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E2F transcription factor-1 regulates oxidative metabolism

Nature Cell Biology volume 13, pages 1146–1152 (2011)Cite this article

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Abstract

Cells respond to stress by coordinating proliferative and metabolic pathways. Starvation restricts cell proliferative (glycolytic) and activates energy productive (oxidative) pathways. Conversely, cell growth and proliferation require increased glycolytic and decreased oxidative metabolism levels1. E2F transcription factors regulate both proliferative and metabolic genes2,3. E2Fs have been implicated in the G1/S cell-cycle transition, DNA repair, apoptosis, development and differentiation2,3,4. In pancreatic β-cells, E2F1 gene regulation facilitated glucose-stimulated insulin secretion5,6. Moreover, mice lacking E2F1 (E2f1−/−) were resistant to diet-induced obesity4. Here, we show that E2F1 coordinates cellular responses by acting as a regulatory switch between cell proliferation and metabolism. In basal conditions, E2F1 repressed key genes that regulate energy homeostasis and mitochondrial functions in muscle and brown adipose tissue. Consequently, E2f1−/− mice had a marked oxidative phenotype. An association between E2F1 and pRB was required for repression of genes implicated in oxidative metabolism. This repression was alleviated in a constitutively active CDK4 (CDK4R24C) mouse model or when adaptation to energy demand was required. Thus, E2F1 represents a metabolic switch from oxidative to glycolytic metabolism that responds to stressful conditions.

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Figure 1: Loss of E2F1 affects energy expenditure, adaptive thermogenesis, mitochondrial function and physical activity.
Figure 2: Increased E2f1−/− oxidative metabolic gene expression level.
Figure 3: Cold and fasting modulate gene expression through the pRB–E2F1 complex.
Figure 4: Increased O2 consumption, running time and expression of oxidative genes in CDK4R24C/R24C mice.
Figure 5: DNA methylation of proliferative target genes modulates E2F1 transcriptional activity in muscle.

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Acknowledgements

We thank M. Barbacid, B.M. Spiegelman, C. Sardet and L. Le Cam for the gift of materials and D. Greuet, C. Henriquet, S. Hure and J. Teyssier for their technical help. The authors are grateful to C. Cazevieille from Centre de Ressources en Imagerie Cellulaire de Montpellier for her technical assistance, data interpretation and ultrastructural evaluations. We are indebted to the RHEM network (Réseau d’Histologie Expérimentale de Montpellier, IFR122, France) for histology and, in particular, for tissue and slide preparations. Members of the Fajas laboratory are acknowledged for support and discussions. This work was supported by grants from Agence Nationale pour la Recherche (ANR genopath), INSERM-Association pour la Recherche sur le Diabète (PNR Diabète), Association Française des Diabétiques, Société Francophone du Diabète, Association pour la Recherche contre le Cancer, Fondation pour la Recherche Médicale, Ligue Contre le Cancer, European Research Council, National Institutes of Health, Swiss National Science Foundation and EPFL. E.B. was supported by a grant from the Ministère de l’Enseignement Supérieur et de la Recherche; C.C. was supported by a grant from the Agence Nationale pour la Recherche.

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Author notes

  1. Emilie Blanchet and Jean-Sébastien Annicotte: These authors equally contributed to this work

Authors and Affiliations

  1. IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France

    Emilie Blanchet, Jean-Sébastien Annicotte, Sylviane Lagarrigue, Victor Aguilar, Cyrielle Clapé, Carine Chavey, Vanessa Fritz & Lluis Fajas

  2. INSERM, U896, Montpellier F-34298, France

    Emilie Blanchet, Jean-Sébastien Annicotte, Sylviane Lagarrigue, Victor Aguilar, Cyrielle Clapé, Carine Chavey, Vanessa Fritz & Lluis Fajas

  3. Université de Montpellier1, Montpellier, F-34298, France

    Emilie Blanchet, Jean-Sébastien Annicotte, Sylviane Lagarrigue, Victor Aguilar, Cyrielle Clapé, Carine Chavey, Vanessa Fritz & Lluis Fajas

  4. CRLC Val d’Aurelle Paul Lamarque, Montpellier F-34298, France

    Emilie Blanchet, Jean-Sébastien Annicotte, Sylviane Lagarrigue, Victor Aguilar, Cyrielle Clapé, Carine Chavey, Vanessa Fritz & Lluis Fajas

  5. IGMM, Institut de Génétique Moléculaire de Montpellier, Montpellier F-34293, France

    Emilie Blanchet, Jean-Sébastien Annicotte, Sylviane Lagarrigue, Carine Chavey, Vanessa Fritz & Lluis Fajas

  6. CNRS, UMR5535, Montpellier F-34293, France

    Emilie Blanchet, Jean-Sébastien Annicotte, Sylviane Lagarrigue, Carine Chavey, Vanessa Fritz & Lluis Fajas

  7. INRA, UMR0866, Montpellier F-34060, France

    François Casas

  8. INSERM U844, Montpellier F-34295, France

    Florence Apparailly

  9. Ecole Polytechnique Fédérale de Lausanne, 1115 Lausanne, Switzerland

    Johan Auwerx

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  1. Emilie Blanchet
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Contributions

J-S.A. and L.F. designed the study. E.B., J-S.A., S.L., V.A., V.F., C. Chavey and C. Clapé carried out the experiments. F.A., F.C. and J.A. provided reagents and data. J-S.A. and L.F. wrote the manuscript.

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Correspondence to Emilie Blanchet, Jean-Sébastien Annicotte or Lluis Fajas.

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Blanchet, E., Annicotte, JS., Lagarrigue, S. et al. E2F transcription factor-1 regulates oxidative metabolism. Nat Cell Biol 13, 1146–1152 (2011). https://doi.org/10.1038/ncb2309

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