Abstract
BackgroundThe well-established association of chronological age with changes in DNA methylation is primarily founded on the analysis of large sets of blood samples, while conclusions regarding tissue-specificity are typically based on small number of samples, tissues and CpGs. Here, we systematically investigate the tissue-specific character of age-related DNA methylation changes at the level of the CpG, functional genomic region and nearest gene in a large dataset.ResultsWe assembled a compendium of public data, encompassing genome-wide DNA methylation data (Illumina 450k array) on 8092 samples from 16 different tissues, including 7 tissues with moderate to high sample numbers (Dataset size range 96–1202, Ntotal = 2858). In the 7 tissues (brain, buccal, liver, kidney, subcutaneous fat, monocytes and T-helper cells), we identified 7850 differentially methylated positions that gained (gain-aDMPs; cut-offs: Pbonf ≤ 0.05, effect size ≥ 2%/10 years) and 4,287 that lost DNA methylation with age (loss-aDMPs), 92% of which had not previously been reported for whole blood. The majority of all aDMPs identified occurred in one tissue only (gain-aDMPs: 85.2%; loss-aDMPs: 97.4%), an effect independent of statistical power. This striking tissue-specificity extended to both the functional genomic regions (defined by chromatin state segmentation) and the nearest gene. However, aDMPs did accumulate in regions with the same functional annotation across tissues, namely polycomb-repressed CpG islands for gain-aDMPs and regions marked by active histone modifications for loss-aDMPs.ConclusionOur analysis shows that age-related DNA methylation changes are highly tissue-specific. These results may guide the development of improved tissue-specific markers of chronological and, perhaps, biological age.
Highlights
The well-established association of chronological age with changes in DNA methylation is primarily founded on the analysis of large sets of blood samples, while conclusions regarding tissue-specificity are typically based on small number of samples, tissues and CpGs
To systematically study the occurrence of tissue-specific and tissue-shared age-related differentially methylated positions (aDMPs), we identified aDMPs in tissues for which a moderate to large sample size was available (96 ≤ N≤1202; Additional file 1: Table S1), which included brain (N = 380), buccal (N = 96), liver (N = 147), kidney (N = 171), subcutaneous fat (SAT, N = 648), monocytes (N = 1202) and T-helper cells (Th cells, N = 214)
We focused on a conservative set of aDMPs defined by genome-wide significance (Pbonf ≤ 0.05) and a robust agerelated gain or loss that was larger than 2% per 10 years
Summary
The well-established association of chronological age with changes in DNA methylation is primarily founded on the analysis of large sets of blood samples, while conclusions regarding tissue-specificity are typically based on small number of samples, tissues and CpGs. Here, we systematically investigate the tissue-specific character of age-related DNA methylation changes at the level of the CpG, functional genomic region and nearest gene in a large dataset. The association between DNA methylation and age in humans is well established for whole blood [1,2,3,4,5,6,7,8,9,10], and in adipose tissue, brain and mesenchymal stem cells, loci have been found where DNA methylation changes with age [11,12,13]. A prime example is the CpGs near the ELOVL2 gene that exhibit consistent age-related changes in blood, hMSCs [13] and teeth [14] and other tissues [15, 16], an association that even extends to tissue from
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