TY  - JOUR
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
Y1  - 2013/02/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 248 
EP  - 259 
DO  - 10.1101/gr.141945.112 
VL  - 23 
IS  - 2 
UR  - http://genome.cshlp.org/content/23/2/248.abstract 
N2  - 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. 
ER  -