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Cell Metab. 2015 Mar 3;21(3):392-402. doi: 10.1016/j.cmet.2015.02.002.

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

Author information

1
Grass Center for Bioengineering, Hebrew University of Jerusalem, Jerusalem 9190401, Israel; Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 9190401, Israel; INSERM, U976, Paris 75205, France; Université Paris-Diderot, Paris 75205, France; Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem 91120, Israel. Electronic address: ariehm@ekmd.huji.ac.il.
2
Laboratoire de Physio-Médecine Moléculaire, CNRS UMR7370, Nice 06107, France; Université de Nice Sophia Antipolis, Nice 06100, France.
3
Grass Center for Bioengineering, Hebrew University of Jerusalem, Jerusalem 9190401, Israel; Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
4
Grass Center for Bioengineering, Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
5
Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
6
Faculty of Medicine, Technion, Haifa 31096, Israel.
7
Centre de RMN à Très Hauts Champs, Institut des Sciences Analytiques, CNRS/ENS Lyon/UCB Lyon 1, Lyon 69100, France.
8
Weizmann Institute of Science, Rehovot 76100, Israel.
9
Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 9190401, Israel; The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
10
The Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
11
INSERM, U976, Paris 75205, France; Université Paris-Diderot, Paris 75205, France.
12
Grass Center for Bioengineering, Hebrew University of Jerusalem, Jerusalem 9190401, Israel; Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 9190401, Israel. Electronic address: ynahmias@cs.huji.ac.il.

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.

PMID:
25738455
DOI:
10.1016/j.cmet.2015.02.002
[Indexed for MEDLINE]
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