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

Arieh Moussaieff*, Matthieu Rouleau, Daniel Kitsberg, Merav Cohen, Gahl Levy, Dinorah Barasch, Alina Nemirovski, Shai Shen-Orr, Ilana Laevsky, Michal Amit, David Bomze, Bénédicte Elena-Herrmann, Tali Scherf, Malka Nissim-Rafinia, Stefan Kempa, Joseph Itskovitz-Eldor, Eran Meshorer, Daniel Aberdam, Yaakov Nahmias

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

441 Scopus citations


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.

Original languageAmerican English
Pages (from-to)392-402
Number of pages11
JournalCell Metabolism
Issue number3
StatePublished - 3 Mar 2015

Bibliographical note

Funding Information:
We thank Prof. Nissim Benvenisty, Prof. Ruby Shalom-Feuerstein, Dr. Isabelle Petit, and Dr. Michael Shmoish for important discussions, as well as Eayar Leibovitch, SabinaTsytkin, and Chaya Rachel Calderon for technical support. This work was supported by a European Research Council Starting Grant TMIHCV (no. 242699), Marie Curie International Reintegration Grant microLiverMaturation (no. 248417), the British Council BIRAX Regenerative Medicine award (no. 33BX12HGYN), Agence Nationale pour la Recherche GENOPAT-08 (no. ANR-08-GENO-024), and a Très grandes infrastructures de recherche (TGIR-RMN-THC CNRS FR3050). A.M. was partly supported by an INSERM postdoctoral fellowship.

Publisher Copyright:
© 2015 Elsevier Inc.


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