Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells
Open accessAbstract
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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Naïve mouse ESCs accumulate pools of αKG and acetyl-CoA, which may reinforce the pluripotent state by stimulating more open chromatin.
“Moreover, naïve mouse ESCs accumulate pools of αKG and acetyl-CoA, which may reinforce the pluripotent state by stimulating more open chromatin (165, 211, 212, 213, 214).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [212]
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- Authors
- Moussaieff, A., Rouleau, M., Kitsberg, D., Cohen, M., Levy, G., Barasch, D., Nemirovski, A., Shen-Orr, S., Laevsky, I., Amit, M., Bomze, D., Elena-Herrmann, B., Scherf, T., Nissim-Rafinia, M., Kempa, S., Itskovitz-Eldor, J., Meshorer, E., Aberdam, D., & Nahmias, Y.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Hebrew University of Jerusalem (IL)
- Technion – Israel Institute of Technology (IL)
- Weizmann Institute of Science (IL)
- Max Delbrück Center (DE)
- Corresponding author
- Moussaieff, Arieh
- Nahmias, Yaakov
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 21
- Issue
- 3
- Pages
- 392-402
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2072844557
- Cited by
- 666
- References
- 23
- Citations by year
- 2026: 31 · 2025: 47 · 2024: 55 · 2023: 53 · 2022: 65 · 2021: 70 · 2020: 76 · 2019: 74 · 2018: 73 · 2017: 56 · 2016: 47 · 2015: 19
- FWCI
- 28.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-08-GENO-0024)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- embryonic stem cell differentiation, glycolysis, acetyl-CoA, histone acetylation, histone deacetylation, metabolic switch, acetate, stem cell metabolism, NMR metabolomics
- MeSH terms
- Acetyl Coenzyme A, Acetylation, Animals, Cell Differentiation, Cell Line, Glycolysis, Histones, Humans, Transcription, Genetic, Mice, Embryonic Stem Cells
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