Abstract

Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD+-derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain was essential for sustained optimal mitochondrial function but dispensable for gene regulation. Through direct binding, macroH2A1.1 inhibits basal poly-ADP ribose polymerase 1 (PARP-1) activity and thus reduces nuclear NAD+ consumption. The resultant accumulation of the NAD+ precursor NMN allows for maintenance of mitochondrial NAD+ pools that are critical for respiration. Our data indicate that macroH2A1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD+ consumption and establishing a buffer of NAD+ precursors in differentiated cells.

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Acknowledgements

We thank P. Muñoz Canoves for tools, training and advice; E. Gallardo (Institut de Recerca Hospital de la Santa Creu i Sant Pau, Barcelona, Spain) for primary human myoblasts; S. Samino for help with metabolomics analyses; S.-V. Forcales, A. Mikoč and the Ahel lab for helpful discussions; and the departments of pathology and biochemistry of the Hospital Universitari Germans Trias I Pujol (HGTP) for excellent support. This project was supported by MINECO (grants SAF2012-39749 and BFU2015-66559-P to M.B.; grant SAF2012-37427 to M.S.), AFM-Téléthon (grant 18738 to M.B.), the Marie Skłodowska Curie training network 'ChroMe' (grant H2020-MSCA-ITN-2015-675610 to M.B., A.G.L., O.Y. and J.A.P.), the Minerva Foundation (ARCHES award to T.P.), DZD (T.P.), the ERC (grants 281641 and 682679 to J.A.P.), DFG (grants SFB 646 and SFB 1064 to A.G.L.), the Wellcome Trust (grant 101794 to I.A.), Cancer Research UK (grant C35050/A22284 to I.A.), the Unity through Knowledge Fund (grant UKF 1B 2/13 to I.A.), ISCIII (grant PI15/00701 to P.M.G.-R.), MECD (FPU14/06542 to D.C.), AGAUR (FI fellowship to M.P.M.), and a Juan de la Cierva fellowship (JCI-2011-10831 to J.D.). Work in the Buschbeck lab is further supported by the Deutsche José Carreras Leukaemie Stiftung (DJCLS R 14/16), MINECO–ISCIII (PIE16/00011) and AGAUR (2014-SGR-35). Research at the IJC is supported by the 'La Caixa' Foundation, the Fundació Internacional Josep Carreras, Celgene Spain and the CERCA Programme/Generalitat de Catalunya.

Author information

Author notes

    • Melanija Posavec Marjanović

    Present address: Institute Ruđer Bošković Zagreb, Croatia.

    • Melanija Posavec Marjanović
    •  & Sarah Hurtado-Bagès

    These authors contributed equally to this work.

Affiliations

  1. Programme of Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (PMPPC-IGTP), Badalona, Spain.

    • Melanija Posavec Marjanović
    • , Mònica Suelves
    •  & Marcus Buschbeck
  2. Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Spain.

    • Melanija Posavec Marjanović
    •  & Sarah Hurtado-Bagès
  3. Josep Carreras Leukemia Research Institute (IJC), Campus ICO–Germans Trias I Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.

    • Sarah Hurtado-Bagès
    • , Vanesa Valero
    • , Roberto Malinverni
    • , David Corujo
    • , Iva Guberovic
    • , Julien Douet
    •  & Marcus Buschbeck
  4. Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.

    • Maximilian Lassi
    •  & Raffaele Teperino
  5. German Center for Diabetes Research (DZD), Neuherberg, Germany.

    • Maximilian Lassi
    •  & Raffaele Teperino
  6. Université de Lyon, Centre de Recherche en Cancérologie de Lyon, Cancer Cell Plasticity Department, UMR INSERM 1052 CNRS 5286, Centre Léon Bérard, Lyon, France.

    • Hélène Delage
    •  & Philippe Bouvet
  7. Metabolomics Platform, Department of Electronic Engineering (DEEEA), Universitat Rovira i Virgili, Tarragona, Spain.

    • Miriam Navarro
    •  & Oscar Yanes
  8. Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.

    • Miriam Navarro
    •  & Oscar Yanes
  9. Department of Physiological Sciences II, Faculty of Medicine, University of Barcelona, Barcelona, Spain.

    • Pau Gama-Perez
    •  & Pablo M Garcia-Roves
  10. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.

    • Ivan Ahel
  11. Biomedical Center Munich (BMC)–Physiological Chemistry, Center for Integrated Protein Science Munich, Munich Cluster for Systems Neurology, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Germany.

    • Andreas G Ladurner
  12. Université de Lyon, Ecole Normale Supérieure de Lyon, Lyon, France.

    • Philippe Bouvet
  13. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.

    • Raffaele Teperino
    •  & J Andrew Pospisilik

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Contributions

M.P.M., R.T. and M.B. conceived the project; M.P.M., S.H.-B., M.S., P.B., I.A., A.G.L., P.M.G.-R., O.Y., J.A.P., R.T. and M.B. designed experiments and interpreted data; O.Y. contributed methods; M.P.M., S.H.-B., M.L., V.V., H.D., M.N., D.C., I.G., J.D. and P.G.-P. performed experiments; R.M. analyzed high-content data; and M.P.M., J.A.P., R.T. and M.B. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Raffaele Teperino or Marcus Buschbeck.

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DOI

https://doi.org/10.1038/nsmb.3481

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