α-Ketoglutarate promotes trophectoderm induction and maturation from naive human embryonic stem cells

Development and lineage choice are driven by interconnected transcriptional, epigenetic and metabolic changes. Specific metabolites, such as α-ketoglutarate (αKG), function as signalling molecules affecting the activity of chromatin-modifying enzymes. However, how metabolism coordinates cell-state changes, especially in human pre-implantation development, remains unclear. Here we uncover that inducing naive human embryonic stem cells towards the trophectoderm lineage results in considerable metabolic rewiring, characterized by αKG accumulation. Elevated αKG levels potentiate the capacity of naive embryonic stem cells to specify towards the trophectoderm lineage. Moreover, increased αKG levels promote blastoid polarization and trophectoderm maturation. αKG supplementation does not affect global histone methylation levels; rather, it decreases acetyl-CoA availability, reduces histone acetyltransferase activity and weakens the pluripotency network. We propose that metabolism functions as a positive feedback loop aiding in trophectoderm fate induction and maturation, highlighting that global metabolic rewiring can promote specificity in cell fate decisions through intricate regulation of signalling and chromatin.