Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains
- Vardhman K. Rakyan1,5,7,
- Thomas A. Down2,5,
- Siarhei Maslau2,
- Toby Andrew3,
- Tsun-Po Yang4,
- Huriya Beyan1,
- Pamela Whittaker4,
- Owen T. McCann4,
- Sarah Finer1,
- Ana M. Valdes3,
- R. David Leslie1,
- Panogiotis Deloukas4,6,7 and
- Timothy D. Spector3,6
- 1 Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom;
- 2 The Gurdon Institute and Department of Genetics, University of Cambridge, Cambridge CB2 1QN, United Kingdom;
- 3 Department of Twin Research and Genetic Epidemiology, King's College London, St. Thomas' Hospital Campus, London SE1 7EH, United Kingdom;
- 4 The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom
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.
Footnotes
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↵7 Corresponding authors.
E-mail v.rakyan{at}qmul.ac.uk.
E-mail panos{at}sanger.ac.uk.
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[Supplemental material is available online at http://www.genome.org. The microarray data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession nos. GSE20236 and GSE20242.]
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Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.103101.109.
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- Received November 16, 2009.
- Accepted January 27, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press
