Aging effects on DNA methylation modules in human brain and blood tissue

Abstract

BackgroundSeveral recent studies reported aging effects on DNA methylation levels of individual CpG dinucleotides. But it is not yet known whether aging-related consensus modules, in the form of clusters of correlated CpG markers, can be found that are present in multiple human tissues. Such a module could facilitate the understanding of aging effects on multiple tissues.ResultsWe therefore employed weighted correlation network analysis of 2,442 Illumina DNA methylation arrays from brain and blood tissues, which enabled the identification of an age-related co-methylation module. Module preservation analysis confirmed that this module can also be found in diverse independent data sets. Biological evaluation showed that module membership is associated with Polycomb group target occupancy counts, CpG island status and autosomal chromosome location. Functional enrichment analysis revealed that the aging-related consensus module comprises genes that are involved in nervous system development, neuron differentiation and neurogenesis, and that it contains promoter CpGs of genes known to be down-regulated in early Alzheimer's disease. A comparison with a standard, non-module based meta-analysis revealed that selecting CpGs based on module membership leads to significantly increased gene ontology enrichment, thus demonstrating that studying aging effects via consensus network analysis enhances the biological insights gained.ConclusionsOverall, our analysis revealed a robustly defined age-related co-methylation module that is present in multiple human tissues, including blood and brain. We conclude that blood is a promising surrogate for brain tissue when studying the effects of age on DNA methylation profiles.

DNA methylation and healthy human aging

“…From adulthood to advanced age, overall levels of DNA methylation remain stable in blood, while interindividual variability increases over that time (Talens et al ., 2012; Weidner et al ., 2014). Postadulthood, many studies have found a mean decrease in blood DNA methylation with increasing age (Bjornsson et al ., 2004; Boks et al ., 2009; Heyn et al ., 2012; Horvath et al ., 2012; Hannum et al ., 2013; Johansson et al ., 2013; Florath et al ., 2014; Weidner et al ., 2014). These changes are less likely to occur in promoters and more likely to be observed in enhancers (Johansson et al ., 2013).…”

“…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). …”

“…Gain of DNA methylation during aging has been reported to be enriched at targets of Polycomb proteins, which generally show high levels of DNA methylation (Viré et al ., 2006; Teschendorff et al ., 2010; Heyn et al ., 2012; Horvath et al ., 2012). Beyond Polycomb targets, we can expect future research will decipher the chromatin neighborhoods associated with aging‐related DNA methylation changes.…”

“…Overall, most tissues fit with the pattern of increase in average DNA methylation early in life, with a gradual decrease later in life (Grönniger et al ., 2010; Ong & Holbrook, 2014). For example, many studies have shown that brain regions follow this pattern, showing rapid changes in DNA methylation in the early life period and then slowing gradually over the lifespan (Horvath et al ., 2012; Numata et al ., 2012 Lister et al ., 2013). Given that DNA methylation profiles are highly divergent in different tissues, comparing DNA methylation across tissues presents unique challenges.…”

“…In addition to general patterns of DNA methylation change with age, it has been repeatedly shown that DNA methylation levels at specific sites in the genome are so highly associated with age and that in some cases, they have been used to accurately predict chronological age (Bocklandt et al ., 2011; Horvath et al ., 2012; Hannum et al ., 2013; Florath et al ., 2014; Weidner et al ., 2014). These sites underlie the concept of the ‘epigenetic clock’.…”