title: Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains.
abstract: There is a growing realization that some aging-associated phenotypes/diseases have an epigenetic basis. Here, we report the first genome-scale study of epigenomic dynamics during normal human aging. We identify aging-associated differentially methylated regions (aDMRs) in whole blood in a discovery cohort, and then replicate these aDMRs in sorted CD4(+) T-cells and CD14(+) monocytes in an independent cohort, suggesting that aDMRs occur in precursor haematopoietic cells. Further replication of the aDMRs in buccal cells, representing a tissue that originates from a different germ layer compared with blood, demonstrates that the aDMR signature is a multitissue phenomenon. Moreover, we demonstrate that aging-associated DNA hypermethylation occurs predominantly at bivalent chromatin domain promoters. This same category of promoters, associated with key developmental genes, is frequently hypermethylated in cancers and in vitro cell culture, pointing to a novel mechanistic link between aberrant hypermethylation in cancer, aging, and cell culture.
authors.affiliation: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK. v.rakyan@qmul.ac.uk
authors.forename: Vardhman K
authors.initials: VK
authors.lastname: Rakyan
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Down
authors.forename: Siarhei
authors.initials: S
authors.lastname: Maslau
authors.forename: Toby
authors.initials: T
authors.lastname: Andrew
authors.forename: Tsun-Po
authors.initials: TP
authors.lastname: Yang
authors.forename: Huriya
authors.initials: H
authors.lastname: Beyan
authors.forename: Pamela
authors.initials: P
authors.lastname: Whittaker
authors.forename: Owen T
authors.initials: OT
authors.lastname: McCann
authors.forename: Sarah
authors.initials: S
authors.lastname: Finer
authors.forename: Ana M
authors.initials: AM
authors.lastname: Valdes
authors.forename: R David
authors.initials: RD
authors.lastname: Leslie
authors.forename: Panogiotis
authors.initials: P
authors.lastname: Deloukas
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D001773:Blood Cells / Q000378:metabolism; D045744:Cell Line, Tumor / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D002843:Chromatin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015331:Cohort Studies; D019175:DNA Methylation / Q000502:physiology; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D050437:Genes, Developmental / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D013379:Substrate Specificity; D014427:Twins / Q000235:genetics; D055815:Young Adult
chemical_list: D002843:Chromatin