Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer

Teschendorff, Andrew E.; Menon, Usha; Gentry‐Maharaj, Aleksandra; Ramus, Susan J.; Weisenberger, Daniel J.; Shen, Hui; Campan, Mihaela; Noushmehr, Houtan; Bell, Christopher G.; Maxwell, Alexander P.; Savage, David A.; Mueller-Holzner, Elisabeth; Marth, Christian; Kocjan, Gabrijela; Gayther, Simon A.; Jones, Allison; Beck, Stephan; Wagner, Wolfgang; Laird, Peter W.; Jacobs, Ian; Widschwendter, Martin

doi:10.1101/gr.103606.109

Cited by 769 publications

(790 citation statements)

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“…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).…”

Section: Resultsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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Reduced DNA methylation patterning and transcriptional connectivity define human skin aging

et al. 2016

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SummaryEpigenetic changes represent an attractive mechanism for understanding the phenotypic changes associated with human aging. Age‐related changes in DNA methylation at the genome scale have been termed ‘epigenetic drift’, but the defining features of this phenomenon remain to be established. Human epidermis represents an excellent model for understanding age‐related epigenetic changes because of its substantial cell‐type homogeneity and its well‐known age‐related phenotype. We have now generated and analyzed the currently largest set of human epidermis methylomes (N = 108) using array‐based profiling of 450 000 methylation marks in various age groups. Data analysis confirmed that age‐related methylation differences are locally restricted and characterized by relatively small effect sizes. Nevertheless, methylation data could be used to predict the chronological age of sample donors with high accuracy. We also identified discontinuous methylation changes as a novel feature of the aging methylome. Finally, our analysis uncovered an age‐related erosion of DNA methylation patterns that is characterized by a reduced dynamic range and increased heterogeneity of global methylation patterns. These changes in methylation variability were accompanied by a reduced connectivity of transcriptional networks. Our findings thus define the loss of epigenetic regulatory fidelity as a key feature of the aging epigenome.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reduced DNA methylation patterning and transcriptional connectivity define human skin aging

et al. 2016

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“…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.…”

Section: Dna Methylation Dynamics During Agingmentioning

confidence: 99%

“…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

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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.

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“…Our results show that CpGs in epigenetic clock sequences which possess G4 in addition to the above characteristics and could thus be characterized as potential PRC2 RNA target sites, undergo a methylation decrease during aging. Teschendorff et al [41] previously reported that PRC2 sequences are mostly hypermethylated by aging. However, only 12% of the hypermethylated CpGs reported by Teschendorff et al [41]are included among the epigenetic clock CpGs.…”

Section: Discussionmentioning

confidence: 99%

Age-dependent methylation in epigenetic clock CpGs is associated with G-quadruplex, co-transcriptionally formed RNA structures and tentative splice sites

et al. 2018

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Horvath’s epigenetic clock consists of 353 CpGs whose methylation levels can accurately predict the age of individuals. Using bioinformatics analysis, we investigated the conformation, energy characteristics and presence of tentative splice sites of the sequences surrounding the epigenetic clock CpGs, in relation to the median methylation changes in different ages, the presence of CpG islands and their position in genes. Common characteristics in the 100 nt sequences surrounding the epigenetic clock CpGs are G-quadruplexes and/or tentative splice site motifs. Median methylation increases significantly in sequences which adopt less stable structures during transcription. Methylation is higher when CpGs overlap with G-quadruplexes than when they precede them. Median methylation in epigenetic clock CpGs is higher in sequences expressed as single products rather than in multiple products and those containing single donors and multiple acceptors. Age-related methylation variation is significant in sequences without G-quadruplexes, particularly those producing low stability nascent RNA and those with splice sites. CpGs in sequences close to transcription start sites and those which are possibly never expressed (hypothetical proteins) undergo similar extent of age-related median methylation decrease and increase. Preservation of methylation is observed in CpG islands without G-quadruplexes, contrary to CpGs far from CpG islands (open sea). Sequences containing G-quadruplexes and RNA pseudoknots, determining the recognition by H3K27 histone methyltransferase, are hypomethylated. The presented structural DNA and co-transcriptional RNA analysis of epigenetic clock sequences, foreshadows the association of age-related methylation changes with the principle biological processes of DNA and histone methylation, splicing and chromatin silencing.

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Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer

Cited by 769 publications

References 37 publications

Reduced DNA methylation patterning and transcriptional connectivity define human skin aging

Reduced DNA methylation patterning and transcriptional connectivity define human skin aging

DNA methylation and healthy human aging

Age-dependent methylation in epigenetic clock CpGs is associated with G-quadruplex, co-transcriptionally formed RNA structures and tentative splice sites

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