Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape

Day, Kenneth; Waite, Lindsay L.; Thalacker‐Mercer, Anna; West, Andrew B.; Bamman, Marcas M.; Brooks, James D.; Myers, R; Absher, Devin

doi:10.1186/gb-2013-14-9-r102

Cited by 303 publications

(270 citation statements)

References 64 publications

Supporting

Mentioning

241

Contrasting

Order By: Relevance

“…Genes affected by this process are associated with developmental regulation (Easwaran et al., 2012), implying a possible stem cell origin of cancer whereby aberrant hypermethylation could promote a continuously self‐renewing embryonic‐like state in cancer cells (Teschendorff et al., 2010). Interestingly, promoter hypermethylation of polycomb‐target genes was later described in aging blood (Rakyan et al., 2010; Teschendorff et al., 2010) and other tissue types such as mesenchymal stem cells (Fernández et al., 2015), ovary (Teschendorff et al., 2010), brain, kidney, and skeletal muscle (Day et al., 2013), findings which were also confirmed using whole‐genome bisulfite sequencing (Heyn et al., 2012). …”

Section: Introductionmentioning

confidence: 52%

“…The distribution of hypermethylated CpGs was found to be similar to that of the array, which is to a certain extent to be expected because it was designed to interrogate a promoter‐ and CpG dense‐biased portion of the genome. Nonetheless, hypermethylation changes always occurred in far more CpG‐dense regions than hypomethylation changes (Day et al., 2013; Yuan et al., 2015), and this observed effect was especially noticeable for aging dmCpGs.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

et al. 2018

View full text Add to dashboard Cite

SummaryCancer is an aging‐associated disease, but the underlying molecular links between these processes are still largely unknown. Gene promoters that become hypermethylated in aging and cancer share a common chromatin signature in ES cells. In addition, there is also global DNA hypomethylation in both processes. However, the similarity of the regions where this loss of DNA methylation occurs is currently not well characterized, and it is unknown if such regions also share a common chromatin signature in aging and cancer. To address this issue, we analyzed TCGA DNA methylation data from a total of 2,311 samples, including control and cancer cases from patients with breast, kidney, thyroid, skin, brain, and lung tumors and healthy blood, and integrated the results with histone, chromatin state, and transcription factor binding site data from the NIH Roadmap Epigenomics and ENCODE projects. We identified 98,857 CpG sites differentially methylated in aging and 286,746 in cancer. Hyper‐ and hypomethylated changes in both processes each had a similar genomic distribution across tissues and displayed tissue‐independent alterations. The identified hypermethylated regions in aging and cancer shared a similar bivalent chromatin signature. In contrast, hypomethylated DNA sequences occurred in very different chromatin contexts. DNA hypomethylated sequences were enriched at genomic regions marked with the activating histone posttranslational modification H3K4me1 in aging, while in cancer, loss of DNA methylation was primarily associated with the repressive H3K9me3 mark. Our results suggest that the role of DNA methylation as a molecular link between aging and cancer is more complex than previously thought.

show abstract

Section: Introductionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Some evidence show that age-related hypermethylation are more conserved across different tissues than hypomethylation [5,26]. However, we only studied blood samples and adjusted methylation data using estimated cellular compositions [20].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins

et al. 2018

View full text Add to dashboard Cite

Age-related changes in DNA methylation were observed in cross-sectional studies, but longitudinal evidence is still limited. Here, we aimed to characterize longitudinal age-related methylation patterns using 1011 blood samples collected from 385 Swedish twins (age at entry: mean 69 and standard deviation 9.7, 73 monozygotic and 96 dizygotic pairs) up to five times (mean 2.6) over 20 years (mean 8.7). We identified 1316 age-associated methylation sites (P<1.3×10−7) using a longitudinal epigenome-wide association study design. We measured how estimated cellular compositions changed with age and how much they confounded the age effect. We validated the results in two independent longitudinal cohorts, where 118 CpGs were replicated in Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, 390 samples) (P<3.9×10−5), 594 in Lothian Birth Cohort (LBC, 3018 samples) (P<5.1×10−5) and 63 in both. Functional annotation of age-associated CpGs showed enrichment in CCCTC-binding factor (CTCF) and other transcription factor binding sites. We further investigated genetic influences on methylation and found no interaction between age and genetic effects in the 1316 age-associated CpGs. Moreover, in the same CpGs, methylation differences within twin pairs increased with 6.4% over 10 years, where monozygotic twins had smaller intra-pair differences than dizygotic twins. In conclusion, we show that age-related methylation changes persist in a longitudinal perspective, and are fairly stable across cohorts. The changes are under genetic influence, although this effect is independent of age. Moreover, methylation variability increase over time, especially in age-associated CpGs, indicating the increase of environmental contributions on DNA methylation with age.

show abstract

“…When tracked in a large population, the distribution of DNA methylation levels suggests that these sites change rapidly with age until adulthood, at which point the rate of change slows considerably (Horvath, 2013; Lister et al ., 2013). An important characteristic of the epigenetic clock is that it can be tissue specific, meaning that different sites may be better correlated with age in specific tissues, although pan‐tissue epigenetic clocks have also been identified (Teschendorff et al ., 2010; Horvath et al ., 2012; Day et al ., 2013). In one study, an analysis examining 20 different tissues using a multitissue‐derived age predictor found that tissues differ in their apparent epigenetic ages, with some reflecting chronological age more accurately than others (Horvath, 2013).…”

Section: Epigenetic Drift Vs the Epigenetic Clock: Two Phenomena Undmentioning

confidence: 99%

DNA methylation and healthy human aging

2015

View full text Add to dashboard Cite

SummaryThe process of aging results in a host of changes at the cellular and molecular levels, which include senescence, telomere shortening, and changes in gene expression. Epigenetic patterns also change over the lifespan, suggesting that epigenetic changes may constitute an important component of the aging process. The epigenetic mark that has been most highly studied is DNA methylation, the presence of methyl groups at CpG dinucleotides. These dinucleotides are often located near gene promoters and associate with gene expression levels. Early studies indicated that global levels of DNA methylation increase over the first few years of life and then decrease beginning in late adulthood. Recently, with the advent of microarray and next‐generation sequencing technologies, increases in variability of DNA methylation with age have been observed, and a number of site‐specific patterns have been identified. It has also been shown that certain CpG sites are highly associated with age, to the extent that prediction models using a small number of these sites can accurately predict the chronological age of the donor. Together, these observations point to the existence of two phenomena that both contribute to age‐related DNA methylation changes: epigenetic drift and the epigenetic clock. In this review, we focus on healthy human aging throughout the lifetime and discuss the dynamics of DNA methylation as well as how interactions between the genome, environment, and the epigenome influence aging rates. We also discuss the impact of determining ‘epigenetic age’ for human health and outline some important caveats to existing and future studies.

show abstract

Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape

Cited by 303 publications

References 64 publications

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins

DNA methylation and healthy human aging

Contact Info

Product

Resources

About