TY - JOUR
T1 - Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells
AU - Moussaieff, Arieh
AU - Rouleau, Matthieu
AU - Kitsberg, Daniel
AU - Cohen, Merav
AU - Levy, Gahl
AU - Barasch, Dinorah
AU - Nemirovski, Alina
AU - Shen-Orr, Shai
AU - Laevsky, Ilana
AU - Amit, Michal
AU - Bomze, David
AU - Elena-Herrmann, Bénédicte
AU - Scherf, Tali
AU - Nissim-Rafinia, Malka
AU - Kempa, Stefan
AU - Itskovitz-Eldor, Joseph
AU - Meshorer, Eran
AU - Aberdam, Daniel
AU - Nahmias, Yaakov
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/3/3
Y1 - 2015/3/3
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84924369505
U2 - 10.1016/j.cmet.2015.02.002
DO - 10.1016/j.cmet.2015.02.002
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C2 - 25738455
AN - SCOPUS:84924369505
SN - 1550-4131
VL - 21
SP - 392
EP - 402
JO - Cell Metabolism
JF - Cell Metabolism
IS - 3
ER -