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

被引：101

作者：

Slieker, Roderick C. ^{[1
]}

van Iterson, Maarten ^{[1
]}

Luijk, Rene ^{[1
]}

Beekman, Marian ^{[1
]}

Zhernakova, Daria V. ^{[2
]}

Moed, Matthijs H. ^{[1
]}

Mei, Hailiang ^{[3
]}

van Galen, Michiel ^{[4
]}

Deelen, Patrick ^{[2
]}

Bonder, Marc Jan ^{[2
]}

Zhernakova, Alexandra ^{[2
]}

Uitterlinden, Andre G. ^{[5
]}

Tigchelaar, Ettje F. ^{[2
]}

Stehouwer, Coen D. A. ^{[6
,7
]}

Schalkwijk, Casper G. ^{[6
,7
]}

van der Kallen, Carla J. H. ^{[6
,7
]}

Hofman, Albert ^{[8
]}

van Heemst, Diana ^{[9
]}

de Geus, Eco J. ^{[10
]}

van Dongen, Jenny ^{[10
]}

Deelen, Joris ^{[1
]}

van den Berg, Leonard H. ^{[11
]}

van Meurs, Joyce ^{[5
]}

Jansen, Rick ^{[12
]}

't Hoen, Peter A. C. ^{[4
]}

Franke, Lude ^{[2
]}

Wijmenga, Cisca ^{[2
]}

Veldink, Jan H. ^{[11
]}

Swertz, Morris A. ^{[13
]}

van Greevenbroek, Marleen M. J. ^{[6
,7
]}

van Duijn, Cornelia M. ^{[14
]}

Boomsma, Dorret I. ^{[10
]}

Slagboom, P. Eline ^{[1
]}

Heijmans, Bastiaan T. ^{[1
]}

机构：

[1] Leiden Univ, Med Ctr, Mol Epidemiol Sect, Einthovenweg 20, NL-2333 ZC Leiden, Netherlands

[2] Univ Med Ctr Groningen, Dept Genet, Antonius Deusinglaan 1, NL-9713 AV Groningen, Netherlands

[3] Leiden Univ, Med Ctr, Sequence Anal Support Core, Einthovenweg 20, NL-2333 ZC Leiden, Netherlands

[4] Leiden Univ, Med Ctr, Dept Human Genet, Einthovenweg 20, NL-2333 ZC Leiden, Netherlands

[5] Erasmus Univ, Med Ctr, Dept Internal Med, Wytemaweg 80, NL-3015 CN Rotterdam, Netherlands

[6] Maastricht Univ, Med Ctr, Dept Internal Med, Univ Singel 50, NL-6229 ER Maastricht, Netherlands

[7] Maastricht Univ, Med Ctr, Sch Cardiovasc Dis CARIM, Univ Singel 50, NL-6229 ER Maastricht, Netherlands

[8] Erasmus Univ, Med Ctr, Dept Epidemiol, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands

[9] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands

[10] Vrije Univ Amsterdam, Dept Biol Psychol, Neurosci Campus Amsterdam,Boechorststr 1, NL-1081 BT Amsterdam, Netherlands

[11] Univ Med Ctr Utrecht, Brain Ctr Rudolf Magnus, Dept Neurol, Univ Weg 100, NL-3584 CG Utrecht, Netherlands

[12] Vrije Univ Amsterdam, Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam,AJ Ernststr 1187, NL-1081 HL Amsterdam, Netherlands

[13] Univ Groningen, Univ Med Ctr Groningen, Genom Coordinat Ctr, Hanzepl 1, NL-9713 GZ Groningen, Netherlands

[14] Erasmus Univ, Med Ctr, Dept Genet Epidemiol, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands

来源：

GENOME BIOLOGY | 2016年 / 17卷

关键词：

DNA methylation; Ageing; 450k; DNA damage; Variability; DNA-METHYLATION CHANGES; STEM-CELLS; WIDE; GENE; EXPRESSION; REGIONS; HYPOMETHYLATION; WIDESPREAD; POPULATION; TISSUES;

D O I：

10.1186/s13059-016-1053-6

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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.

引用

页数：13

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