Journal
CELL METABOLISM
Volume 21, Issue 3, Pages 392-402Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2015.02.002
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Funding
- European Research Council Starting Grant TMIHCV [242699]
- Marie Curie International Reintegration Grant microLiverMaturation [248417]
- British Council BIRAX Regenerative Medicine award [33BX12HGYN]
- Agence Nationale pour la Recherche GENOPAT [ANR-08-GENO-024]
- Tres grandes infrastructures de recherche [TGIR-RMN-THC CNRS FR3050]
- INSERM
- European Research Council (ERC) [242699] Funding Source: European Research Council (ERC)
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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 acetylCoA, 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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