کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2792386 | 1155047 | 2015 | 11 صفحه PDF | دانلود رایگان |
• 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
SummaryLoss 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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Journal: - Volume 21, Issue 3, 3 March 2015, Pages 392–402