Abstract
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.
Highlights
Age is among the most important risk factors for cancer
Our results confirmed the relationship between DNA hypermethylation in aging and cancer, but they revealed important differences in DNA hypomethylation changes in the two processes that might be important to understand the possible role of DNA methylation as a molecular link between decline related to aging and tumor development
We have looked at the similarities and differences in epigenetic changes associated with cancer and aging
Summary
Age is among the most important risk factors for cancer (de Magalh~aes, 2013; DePinho, 2000). Recent analyses mainly performed in mouse tissue have failed to confirm global hypomethylation during the aging process (Cole et al, 2017; Hahn et al, 2017; Masser et al, 2017) and, to date, no study has provided a back-to-back and systematic comparison of the epigenetic changes that occur in aging and cancer To address this issue, here we have analyzed DNA methylation changes and their associated chromatin patterns in a total of more than 2,300 healthy and tumoral samples obtained from differentially aged individuals, using HumanMethylation450 BeadChip data generated by The Cancer Genome Atlas (TCGA) consortium and other datasets (Bormann et al, 2016; Guintivano, Aryee & Kaminsky, 2013; Hannum et al, 2013). Our results confirmed the relationship between DNA hypermethylation in aging and cancer, but they revealed important differences in DNA hypomethylation changes in the two processes that might be important to understand the possible role of DNA methylation as a molecular link between decline related to aging and tumor development
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