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

Roderick C. Slieker, Maarten van Iterson, Rene Luijk, Marian Beekman, Daria V. Zhernakova, Matthijs H. Moed, Hailiang Mei, Michiel van Galen, Patrick Deelen, Marc Jan Bonder, Alexandra Zhernakova, Andre G. Uitterlinden, Ettje F. Tigchelaar, Coen D. A. Stehouwer, Casper G. Schalkwijk, Carla J. H. van der Kallen, Albert Hofman, Diana van Heemst, Eco J. de Geus, Jenny van DongenJoris Deelen, Leonard H. van den Berg, Joyce van Meurs, Rick Jansen, Peter A. C. 't Hoen, Lude Franke, Cisca Wijmenga, Jan H. Veldink, Morris A. Swertz, Marleen M. J. van Greevenbroek, Cornelia M. van Duijn, Dorret I. Boomsma, P. Eline Slagboom, Bastiaan T. Heijmans*, BIOS Consortium

*Corresponding author voor dit werk

OnderzoeksoutputAcademicpeer review

106 Citaten (Scopus)
281 Downloads (Pure)


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.

Originele taal-2English
Aantal pagina's13
TijdschriftGenome Biology
StatusPublished - 22-sep.-2016


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