Pluripotent stem cells escape from senescence-associated DNA methylation changes. 


Author: Koch CM, Reck K, Shao K, Lin Q, Joussen S, Ziegler P, Walenda G, Drescher W, Opalka B, May T, Brummendorf TH, Zenke M, Saric T, Wagner W.

Affiliation: Helmholtz Institute for Biomedical Engineering, RWTH Medical School, Aachen, Germany; 
Conference/Journal: Genome Res. 
Date published: 2012 Oct 18
Other:
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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.

PMID: 23080539