title: Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals.
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.
authors.affiliation: Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Schwörer
authors.affiliation: Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Becker
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Auguste-Piccard-Hof 1, 8093 Zürich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Feller
authors.affiliation: Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Ali H
authors.initials: AH
authors.lastname: Baig
authors.affiliation: Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Köber
authors.affiliation: Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Henriette
authors.initials: H
authors.lastname: Henze
authors.affiliation: Institute of Medical Systems Biology, Ulm University, James-Franck-Ring, 89081 Ulm, Germany.
authors.forename: Johann M
authors.initials: JM
authors.lastname: Kraus
authors.affiliation: Molecular and Computational Biology Program, University of Southern California, 1050 Childs Way, Los Angeles, California 90089, USA.
authors.forename: Beibei
authors.initials: B
authors.lastname: Xin
authors.affiliation: Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, DKFZ, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Lipka
authors.affiliation: Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Christy S
authors.initials: CS
authors.lastname: Varghese
authors.affiliation: Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Molecular and Computational Biology Program, University of Southern California, 1050 Childs Way, Los Angeles, California 90089, USA.
authors.forename: Remo
authors.initials: R
authors.lastname: Rohs
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Auguste-Piccard-Hof 1, 8093 Zürich, Switzerland.|Faculty of Science, University of Zürich, Zürich, Switzerland.
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.affiliation: Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, Minnesotta 55905, USA.
authors.forename: Kay L
authors.initials: KL
authors.lastname: Medina
authors.affiliation: Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.|Institute of Medical Systems Biology, Ulm University, James-Franck-Ring, 89081 Ulm, Germany.
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kestler
authors.affiliation: Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Francesco
authors.initials: F
authors.lastname: Neri
authors.affiliation: Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: von Maltzahn
authors.affiliation: Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Tümpel
authors.affiliation: Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.|Faculty of Medicine, Friedrich-Schiller-University, Jena, Germany.
authors.forename: K Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000375:Aging; D000818:Animals; D016922:Cellular Senescence / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004843:Epistasis, Genetic; D005260:Female; D048788:Growth and Development / Q000235:genetics*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology* / Q000378:metabolism*; D013312:Stress, Physiological / Q000235:genetics*
chemical_list: D002843:Chromatin; D018398:Homeodomain Proteins; C097899:homeobox protein HOXA9