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Nature. 2016 Dec 15;540(7633):428-432. doi: 10.1038/nature20603. Epub 2016 Nov 30.

Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals.

Author information

1
Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
2
Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Auguste-Piccard-Hof 1, 8093 Zürich, Switzerland.
3
Institute of Medical Systems Biology, Ulm University, James-Franck-Ring, 89081 Ulm, Germany.
4
Molecular and Computational Biology Program, University of Southern California, 1050 Childs Way, Los Angeles, California 90089, USA.
5
Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
6
Division of Epigenomics and Cancer Risk Factors, DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
7
Faculty of Science, University of Zürich, Zürich, Switzerland.
8
Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, Minnesotta 55905, USA.
9
Faculty of Medicine, Friedrich-Schiller-University, Jena, Germany.

Abstract

The functionality of stem cells declines during ageing, and this decline contributes to ageing-associated impairments in tissue regeneration and function. Alterations in developmental pathways have been associated with declines in stem-cell function during ageing, 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 ageing. 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 signalling. 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.

PMID:
27919074
PMCID:
PMC5415306
DOI:
10.1038/nature20603
[Indexed for MEDLINE]
Free PMC Article

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