Cell Metabolism
Volume 21, Issue 3, 3 March 2015, Pages 392-402
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Article
Glycolysis-Mediated Changes in Acetyl-CoA and Histone Acetylation Control the Early Differentiation of Embryonic Stem Cells

https://doi.org/10.1016/j.cmet.2015.02.002Get rights and content
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Highlights

  • The metabolic profile of embryonic stem cell changes within hours of differentiation

  • Glycolytic production of acetyl-CoA promotes histone acetylation during pluripotency

  • Glycolysis inhibition leads to deacetylation and differentiation of pluripotent cells

  • Pharmacologic modulation of acetyl-CoA regulates pluripotency

Summary

Loss of pluripotency is a gradual event whose initiating factors are largely unknown. Here we report the earliest metabolic changes induced during the first hours of differentiation. High-resolution NMR identified 44 metabolites and a distinct metabolic transition occurring during early differentiation. Metabolic and transcriptional analyses showed that pluripotent cells produced acetyl-CoA through glycolysis and rapidly lost this function during differentiation. Importantly, modulation of glycolysis blocked histone deacetylation and differentiation in human and mouse embryonic stem cells. Acetate, a precursor of acetyl-CoA, delayed differentiation and blocked early histone deacetylation in a dose-dependent manner. Inhibitors upstream of acetyl-CoA caused differentiation of pluripotent cells, while those downstream delayed differentiation. Our results show a metabolic switch causing a loss of histone acetylation and pluripotent state during the first hours of differentiation. Our data highlight the important role metabolism plays in pluripotency and suggest that a glycolytic switch controlling histone acetylation can release stem cells from pluripotency.

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