Metabolic rewiring underpins human trophoblast induction

Abstract Development is driven by a sequence of molecularly interconnected transcriptional, epigenetic, and metabolic changes. Specific metabolites, like α-ketoglutarate (αKG), function as signalling molecules affecting the activity of chromatin modifying enzymes. It remains unclear, how such non-canonical function of metabolism coordinates specific cell-state changes especially in early development. Here we uncover that when naive human embryonic stem cells (nESC) are induced towards human trophoblast stem cells (hiTSC) a significant metabolic rewiring occurs, characterised by the accumulation of αKG. In vivo transcriptomic data further confirmed that metabolic rewiring likely takes place in the nascent trophectoderm (TE). We show that the intracellular αKG level is an important regulator of TE fate acquisition. Indeed, a dimethyl-αKG (dm-αKG) treatment of nESC increases their competence towards TE-like cells during hiTSC induction. Moreover, dm-αKG also increased the robustness of blastoid polarisation, marking the first step of TE induction. Surprisingly, dm-αKG treatment does not affect global histone methylation levels in nESC, but rather leads to decreased H3K27ac and weakening of the pluripotency network. Further functional assays confirmed that both reduced histone acetyltransferase activity and increased αKG level promote nESC competence towards TE-lineage but not extraembryonic mesoderm. We propose that an increased αKG level regulates pluripotency through deacetylation, thus creating a positive feedback loop promoting the induction of TE fate.