title: Bistable Epigenetic States Explain Age-Dependent Decline in Mesenchymal Stem Cell Heterogeneity.
abstract: The molecular mechanisms by which heterogeneity, a major characteristic of stem cells, is achieved are yet unclear. We here study the expression of the membrane stem cell antigen-1 (Sca-1) in mouse bone marrow mesenchymal stem cell (MSC) clones. We show that subpopulations with varying Sca-1 expression profiles regenerate the Sca-1 profile of the mother population within a few days. However, after extensive replication in vitro, the expression profiles shift to lower values and the regeneration time increases. Study of the promoter of Ly6a unravels that the expression level of Sca-1 is related to the promoter occupancy by the activating histone mark H3K4me3. We demonstrate that these findings can be consistently explained by a computational model that considers positive feedback between promoter H3K4me3 modification and gene transcription. This feedback implicates bistable epigenetic states which the cells occupy with an age-dependent frequency due to persistent histone (de-)modification. Our results provide evidence that MSC heterogeneity, and presumably that of other stem cells, is associated with bistable epigenetic states and suggest that MSCs are subject to permanent state fluctuations. Stem Cells 2017;35:694-704.
authors.affiliation: INSERM U972, University Paris 11, Hôpital Paul Brousse, Villejuif, France.|Faculty of Biology, Mouloud Mammeri University, Tizi-ouzou, Algeria.
authors.forename: Zahia
authors.initials: Z
authors.lastname: Hamidouche
authors.affiliation: Interdisciplinary Center for Bioinformatics, University Leipzig, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Rother
authors.affiliation: Interdisciplinary Center for Bioinformatics, University Leipzig, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Przybilla
authors.affiliation: Interdisciplinary Center for Bioinformatics, University Leipzig, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Krinner
authors.affiliation: INSERM U972, University Paris 11, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Clay
authors.affiliation: Interdisciplinary Center for Bioinformatics, University Leipzig, Germany.|LIFE: Leipzig Research Center for Civilization Diseases, University Leipzig, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Hopp
authors.affiliation: Interdisciplinary Center for Bioinformatics, University Leipzig, Germany.|Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Fabian
authors.affiliation: Interdisciplinary Center for Bioinformatics, University Leipzig, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stolzing
authors.affiliation: Interdisciplinary Center for Bioinformatics, University Leipzig, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Binder
authors.affiliation: INSERM U972, University Paris 11, Hôpital Paul Brousse, Villejuif, France.|IBPS Laboratory of Developmental Biology, University Pierre & Marie Curie, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Charbord
authors.affiliation: Interdisciplinary Center for Bioinformatics, University Leipzig, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Galle
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002999:Clone Cells; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D008565:Membrane Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008957:Models, Genetic; D011401:Promoter Regions, Genetic
chemical_list: D000950:Antigens, Ly; C074650:Ly6a protein, mouse; D008565:Membrane Proteins
keywords: Aging; Epigenetics; FACS; Mesenchymal stem cells; Methylation