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 agingassociated 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.

Reduced DNA methylation patterning and transcriptional connectivity define human skin aging

“…Both hypomethylation and hypermethylation have previously been implied in human tissue aging (Rakyan et al ., 2010; Teschendorff et al ., 2010; Heyn et al ., 2012; Vandiver et al ., 2015; Yuan et al ., 2015). This includes the hypomethylation of megabase‐scale blocks, which has recently been described in aged and sun‐exposed human skin (Vandiver et al ., 2015).…”

“…While the key features of epigenetic drift remain to be defined, several observations have been made that characterize age‐related methylation changes across human tissues. These include the hypermethylation of stem cell genes (Rakyan et al ., 2010; Teschendorff et al ., 2010), a general linear correlation between the methylation level of certain CpGs and the chronological age (Hannum et al ., 2013; Horvath, 2013; Weidner et al ., 2014), and the hypermethylation of CpG islands (Yuan et al ., 2015). The molecular and phenotypic consequences of these alterations remain a topic of active research.…”

DNA methylation and healthy human aging

“…These changes are less likely to occur in promoters and more likely to be observed in enhancers (Johansson et al ., 2013). Regions that gain DNA methylation with age are enriched for CpG islands, while nonislands tend to lose DNA methylation with age (Rakyan et al ., 2010; Heyn et al ., 2012; Horvath et al ., 2012; Florath et al ., 2014; Weidner et al ., 2014). …”

“…The hypothesis behind this phenomenon rests upon the idea that specific sites in the genome undergo changes in DNA methylation with age that are progressive and common across individuals and sometimes even tissues (Horvath, 2013). Several recent studies have attempted to differentiate sites comprising the epigenetic clock from background epigenetic drift by determining which CpG sites that change with age are found across a population (Rakyan et al ., 2010; Bocklandt et al ., 2011; Bell et al ., 2012; Horvath et al ., 2012; Numata et al ., 2012; Horvath, 2013; Florath et al ., 2014; Weidner et al ., 2014). Interestingly, although epigenetic age and chronological age are highly correlated across study population, there is significant interindividual variability (Horvath, 2013; Weidner et al ., 2014).…”

The aging epigenome: DNA methylation from the cradle to the grave

“…The specificity of age-related methylation changes was further supported by the observation that hypermethylation occurs preferentially at bivalent chromatin domains, which suggests the mechanistic involvement of chromatin-modifying factors in this process [6,7]. …”