α-ketoglutarate promotes the specialization of primordial germ cell-like cells through regulating epigenetic reprogramming

There is growing evidence that cellular metabolism can directly participate in epigenetic dynamics and consequently modulate gene expression. However, the role of metabolites in activating the key gene regulatory network for specialization of germ cell lineage remains largely unknown. Here, we identified some cellular metabolites with significant changes by untargeted metabolomics between mouse epiblast-like cells (EpiLCs) and primordial germ cell-like cells (PGCLCs). More importantly, we found that inhibition of glutaminolysis by bis-2(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) impeded PGCLC specialization, but the impediment could be rescued by addition of alpha-ketoglutarate (alpha KG), the intermediate metabolite of oxidative phosphorylation and glutaminolysis. Moreover, adding aKG alone to the PGCLC medium accelerated the PGCLC specialization through promoting H3K27me3 demethylation. Thus, our study reveals the importance of metabolite alpha KG in the germ cell fate determination and highlights the essential role of cellular metabolism in shaping the cell identities through epigenetic events.

Automated summary

This study reveals the significant role of metabolites in activating gene regulatory networks and promoting specialization of germ cell lineage. Inhibition of glutaminolysis hinders the specialization of PGCLCs, which can be rescued by adding alpha-ketoglutarate to promote H3K27me3 demethylation and accelerate PGCLC specialization.