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

By Andrew E. Teschendorff, U. Menon, A. Gentry-Maharaj, S. Ramus, D. Weisenberger, Hui Shen, Mihaela Campan, Houtan Noushmehr, C. Bell, A. Maxwell and 11 more. Genome Research, 2010

867 citations recorded by the source corpus.

Polycomb group proteins (PCGs) are involved in repression of genes that are required for stem cell differentiation. Recently, it was shown that promoters of PCG target genes (PCGTs) are 12-fold more likely to be methylated in cancer than non-PCGTs. Age is the most important demographic risk factor for cancer, and we hypothesized that its carcinogenic potential may be referred by irreversibly stabilizing stem cell features. To test this, we analyzed the methylation status of over 27,000 CpGs mapping to promoters of approximately 14,000 genes in whole blood samples from 261 postmenopausal women. We demonstrate that stem cell PCGTs are far more likely to become methylated with age than non-targets (odds ratio = 5.3 [3.8-7.4], P < 10(-10)), independently of sex, tissue type, disease state, and methylation platform. We identified a specific subset of 69 PCGT CpGs that undergo hypermethylation with age and validated this methylation signature in seven independent data sets encompassing over 900 samples, including normal and cancer solid tissues and a population of bone marrow mesenchymal stem/stromal cells (P < 10(-5)). We find that the age-PCGT methylation signature is present in preneoplastic conditions and may drive gene expression changes associated with carcinogenesis. These findings shed substantial novel insights into the epigenetic effects of aging and support the view that age may predispose to malignant transformation by irreversibly stabilizing stem cell features.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/09ba3434cfd362f92e2c067942e4b66ed7e9f5d0

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Citations in the corpus

Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population (2012, neutral): “multiple tissues and organisms [11,12,13,14,15].”
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Aging of blood can be tracked by DNA methylation changes at just three CpG sites (2014, methodology): “This may indicate that AR-DNAm changes are due to loss of DNAm maintenance at specific regions; hypermethylation happens in regions associated with repressive histone marks [15] and polycomb group protein targets [16], whereas hypomethylation may be enriched with other histone modifications, transcr”
Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases (2016, background): “…Yang, Korn, Burwinkel, & Brenner, 2011; Shenker et al.; Sun, 2014; Sun, Smith, et al., 2013), poor nutrition(Waterland & Jirtle, 2003), genetic factors (Sun, 2014; D. Zhang et al., 2010), and age – all well known risk factors human diseases (Bocklandt et al., 2011; Teschendorff et al., 2010).”
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Epigenetic Predictor of Age (2011, background): “Recently, unbiased genomewide studies have documented age effects on DNA methylation in cultured cells [4], mice [5], and humans [6,7,8].”
metilene: fast and sensitive calling of differentially methylated regions from bisulfite sequencing data (2016, background): “Furthermore, differential DNA methylation plays a role in many cancers, such as medulloblastoma (Hovestadt et al. 2014) and B-cell lymphoma (Kretzmer et al. 2015), and connects risk factors like age (Teschendorff et al. 2010) and smoking (Teschendorff et al. 2015) with cancer.”
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DNA methylation: superior or subordinate in the epigenetic hierarchy? (2011, background): “DNA methylation of PcG target genes is present in preneoplastic conditions and may lead to aberrant gene expression associated with carcinogenesis.(71) Our laboratory reported that approximately 47% of DNMT3B-regulated genes were bound by PRC1 or PRC2 in human colon cancer, and we demonstrated a nov”