Bistable epigenetic states explain age-dependent decline in mesenchymal stem cell heterogeneity
journal contributionposted on 2016-11-03, 11:27 authored by Zahia Hamidouche, Karen Rother, Jens Przybilla, Axel Krinner, Dennis Clay, Lydia Hopp, Claire Fabian, Alexandra StolzingAlexandra Stolzing, Hans Binder, Pierre Charbord, Joerg Galle
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. This article is protected by copyright. All rights reserved.
The study was supported by the BMBF grants HNPCC‐Sys (grant number: 031 6065A) and INDRA (grant number: 031A312) and by the DFG grant SPP1463 (grant number GA637/4‐1). Work was further supported by a grant from Institute National du Cancer (INCA project "Bortes") and by a grant from the European Community (contract N° 223236, project "Cascade", FP7).
- Mechanical, Electrical and Manufacturing Engineering
Published inStem Cells
CitationHAMIDOUCHE, Z. ...et al., 2016. Bistable epigenetic states explain age-dependent decline in mesenchymal stem cell heterogeneity. Stem Cells, 35 (3), pp. 694–704.
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NotesThis is an Open Access Article. It is published by AlphaMed Press under the Creative Commons Attribution -NonCommercial-NoDerivatives 4.0 International Licence (CC BY-NC-ND). Full details of this licence are available at: http://creativecommons.org/licenses/by-nc-nd/4.0/