Nutritional and metabolic control of germ cell fate through O-GlcNAc regulation

Fate determination of primordial germ cells (PGCs) is regulated in a multi-layered manner, involving signaling pathways, epigenetic mechanisms and transcriptional control. Epigenetic mechanisms are expected to be closely related with metabolic mechanisms but the detailed molecular machinery linking these two layers remain poorly understood. Here, we show that the hexosamine biosynthetic pathway controls PGC fate determination via O-linked ?-N-acetylglucosamine (O-GlcNAc) modification. Consistent with this model, reduction of carbohydrate metabolism via a maternal ketogenic diet that decreases O-GlcNAcylation levels causes repression of PGC formation in vivo. Further, the effect of maternal ketogenic diet intake until mid-gestation affected the number of ovarian germ cells in newborn pups. Taken together, we show that nutritional and metabolic mechanisms play a previously unappreciated role in PGC fate determination. Overall design: To ivestigate the role of glucose and its metabolic pathways in germ cell formation, we prepared the primordial germ cell-like cells (PGCLCs) cultured with or without glucose/ Further we preprared the PGCLCs cultured with OSMI-1, an O-GlcNAc transferase (OGT) inhibitor, to examine the contribution of O-GlcNAcylation in PGCLC induction. We then performed RNA-seq analysis of 4 different conditions with 2 biological replicates.