Abstract
Ageing leaves characteristic traces in the DNA methylation make-up of the genome. However, the importance of DNA methylation in ageing remains unclear. The study of subtelomeric regions could give promising insights into this issue. Previously reported associations between susceptibility to age-related diseases and epigenetic instability at subtelomeres suggest that the DNA methylation profile of subtelomeres undergoes remodelling during ageing. In the present work, this hypothesis has been tested in the context of the European large-scale project MARK-AGE. In this cross-sectional study, we profiled the DNA methylation of chromosomes 5 and 21 subtelomeres, in more than 2000 age-stratified women and men recruited in eight European countries. The study included individuals from the general population as well as the offspring of nonagenarians and Down syndrome subjects, who served as putative models of delayed and accelerated ageing, respectively. Significant linear changes of subtelomeric DNA methylation with increasing age were detected in the general population, indicating that subtelomeric DNA methylation changes are typical signs of ageing. Data also show that, compared to the general population, the dynamics of age-related DNA methylation changes are attenuated in the offspring of centenarian, while they accelerate in Down syndrome individuals. This result suggests that subtelomeric DNA methylation changes reflect the rate of ageing progression. We next attempted to trace the age-related changes of subtelomeric methylation back to the influence of diverse variables associated with methylation variations in the population, including demographics, dietary/health habits and clinical parameters. Results indicate that the effects of age on subtelomeric DNA methylation are mostly independent of all other variables evaluated.
Highlights
Subtelomeres are transition DNA regions, ranging in size from 10 to 300 kb, which are found between chromosome-specific sequences and the telomeric repeats
In order to investigate the possible functional importance of subtelomeric DNA methylation, we examined the relationship between Methylation Age of SubTelomere index (MAST), telomere length and age
Previous studies indicate the possibility that epigenetic changes occur at subtelomeric DNA regions in both physiological and abnormal ageing [19,20,21,22,23, 29, 42]
Summary
Subtelomeres are transition DNA regions, ranging in size from 10 to 300 kb, which are found between chromosome-specific sequences and the telomeric repeats. Subtelomeres are poor in unique DNA sequences and genes. Instead, they are predominantly made up of a complex “patchwork” of blocks of sequences repeated in low copy numbers and characterised by a good intraand inter-chromosomal sequence preservation [1,2,3]. Subtelomeric domains are considered heterochromatic regions, similar to telomeres. They contain HP1 protein and display histone modifications, such as H4K20me and H3K9me, which are typical of heterochromatin. Subtelomeres tend to be strongly methylated both in humans and mice, and telomere elongation has been shown to be associated with subtelomeric hypomethylation, either following knockout of DNA methyltransferase enzymes [6] or in pathological conditions like cancer [7]
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