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. 2016 Sep 22;17(1):191.
doi: 10.1186/s13059-016-1053-6.

Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms

Roderick C Slieker  1 , Maarten van Iterson  1 , René Luijk  1 , Marian Beekman  1 , Daria V Zhernakova  2 , Matthijs H Moed  1 , Hailiang Mei  3 , Michiel van Galen  4 , Patrick Deelen  2 , Marc Jan Bonder  2 , Alexandra Zhernakova  2 , André G Uitterlinden  5 , Ettje F Tigchelaar  2 , Coen D A Stehouwer  6 , Casper G Schalkwijk  6 , Carla J H van der Kallen  6 , Albert Hofman  7 , Diana van Heemst  8 , Eco J de Geus  9 , Jenny van Dongen  9 , Joris Deelen  1 , Leonard H van den Berg  10 , Joyce van Meurs  5 , Rick Jansen  11 , Peter A C 't Hoen  4 , Lude Franke  2 , Cisca Wijmenga  2 , Jan H Veldink  10 , Morris A Swertz  12 , Marleen M J van Greevenbroek  6 , Cornelia M van Duijn  13 , Dorret I Boomsma  9 ; BIOS consortium; P Eline Slagboom  1 , Bastiaan T Heijmans  14
Affiliations

Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms

Roderick C Slieker et al. Genome Biol. .

Abstract

Background: Epigenetic change is a hallmark of ageing but its link to ageing mechanisms in humans remains poorly understood. While DNA methylation at many CpG sites closely tracks chronological age, DNA methylation changes relevant to biological age are expected to gradually dissociate from chronological age, mirroring the increased heterogeneity in health status at older ages.

Results: Here, we report on the large-scale identification of 6366 age-related variably methylated positions (aVMPs) identified in 3295 whole blood DNA methylation profiles, 2044 of which have a matching RNA-seq gene expression profile. aVMPs are enriched at polycomb repressed regions and, accordingly, methylation at those positions is associated with the expression of genes encoding components of polycomb repressive complex 2 (PRC2) in trans. Further analysis revealed trans-associations for 1816 aVMPs with an additional 854 genes. These trans-associated aVMPs are characterized by either an age-related gain of methylation at CpG islands marked by PRC2 or a loss of methylation at enhancers. This distinct pattern extends to other tissues and multiple cancer types. Finally, genes associated with aVMPs in trans whose expression is variably upregulated with age (733 genes) play a key role in DNA repair and apoptosis, whereas downregulated aVMP-associated genes (121 genes) are mapped to defined pathways in cellular metabolism.

Conclusions: Our results link age-related changes in DNA methylation to fundamental mechanisms that are thought to drive human ageing.

Keywords: 450k; Ageing; DNA damage; DNA methylation; Variability.

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Figures

Fig. 1
Fig. 1
Discovery of aVMPs in whole blood of 3295 individuals. a Flow chart of the different sets of CpGs identified in the current study, in cis and in trans. QC quality control. b Shannon entropy (y-axis) against age (x-axis) in 3295 individuals. c Volcano plot of the DNA methylation change in average (x-axis) against the change in variability (y-axis). d Examples of the three classes of aVMPs identified: aVMPs without a change in average (constant-aVMPs, cg21752383), aVMPs with a gain in DNA methylation (gain-aVMPs; cg01873886), and aVMPs with a loss in methylation (loss-aVMPs; cg14127336)
Fig. 2
Fig. 2
Validation of aVMPs in whole blood of 643 and purified monocytes of 1202 individuals. a Change in variability in the discovery (x-axis) against the whole blood and monocyte validation (y-axis) datasets. Red dots represent the monocyte validation dataset, blue dots represent the whole blood validation dataset. b The aVMPs that validate in whole blood and monocytes. c Density plot of average DNA methylation of validated aVMPs in the discovery dataset and validation datasets
Fig. 3
Fig. 3
Characterization of genomic regions harboring aVMPs and associations of gene expression in cis. a Enrichment (odds ratio, y-axis) of aVMPs in chromatin state segments (x-axis) in blood. b Overlap between chromatin state segmentation data in blood and in human embryonic stem cells (hESCs). Numbers represent the number of aVMPs that overlap between segments. c Frequency of aVMPs (y-axis) in 100-kb windows across the genome (blue bars) and their association with gene expression in cis in red. d Frequency of age-related variably methylated regions (aVMRs; x-axis) on each of the autosomal chromosomes (y-axis). e Increased variability (y-axis, top panel) of the protocadherin cluster (bottom panel). Abbreviations: TssA Active transcription start site, TssAFlnk flanking active transcription start site, TxFlnk transcription at gene 5′ and 3′, Tx strong transcription, TxWk weak transcription, EnhG genic enhancers, Enh enhancers, ZNF/Rpts ZNF genes plus repeats, Het heterochromatin, TssBiv bivalent/poised transcription start site, BivFlnk flanking bivalent transcription start site/enhancer, EnhBiv bivalent enhancer, ReprPC repressed polycomb, ReprPCWk weak repressed polycomb, Quies quiescent/low
Fig. 4
Fig. 4
Identification and characterization of aVMPs associated with gene expression in trans. a Correlation between DNA methylation of 1816 aVMPs (columns) and gene expression of 854 genes (rows). b TPRG1 is associated with 1296 aVMPs and cg13246235 with the expression of 853 genes. Blue lines represent the associations between the gene expression of TPRG1 and the DNA methylation of 1296 aVMPs. Red lines represent the associations between the DNA methylation of cg13246235 and the expression of 853 genes. c Z-score of individuals (columns) versus young individuals (<30 years) of trans-aVMPs (rows). The bar on the bottom left represents the average DNA methylation (DNAm) at a young age (<30 years). The bar on the top represents the age from low age (white) to high age (green). d Fraction and enrichment of gain- and loss-aVMPs in genomic features. CGI CpG island. Blue, fraction of loss-aVMPs; purple, fraction of gain-aVMPs. e Enrichment (odds ratio, y-axis) of gain- and loss-aVMPs in chromatin state segments (x-axis). f Average DNA methylation of aVMPs in various cancer types compared with their normal tissue counterpart. Abbreviations: TssA Active transcription start site, TssAFlnk flanking active transcription start site, TxFlnk transcription at gene 5' and 3', Tx strong transcription, TxWk weak transcription, EnhG genic enhancers, Enh enhancers, ZNF/Rpts ZNF genes plus repeats, Het heterochromatin, TssBiv bivalent/poised transcription start site, BivFlnk flanking bivalent transcription start site/enhancer, EnhBiv bivalent enhancer, ReprPC repressed polycomb, ReprPCWk weak repressed polycomb, Quies quiescent/low
Fig. 5
Fig. 5
Annotation of genes associated with aVMP methylation in trans. a Correlation between genes associated with aVMP methylation in trans. b Enrichment of trans-genes in GO terms. c Examples of genes identified in each GO category
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