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

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

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 journal › Article › peer-review

441 Scopus citations

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.

Original language	American English
Pages (from-to)	392-402
Number of pages	11
Journal	Cell Metabolism
Volume	21
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2015.02.002
State	Published - 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.

Access to Document

10.1016/j.cmet.2015.02.002

Cite this

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. (2015). Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metabolism, 21(3), 392-402. https://doi.org/10.1016/j.cmet.2015.02.002

@article{adc26e1ff49543b28834ffbe193d061b,

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

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.",

author = "Arieh Moussaieff and Matthieu Rouleau and Daniel Kitsberg and Merav Cohen and Gahl Levy and Dinorah Barasch and Alina Nemirovski and Shai Shen-Orr and Ilana Laevsky and Michal Amit and David Bomze and B{\'e}n{\'e}dicte Elena-Herrmann and Tali Scherf and Malka Nissim-Rafinia and Stefan Kempa and Joseph Itskovitz-Eldor and Eran Meshorer and Daniel Aberdam and Yaakov Nahmias",

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 Tr{\`e}s grandes infrastructures de recherche (TGIR-RMN-THC CNRS FR3050). A.M. was partly supported by an INSERM postdoctoral fellowship. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = mar,

day = "3",

doi = "10.1016/j.cmet.2015.02.002",

language = "American English",

volume = "21",

pages = "392--402",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "3",

}

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 2015, 'Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells', Cell Metabolism, vol. 21, no. 3, pp. 392-402. https://doi.org/10.1016/j.cmet.2015.02.002

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 - 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.

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 - http://www.scopus.com/inward/record.url?scp=84924369505&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2015.02.002

DO - 10.1016/j.cmet.2015.02.002

M3 - Article

C2 - 25738455

AN - SCOPUS:84924369505

SN - 1550-4131

VL - 21

SP - 392

EP - 402

JO - Cell Metabolism

JF - Cell Metabolism

IS - 3

ER -

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

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Cite this