Pluripotent stem cells escape from senescence-associated DNA methylation changes
- Carmen M Koch1,
- Kristina Reck1,
- Kaifeng Shao2,
- Qiong Lin3,
- Sylvia Joussen1,
- Patrick Ziegler4,
- Gudrun Walenda1,
- Wolf Drescher5,
- Bertram Opalka6,
- Tobias May7,
- Tim Hendrik Brummendorf4,
- Martin Zenke3,
- Tomo Saric2 and
- Wolfgang Wagner1,8
- 1 Helmholtz Institute for Biomedical Engineering, RWTH Medical School, Aachen, Germany;
- 2 Institute for Neurophysiology, University of Cologne, Cologne, Germany;
- 3 Institute for Biomedical Engineering - Cell Biology, RWTH Medical School, Aachen, Germany;
- 4 Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Medical School, Aachen, Germa;
- 5 Department for Orthopedics, RWTH Medical School, Aachen, Germany;
- 6 Department for Hematology, West German Cancer Center, University of Duisburg-Essen, Essen, Germany;
- 7 Department for Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunsc
- ↵* Corresponding author; email: wwagner{at}ukaachen.de
Abstract
Pluripotent stem cells evade replicative senescence, whereas other primary cells lose their proliferation and differentiation potential after a limited number of cell divisions - and this is accompanied by specific senescence-associated DNA methylation (SA-DNAm) changes. Here, we investigate SA-DNAm changes in mesenchymal stromal cells (MSC) upon long-term culture, irradiation-induced senescence, immortalization and reprogramming into induced pluripotent stem cells (iPSC) using high density HumanMethylation450 BeadChips. SA-DNAm changes are highly reproducible and they are enriched in intergenic and non-promoter regions of developmental genes. Furthermore, particularly SA-hypomethylation appears to be associated with H3K9me3, H3K27me3 and Polycomb-group 2 target genes. We demonstrate that ionizing irradiation, although associated with a senescence phenotype, does not affect SA-DNAm. Furthermore, overexpression of the catalytic subunit of the human telomerase (TERT) or conditional immortalization with a doxycycline-inducible system (TERT and SV40 TAg) result in telomere extension but do not prevent SA-DNAm. In contrast, we demonstrate that reprogramming into iPSC prevents almost the entire set of SA-DNAm changes. Our results indicate that long-term culture is associated with an epigenetically controlled process which stalls cells in a particular functional state, whereas irradiation-induced senescence and immortalization are not causally related to this process. Absence of SA-DNAm in pluripotent cells may play a central role for their escape from cellular senescence.
- Received April 20, 2012.
- Accepted October 2, 2012.
- © 2012, Published by Cold Spring Harbor Laboratory Press
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