Research Article: Distinct chromatin signatures of DNA hypomethylation in aging and cancer

Date Published: March 05, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Raúl F. Pérez, Juan Ramón Tejedor, Gustavo F. Bayón, Agustín F. Fernández, Mario F. Fraga.


Cancer 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.

Partial Text

Age is among the most important risk factors for cancer (de Magalhães, 2013; DePinho, 2000). However, the underlying molecular mechanisms governing this relationship are still poorly understood. Recent research has established polycomb‐target gene promoter hypermethylation as a common epigenetic characteristic of cancer (Schlesinger et al., 2007; Widschwendter et al., 2007). In this scenario, prior to alteration these promoters display an embryonic stem cell “bivalent chromatin pattern” consisting of the repressive histone mark H3K27me3 and the active mark H3K4me3 (Ohm et al., 2007). 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).

Although it is widely accepted that cancer is an age‐dependent disease, the underlying molecular mechanisms are still poorly characterized. In this work, we have looked at the similarities and differences in epigenetic changes associated with cancer and aging.

None declared.

M.F.F., A.F.F., and G.F.B. conceived, coordinated, and supervised the study. M.F.F, R.F.P., and J.R.T. designed all aspects of the research and contributed equally to this work. R.F.P. and J.R.T. collected the data and performed computational analyses. M.F.F., A.F.F., R.F.P., and J.R.T. wrote the manuscript. All authors revised, read, and approved the final manuscript.




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