MYC Controls Human Pluripotent Stem Cell Fate Decisions through Regulation of Metabolic Flux

Highlights

• Metabolic switching during hPSC differentiation is germ layer-specific

• Switching is restricted to mesoderm and endoderm following exit from pluripotency

• Early ectodermal differentiation requires maintenance of high glycolytic flux

• Switching is controlled by MYC/MYCN and couples metabolism to cell fate decisions

Summary

As human pluripotent stem cells (hPSCs) exit pluripotency, they are thought to switch from a glycolytic mode of energy generation to one more dependent on oxidative phosphorylation. Here we show that, although metabolic switching occurs during early mesoderm and endoderm differentiation, high glycolytic flux is maintained and, in fact, essential during early ectoderm specification. The elevated glycolysis observed in hPSCs requires elevated MYC/MYCN activity. Metabolic switching during endodermal and mesodermal differentiation coincides with a reduction in MYC/MYCN and can be reversed by ectopically restoring MYC activity. During early ectodermal differentiation, sustained MYCN activity maintains the transcription of “switch” genes that are rate-limiting for metabolic activity and lineage commitment. Our work, therefore, shows that metabolic switching is lineage-specific and not a required step for exit of pluripotency in hPSCs and identifies MYC and MYCN as developmental regulators that couple metabolism to pluripotency and cell fate determination.