Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells.
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.
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.
Arieh
A
Moussaieff
Laboratoire de Physio-Médecine Moléculaire, CNRS UMR7370, Nice 06107, France; Université de Nice Sophia Antipolis, Nice 06100, France.
Matthieu
M
Rouleau
Grass Center for Bioengineering, Hebrew University of Jerusalem, Jerusalem 9190401, Israel; Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
Daniel
D
Kitsberg
Grass Center for Bioengineering, Hebrew University of Jerusalem, Jerusalem 9190401, Israel; Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
Merav
M
Cohen
Grass Center for Bioengineering, Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
Gahl
G
Levy
Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Dinorah
D
Barasch
Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Alina
A
Nemirovski
Faculty of Medicine, Technion, Haifa 31096, Israel.
Shai
S
Shen-Orr
Faculty of Medicine, Technion, Haifa 31096, Israel.
Ilana
I
Laevsky
Faculty of Medicine, Technion, Haifa 31096, Israel.
Michal
M
Amit
Grass Center for Bioengineering, Hebrew University of Jerusalem, Jerusalem 9190401, Israel; Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 9190401, Israel.
David
D
Bomze
Centre de RMN à Très Hauts Champs, Institut des Sciences Analytiques, CNRS/ENS Lyon/UCB Lyon 1, Lyon 69100, France.
Bénédicte
B
Elena-Herrmann
Weizmann Institute of Science, Rehovot 76100, Israel.
Tali
T
Scherf
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.
Malka
M
Nissim-Rafinia
The Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
Stefan
S
Kempa
Faculty of Medicine, Technion, Haifa 31096, Israel.
Joseph
J
Itskovitz-Eldor
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.
Eran
E
Meshorer
INSERM, U976, Paris 75205, France; Université Paris-Diderot, Paris 75205, France.
Daniel
D
Aberdam
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.
Yaakov
Y
Nahmias
D000105:Acetyl Coenzyme A / Q000235:genetics / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000502:physiology*; D006019:Glycolysis / Q000235:genetics / Q000502:physiology*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology
D006657:Histones; D000105:Acetyl Coenzyme A