Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells

Cell Metabolism
Arieh MoussaieffYaakov Nahmias

Abstract

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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Citations

Feb 2, 2016·Biochimica Et Biophysica Acta·Atan Gross
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Apr 5, 2016·Proceedings of the National Academy of Sciences of the United States of America·Danny BavliYaakov Nahmias
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