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

Genome Biology, Sep 2016

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.

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

Slieker et al. Genome Biology Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms Roderick C. Slieker 0 2 Maarten van Iterson 0 2 René Luijk 0 2 Marian Beekman 0 2 Daria V. Zhernakova 2 Matthijs H. Moed 0 2 Hailiang Mei 2 Michiel van Galen 2 Patrick Deelen 2 Marc Jan Bonder 2 Alexandra Zhernakova 2 André G. Uitterlinden 2 Ettje F. Tigchelaar 2 Coen D. A. Stehouwer 2 Casper G. Schalkwijk 2 Carla J. H. van der Kallen 2 Albert Hofman 2 3 Diana van Heemst 2 5 Eco J. de Geus 2 4 Jenny van Dongen 2 4 Joris Deelen 0 2 Leonard H. van den Berg 1 2 Joyce van Meurs 2 Rick Jansen 2 7 Peter A. C. 't Hoen 2 Lude Franke 2 Cisca Wijmenga 2 Jan H. Veldink 1 2 Morris A. Swertz 2 8 Marleen M. J. van Greevenbroek 2 Cornelia M. van Duijn 2 6 Dorret I. Boomsma 2 4 BIOS consortium 2 P. Eline Slagboom 0 2 Bastiaan T. Heijmans 0 2 0 Molecular Epidemiology section, Leiden University Medical Center , Einthovenweg 20, 2333 ZC Leiden , The Netherlands 1 Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht , Universiteitsweg 100, 3584 CG Utrecht , The Netherlands 2 Center , Universiteitssingel 50, 6229 ER Maastricht , The Netherlands 3 Department of Epidemiology, Erasmus University Medical Center , Dr. Molewaterplein 50, 3015 GE Rotterdam , The Netherlands 4 Department of Biological Psychology, VU University Amsterdam , Neuroscience Campus Amsterdam, Van der Boechorststraat 1, 1081 BT Amsterdam , The Netherlands 5 Department of Gerontology and Geriatrics, Leiden University Medical Center , Albinusdreef 2, 2333 ZA Leiden , The Netherlands 6 Department of Genetic Epidemiology, Erasmus University Medical Center , Dr. Molewaterplein 50, 3015 GE Rotterdam , The Netherlands 7 Department of Psychiatry, VU University Medical Center , Neuroscience Campus Amsterdam, A.J. Ernststraat 1187, 1081 HL Amsterdam , The Netherlands 8 Genomics Coordination Center, University Medical Center Groningen, University of Groningen , Hanzeplein 1, 9713 GZ Groningen , The Netherlands 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. DNA methylation; Ageing; 450k; DNA damage; Variability - Background Studies of model organisms such as yeast, nematodes, and mice have shown that the accumulation of cellular damage is a fundamental cause of ageing across species [1–3]. Epigenetic dysregulation is thought to play a key role in this process [4, 5]. Numerous human population studies have now shown that changes in DNA methylation of CpG dinucleotides, a key epigenetic mechanism [6], are strongly associated with chronological age. Although these epigenetic changes are in part a by-product of age-related changes in the cellular composition of the studied tissue [7–9], many age-related differentially methylated positions (aDMPs) observed in blood samples are independent of cell composition [8–19]. Additional studies showed the consistent occurrence of aDMPs in other tissues [20–22] and species [23] and aDMPs have proven to be a useful tool to predict chronological age [24, 25]. However, aDMPs may not be the most informative marker of the ageing process since they were discovered as close correlates of chronological age instead of biological age [26]. Moreover, only a small proportion of aDMPs are associated with expression changes [12, 17], suggesting that their functional implication may be limited. In contrast, DNA methylation changes that increasingly diverge from chronological age may reflect the increasing inter-individ (...truncated)


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Roderick Slieker, Maarten van Iterson, René Luijk, Marian Beekman, Daria Zhernakova, Matthijs Moed, Hailiang Mei, Michiel van Galen, Patrick Deelen, Marc Bonder, Alexandra Zhernakova, André Uitterlinden, Ettje Tigchelaar, Coen Stehouwer, Casper Schalkwijk, Carla van der Kallen, Albert Hofman, Diana van Heemst, Eco de Geus, Jenny van Dongen, Joris Deelen, Leonard van den Berg, Joyce van Meurs, Rick Jansen, Peter ‘t Hoen, Lude Franke, Cisca Wijmenga, Jan Veldink, Morris Swertz, Marleen van Greevenbroek, Cornelia van Duijn, Dorret Boomsma, , P. Slagboom, Bastiaan Heijmans. Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms, Genome Biology, 2016, pp. 191, 17, DOI: 10.1186/s13059-016-1053-6