Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains

TY - JOUR

T1 - Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains

AU - Rakyan, Vardhman K.

AU - Down, Thomas A.

AU - Maslau, Siarhei

AU - Andrew, Toby

AU - Yang, Tsun-Po

AU - Beyan, Huriya

AU - Whittaker, Pamela

AU - McCann, Owen T.

AU - Finer, Sarah

AU - Valdes, Ana M.

AU - Leslie, R. David

AU - Deloukas, Panogiotis

AU - Spector, Timothy D.

PY - 2010/4

Y1 - 2010/4

N2 - 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.

AB - 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.

U2 - 10.1101/gr.103101.109

DO - 10.1101/gr.103101.109

M3 - Article

VL - 20

SP - 434

EP - 439

JO - Genome Research

JF - Genome Research

IS - 4

ER -