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

Publication date: Available online 28 September 2017
Source:Cell Stem Cell
Author(s): Timothy S. Cliff, Tianming Wu, Benjamin R. Boward, Amelia Yin, Hang Yin, John N. Glushka, James H. Prestegaard, Stephen Dalton
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.

Graphical abstract

Teaser

Cliff et al. show that, contrary to prior understanding, a metabolic switch away from glycolysis is not a required step for human pluripotent stem cell differentiation, and that, in fact, differentiation to ectoderm requires maintenance of high glycolytic flux via MYC/MYCN activity, indicating its role as a developmental regulator.


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