Abstract
Epigenetic modifications of cytosine residues in the DNA play a critical role for cellular differentiation and potentially also for aging. In mesenchymal stromal cells (MSC) from human bone marrow we have previously demonstrated age-associated methylation changes at specific CpG-sites of developmental genes. In continuation of this work, we have now isolated human dermal fibroblasts from young (<23 years) and elderly donors (>60 years) for comparison of their DNA methylation profiles using the Infinium HumanMethylation27 assay. In contrast to MSC, fibroblasts could not be induced towards adipogenic, osteogenic and chondrogenic lineage and this is reflected by highly significant differences between the two cell types: 766 CpG sites were hyper-methylated and 752 CpG sites were hypo-methylated in fibroblasts in comparison to MSC. Strikingly, global DNA methylation profiles of fibroblasts from the same dermal region clustered closely together indicating that fibroblasts maintain positional memory even after in vitro culture. 75 CpG sites were more than 15% differentially methylated in fibroblasts upon aging. Very high hyper-methylation was observed in the aged group within the INK4A/ARF/INK4b locus and this was validated by pyrosequencing. Age-associated DNA methylation changes were related in fibroblasts and MSC but they were often regulated in opposite directions between the two cell types. In contrast, long-term culture associated changes were very consistent in fibroblasts and MSC. Epigenetic modifications at specific CpG sites support the notion that aging represents a coordinated developmental mechanism that seems to be regulated in a cell type specific manner.
Highlights
There is a growing perception that epigenetic modifications, such as DNA methylation and histone modification, play an important role for cellular senescence and aging of the organism [1,2,3]
Simultaneous in vitro differentiation revealed that adipogenic differentiation could be induced in about 40% of the cells within mesenchymal stromal cells (MSC) preparations, whereas hardly any fat droplet formation was observed in fibroblasts (n = 5, Figure 1B,E)
Methylation patterns: epigenetic modifications at specific CpG sites provide a positional memory of the sampling location and there are age-associated DNA methylation changes that may contribute to aging of the skin
Summary
There is a growing perception that epigenetic modifications, such as DNA methylation and histone modification, play an important role for cellular senescence and aging of the organism [1,2,3]. Upon replication the same methylation pattern is established on the newly synthesized DNA strand by DNA methyltransferase 1 (DNMT1) and thereby, the methylation pattern is inherited to both daughter cells This inheritance of epigenetic modifications might provide an ideal mechanism for the regulation of progressive alterations in the course of aging [4]. It was shown that the 5-methylcytosine content decreased upon long-term culture of fibroblasts [8]. This led to the suggestion that the global loss of DNA methylation might be a result of passive demethylation as a consequence of a progressive loss of DNMT1a efficiency [9]. A number of specific loci become hyper-methylated during aging, such as the INK4A/ARF/
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