehydrogenase (PHGDH), the primary enzyme in the serine-glycine–one-carbon (SGOC) metabolic pathway. A concurrent increase was observed in a downstream metabolite, S-adenosylmethionine (SAM), a crucial substrate for protein and nucleic acid methylation. Inhibiting PHGDH in fetal testes resulted in reduced SAM levels in germ cells, accompanied by increases in the number of germ cells and the undifferentiated spermatogonia ratio. Furthermore, PHGDH inhibition led to a decrease in the methylation of histone H3 and DNA, resulting in aberrations in gene expression profiles. In summary, our findings underscore the significant role of certain metabolic mechanisms in the development of male germ cells. Overall design: To ivestigate the role of serine metabolic pathways in male germ cell differentiation, we prepared male germ cells sorted from cultured fetal testes with the addition of DMSO (control) or CBR-5884 (a inhibitor of serine metabolism). We then performed RNA-seq analysis of 2 different conditions with 2 biological replicates.