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

R.C. Slieker; M. van Iterson; R. Luijk; M. Beekman; D.V. Zhernakova; M.H. Moed; H. Mei; M. van Galen; P. Deelen; M.J. Bonder; A. Zhernakova; A.G. Uitterlinden; E.F. Tigchelaar; C.D.A. Stehouwer; C.G. Schalkwijk; C.J.H. van der Kallen; A. Hofman; D. van Heemst; E.J.C. de Geus; J. van Dongen; J. Deelen; L.H. Van den Berg; J. van Meurs; R. Jansen; P.A.C. 't Hoen; L. Franke; C. Wijmenga; J.H. Veldink; M.A. Swertz; M.M.J. van Greevenbroek; C.M. van Duijn; D.I. Boomsma; P.E. Slagboom; B.T. Heijmans

doi:10.1186/s13059-016-1053-6

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

R.C. Slieker, M. van Iterson, R. Luijk, M. Beekman, D.V. Zhernakova, M.H. Moed, H. Mei, M. van Galen, P. Deelen, M.J. Bonder, A. Zhernakova, A.G. Uitterlinden, E.F. Tigchelaar, C.D.A. Stehouwer, C.G. Schalkwijk, C.J.H. van der Kallen, A. Hofman, D. van Heemst, E.J.C. de Geus, J. van DongenJ. Deelen, L.H. Van den Berg, J. van Meurs, R. Jansen, P.A.C. 't Hoen, L. Franke, C. Wijmenga, J.H. Veldink, M.A. Swertz, M.M.J. van Greevenbroek, C.M. van Duijn, D.I. Boomsma, P.E. Slagboom, B.T. Heijmans

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
Pages (from-to)	1-13
Journal	Genome Biology
Volume	17
Issue number	191
DOIs	https://doi.org/10.1186/s13059-016-1053-6
Publication status	Published - 2016

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Netherlands Twin Register (NTR)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s13059-016-1053-6

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Additional file 10: of Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms
Slieker, R. (Contributor), Iterson, M. V. (Contributor), Luijk, R. (Contributor), Beekman, M. (Contributor), Zhernakova, D. (Contributor), Moed, M. (Contributor), Mei, H. (Contributor), Galen, M. V. (Contributor), Deelen, P. (Contributor), Bonder, M. (Contributor), Zhernakova, A. (Contributor), Uitterlinden, A. (Contributor), Tigchelaar, E. (Contributor), Stehouwer, C. (Contributor), Schalkwijk, C. (Contributor), Kallen, C. V. D. (Contributor), Hofman, A. (Contributor), Heemst, D. V. (Contributor), Geus, E. D. (Contributor), Dongen, J. V. (Contributor), Deelen, J. (Contributor), Berg, L. V. D. (Contributor), Meurs, J. V. (Contributor), Jansen, R. (Contributor), Hoen, P. (Contributor), Franke, L. (Contributor), Wijmenga, C. (Contributor), Veldink, J. (Contributor), Swertz, M. (Contributor), Greevenbroek, M. V. (Contributor), Duijn, C. V. (Contributor), Boomsma, D. (Contributor), Slagboom, P. (Contributor) & Heijmans, B. (Contributor), Unknown Publisher, 22 Sept 2016
DOI: 10.6084/m9.figshare.c.3602444_d10.v1, https://springernature.figshare.com/articles/dataset/Additional_file_10_of_Age-related_accrual_of_methylomic_variability_is_linked_to_fundamental_ageing_mechanisms/4336805/1
Dataset
Additional file 5: of Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms
Slieker, R. (Contributor), Iterson, M. V. (Contributor), Luijk, R. (Contributor), Beekman, M. (Contributor), Zhernakova, D. (Contributor), Moed, M. (Contributor), Mei, H. (Contributor), Galen, M. V. (Contributor), Deelen, P. (Contributor), Bonder, M. (Contributor), Zhernakova, A. (Contributor), Uitterlinden, A. (Contributor), Tigchelaar, E. (Contributor), Stehouwer, C. (Contributor), Schalkwijk, C. (Contributor), Kallen, C. V. D. (Contributor), Hofman, A. (Contributor), Heemst, D. V. (Contributor), Geus, E. D. (Contributor), Dongen, J. V. (Contributor), Deelen, J. (Contributor), Berg, L. V. D. (Contributor), Meurs, J. V. (Contributor), Jansen, R. (Contributor), Hoen, P. (Contributor), Franke, L. (Contributor), Wijmenga, C. (Contributor), Veldink, J. (Contributor), Swertz, M. (Contributor), Greevenbroek, M. V. (Contributor), Duijn, C. V. (Contributor), Boomsma, D. (Contributor), Slagboom, P. (Contributor) & Heijmans, B. (Contributor), Unknown Publisher, 22 Sept 2016
DOI: 10.6084/m9.figshare.c.3602444_d5.v1, https://springernature.figshare.com/articles/dataset/Additional_file_5_of_Age-related_accrual_of_methylomic_variability_is_linked_to_fundamental_ageing_mechanisms/4336721/1
Dataset
Additional file 2: of Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms
Slieker, R. (Contributor), Iterson, M. V. (Contributor), Luijk, R. (Contributor), Beekman, M. (Contributor), Zhernakova, D. (Contributor), Moed, M. (Contributor), Mei, H. (Contributor), Galen, M. V. (Contributor), Deelen, P. (Contributor), Bonder, M. (Contributor), Zhernakova, A. (Contributor), Uitterlinden, A. (Contributor), Tigchelaar, E. (Contributor), Stehouwer, C. (Contributor), Schalkwijk, C. (Contributor), Kallen, C. V. D. (Contributor), Hofman, A. (Contributor), Heemst, D. V. (Contributor), Geus, E. D. (Contributor), Dongen, J. V. (Contributor), Deelen, J. (Contributor), Berg, L. V. D. (Contributor), Meurs, J. V. (Contributor), Jansen, R. (Contributor), Hoen, P. (Contributor), Franke, L. (Contributor), Wijmenga, C. (Contributor), Veldink, J. (Contributor), Swertz, M. (Contributor), Greevenbroek, M. V. (Contributor), Duijn, C. V. (Contributor), Boomsma, D. (Contributor), Slagboom, P. (Contributor) & Heijmans, B. (Contributor), Unknown Publisher, 22 Sept 2016
DOI: 10.6084/m9.figshare.c.3602444_d6.v1, https://springernature.figshare.com/articles/dataset/Additional_file_2_of_Age-related_accrual_of_methylomic_variability_is_linked_to_fundamental_ageing_mechanisms/4336739/1
Dataset

