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 Dongen; Joris 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

doi:10.1186/s13059-016-1053-6

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	191
Journal	Genome Biology (Online)
Volume	17
DOIs	https://doi.org/10.1186/s13059-016-1053-6
Publication status	Published - 22 Sept 2016

Keywords

DNA methylation
Ageing
450k
DNA damage
Variability

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Cite this

Slieker, R. C., van Iterson, M., Luijk, R., Beekman, M., Zhernakova, D. V., Moed, M. H., Mei, H., van Galen, M., Deelen, P., Bonder, M. J., Zhernakova, A., Uitterlinden, A. G., Tigchelaar, E. F., Stehouwer, C. D. A., Schalkwijk, C. G., van der Kallen, C. J. H., Hofman, A., van Heemst, D., de Geus, E. J., ... Heijmans, B. T. (2016). Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms. Genome Biology (Online), 17, Article 191. https://doi.org/10.1186/s13059-016-1053-6

@article{765240041828423daabc9b77b6d8043c,

title = "Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms",

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 = "DNA methylation, Ageing, 450k, DNA damage, Variability",

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

year = "2016",

month = sep,

day = "22",

doi = "10.1186/s13059-016-1053-6",

language = "English",

volume = "17",

journal = "Genome Biology (Online)",

issn = "1474-760X",

publisher = "BioMed Central Ltd",

}

Slieker, RC, van Iterson, M, Luijk, R, Beekman, M, Zhernakova, DV, Moed, MH, Mei, H, van Galen, M, Deelen, P, Bonder, MJ, Zhernakova, A, Uitterlinden, AG, Tigchelaar, EF, Stehouwer, CDA , Schalkwijk, CG , van der Kallen, CJH, Hofman, A, van Heemst, D, de Geus, EJ, van Dongen, J, Deelen, J, van den Berg, LH, van Meurs, J, Jansen, R, 't Hoen, PAC, Franke, L, Wijmenga, C, Veldink, JH, Swertz, MA, van Greevenbroek, MMJ, van Duijn, CM, Boomsma, DI, Slagboom, PE & Heijmans, BT 2016, 'Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms', Genome Biology (Online), vol. 17, 191. https://doi.org/10.1186/s13059-016-1053-6

TY - JOUR

T1 - Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms

AU - Slieker, Roderick C.

AU - van Iterson, Maarten

AU - Luijk, Rene

AU - Beekman, Marian

AU - Zhernakova, Daria V.

AU - Moed, Matthijs H.

AU - Mei, Hailiang

AU - van Galen, Michiel

AU - Deelen, Patrick

AU - Bonder, Marc Jan

AU - Zhernakova, Alexandra

AU - Uitterlinden, Andre G.

AU - Tigchelaar, Ettje F.

AU - Stehouwer, Coen D. A.

AU - Schalkwijk, Casper G.

AU - van der Kallen, Carla J. H.

AU - Hofman, Albert

AU - van Heemst, Diana

AU - de Geus, Eco J.

AU - van Dongen, Jenny

AU - Deelen, Joris

AU - van den Berg, Leonard H.

AU - van Meurs, Joyce

AU - Jansen, Rick

AU - 't Hoen, Peter A. C.

AU - Franke, Lude

AU - Wijmenga, Cisca

AU - Veldink, Jan H.

AU - Swertz, Morris A.

AU - van Greevenbroek, Marleen M. J.

AU - van Duijn, Cornelia M.

AU - Boomsma, Dorret I.

AU - Slagboom, P. Eline

AU - Heijmans, Bastiaan T.

PY - 2016/9/22

Y1 - 2016/9/22

N2 - 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.

AB - 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.

KW - DNA methylation

KW - Ageing

KW - 450k

KW - DNA damage

KW - Variability

U2 - 10.1186/s13059-016-1053-6

DO - 10.1186/s13059-016-1053-6

M3 - Article

C2 - 27654999

SN - 1474-760X

VL - 17

JO - Genome Biology (Online)

JF - Genome Biology (Online)

M1 - 191

ER -