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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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).
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