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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. C., ... Heijmans, B. T. (2016). Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms. Genome Biology, 17(191), 1-13. https://doi.org/10.1186/s13059-016-1053-6

@article{b247856703454b7da3c8b378e12b13fa,

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.",

author = "R.C. Slieker and {van Iterson}, M. and R. Luijk and M. Beekman and D.V. Zhernakova and M.H. Moed and H. Mei and {van Galen}, M. and P. Deelen and M.J. Bonder and A. Zhernakova and A.G. Uitterlinden and E.F. Tigchelaar and C.D.A. Stehouwer and C.G. Schalkwijk and {van der Kallen}, C.J.H. and A. Hofman and {van Heemst}, D. and {de Geus}, E.J.C. and {van Dongen}, J. and J. Deelen and {Van den Berg}, L.H. and {van Meurs}, J. and R. Jansen and {'t Hoen}, P.A.C. and L. Franke and C. Wijmenga and J.H. Veldink and M.A. Swertz and {van Greevenbroek}, M.M.J. and {van Duijn}, C.M. and D.I. Boomsma and P.E. Slagboom and B.T. Heijmans",

year = "2016",

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

language = "English",

volume = "17",

pages = "1--13",

journal = "Genome Biology",

issn = "1465-6906",

publisher = "Springer Verlag",

number = "191",

}

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, EJC , 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, vol. 17, no. 191, pp. 1-13. 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, R.C.

AU - van Iterson, M.

AU - Luijk, R.

AU - Beekman, M.

AU - Zhernakova, D.V.

AU - Moed, M.H.

AU - Mei, H.

AU - van Galen, M.

AU - Deelen, P.

AU - Bonder, M.J.

AU - Zhernakova, A.

AU - Uitterlinden, A.G.

AU - Tigchelaar, E.F.

AU - Stehouwer, C.D.A.

AU - Schalkwijk, C.G.

AU - van der Kallen, C.J.H.

AU - Hofman, A.

AU - van Heemst, D.

AU - de Geus, E.J.C.

AU - van Dongen, J.

AU - Deelen, J.

AU - Van den Berg, L.H.

AU - van Meurs, J.

AU - Jansen, R.

AU - 't Hoen, P.A.C.

AU - Franke, L.

AU - Wijmenga, C.

AU - Veldink, J.H.

AU - Swertz, M.A.

AU - van Greevenbroek, M.M.J.

AU - van Duijn, C.M.

AU - Boomsma, D.I.

AU - Slagboom, P.E.

AU - Heijmans, B.T.

PY - 2016

Y1 - 2016

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.

U2 - 10.1186/s13059-016-1053-6

DO - 10.1186/s13059-016-1053-6

M3 - Article

SN - 1465-6906

VL - 17

SP - 1

EP - 13

JO - Genome Biology

JF - Genome Biology

IS - 191

ER -

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

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UN SDGs

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Additional file 10: of Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms

Additional file 5: of Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms

Additional file 2: of Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms

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