RT Journal
A1 Koch, Carmen M.
A1 Reck, Kristina
A1 Shao, Kaifeng
A1 Lin, Qiong
A1 Joussen, Sylvia
A1 Ziegler, Patrick
A1 Walenda, Gudrun
A1 Drescher, Wolf
A1 Opalka, Bertram
A1 May, Tobias
A1 Brümmendorf, Tim
A1 Zenke, Martin
A1 Šarić, Tomo
A1 Wagner, Wolfgang
T1 Pluripotent stem cells escape from senescence-associated DNA methylation changes
JF Genome Research 
JO Genome Research 
YR 2013 
FD February 01 
VO 23 
IS 2 
SP 248 
OP 259 
DO 10.1101/gr.141945.112 
UL http://genome.cshlp.org/content/23/2/248.abstract 
AB 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 nonpromoter regions of developmental genes. Furthermore, SA-hypomethylation in particular 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 that 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.