Abstract

The functionality of stem cells declines during ageing, and this decline contributes to ageing-associated impairments in tissue regeneration and function1. Alterations in developmental pathways have been associated with declines in stem-cell function during ageing2,3,4,5,6, but the nature of this process remains poorly understood. Hox genes are key regulators of stem cells and tissue patterning during embryogenesis with an unknown role in ageing7,8. Here we show that the epigenetic stress response in muscle stem cells (also known as satellite cells) differs between aged and young mice. The alteration includes aberrant global and site-specific induction of active chromatin marks in activated satellite cells from aged mice, resulting in the specific induction of Hoxa9 but not other Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor that separates satellite cell gene expression in aged mice from that in young mice. The activated pathways include most of the currently known inhibitors of satellite cell function in ageing muscle, including Wnt, TGFβ, JAK/STAT and senescence signalling2,3,4,6. Inhibition of aberrant chromatin activation or deletion of Hoxa9 improves satellite cell function and muscle regeneration in aged mice, whereas overexpression of Hoxa9 mimics ageing-associated defects in satellite cells from young mice, which can be rescued by the inhibition of Hoxa9-targeted developmental pathways. Together, these data delineate an altered epigenetic stress response in activated satellite cells from aged mice, which limits satellite cell function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.

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Acknowledgements

We thank Y. Morita and A. Illing for providing guidance regarding FACS analysis. We are thankful to the FLI Core Facilities Functional Genomics (T. Kroll, A. Ploubidou) and DNA Sequencing (M. Groth) for their services. We express our thanks to M. Burkhalter, T. Sperka and A. Illing for discussions and suggestions. We are grateful to B. Wollscheid and S. Goetze for providing support for proteomic measurements. We thank V. Sakk and M. Kettering for mouse husbandry as well as S. Eichwald, K. Tramm and A. Abou Seif for experimental assistance. We are grateful to M. Kessel, M. Kyba, G. Sauvageau and D. Wellik for sharing plasmids with Hox cDNAs. We thank the Structural Genomics Consortium and S. Ackloo for providing access to the epigenetic probe library. We further thank M. Cerletti for providing protocols on SC isolation and E. Perdiguero for advice on infection of SCs before transplantation. Work on this project in K.L.R.’s laboratory was supported by the DGF (RU-745/10, RU-745/12), the ERC (2012-AdG 323136), the state of Thuringia, and intramural funds from the Leibniz association. J.V.M. was supported by a grant from the DFG (MA-3975/2-1). C.F. acknowledges support by the DFG (FE-1544/1-1) and EMBO (long-term postdoctoral fellowship ALTF 55-2015). R.A. was supported by the ERC (AdvGr 670821 (Proteomics 4D)). The funding for the Hoxa9−/− mice to K.L.M. was provided by a grant of the NIH (HL096108). R.R. was supported by a grant from the NIH (R01GM106056). This work was further supported by grants to H.A.K. from the DFG (SFB 1074 project Z1), the BMBF (Gerontosys II, Forschungskern SyStaR, project ID 0315894A), and the European Community’s Seventh Framework Programme 390 (FP7/2007-2013, grant agreement 602783).

Author information

Author notes

    • Stefan Tümpel
    •  & K. Lenhard Rudolph

    These authors jointly supervised this work.

Affiliations

  1. Leibniz-Institute on Aging – Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany

    • Simon Schwörer
    • , Friedrich Becker
    • , Ali H. Baig
    • , Ute Köber
    • , Henriette Henze
    • , Christy S. Varghese
    • , Manuel Schmidt
    • , Hans A. Kestler
    • , Francesco Neri
    • , Julia von Maltzahn
    • , Stefan Tümpel
    •  & K. Lenhard Rudolph
  2. Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Auguste-Piccard-Hof 1, 8093 Zürich, Switzerland

    • Christian Feller
    •  & Ruedi Aebersold
  3. Institute of Medical Systems Biology, Ulm University, James-Franck-Ring, 89081 Ulm, Germany

    • Johann M. Kraus
    •  & Hans A. Kestler
  4. Molecular and Computational Biology Program, University of Southern California, 1050 Childs Way, Los Angeles, California 90089, USA

    • Beibei Xin
    •  & Remo Rohs
  5. Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany

    • André Lechel
  6. Division of Epigenomics and Cancer Risk Factors, DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

    • Daniel B. Lipka
  7. Faculty of Science, University of Zürich, Zürich, Switzerland

    • Ruedi Aebersold
  8. Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, Minnesotta 55905, USA

    • Kay L. Medina
  9. Faculty of Medicine, Friedrich-Schiller-University, Jena, Germany

    • K. Lenhard Rudolph

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Contributions

S.S. designed and performed most experiments, analysed data, interpreted results and wrote the manuscript. F.B. designed and performed RNAi, ChIP and FISH experiments on isolated SCs, analysed data, interpreted results and wrote the manuscript. C.F. and R.A. designed and performed LC–MS experiments, analysed data, interpreted results and wrote the manuscript. A.H.B., U.K., H.H., C.S.V. and M.S. performed individual experiments and analysed data. A.L. performed microarray experiments. D.B.L. provided support and suggestions for ChIP experiments. K.L.M. provided Hoxa9−/− mice. J.M.K. and H.A.K. performed microarray and pathway analysis, analysed putative Hoxa9-binding sites and provided support for statistical analysis. B.X. and R.R. conducted analysis of putative Hoxa9-binding sites. F.N. analysed RNA-sequencing data and performed correlation analysis. J.V.M. and S.T. conceived the project, designed and performed individual experiments, interpreted results and wrote the manuscript. K.L.R. conceived the project, designed experiments, interpreted results and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Julia von Maltzahn or Stefan Tümpel or K. Lenhard Rudolph.

Reviewer Information Nature thanks J. Gil and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature20603

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