A DNA hypermethylation module for the stem/progenitor cell signature of cancer

Abstract

Many DNA-hypermethylated cancer genes are occupied by the Polycomb (PcG) repressor complex in embryonic stem cells (ESCs). Their prevalence in the full spectrum of cancers, the exact context of chromatin involved, and their status in adult cell renewal systems are unknown. Using a genome-wide analysis, we demonstrate that ∼75% of hypermethylated genes are marked by PcG in the context of bivalent chromatin in both ESCs and adult stem/progenitor cells. A large number of these genes are key developmental regulators, and a subset, which we call the “DNA hypermethylation module,” comprises a portion of the PcG target genes that are down-regulated in cancer. Genes with bivalent chromatin have a low, poised gene transcription state that has been shown to maintain stemness and self-renewal in normal stem cells. However, when DNA-hypermethylated in tumors, we find that these genes are further repressed. We also show that the methylation status of these genes can cluster important subtypes of colon and breast cancers. By evaluating the subsets of genes that are methylated in different cancers with consideration of their chromatin status in ESCs, we provide evidence that DNA hypermethylation preferentially targets the subset of PcG genes that are developmental regulators, and this may contribute to the stem-like state of cancer. Additionally, the capacity for global methylation profiling to cluster tumors by phenotype may have important implications for further refining tumor behavior patterns that may ultimately aid therapeutic interventions.

Distinct chromatin signatures of DNA hypomethylation in aging and cancer

“…Interestingly, our gene ontology analyses revealed similar gene functionalities affected by cancer and aging DNA hypermethylation, mainly related to developmental processes, which is in line with the methylation of bivalent chromatin promoters of developmental regulators in cancer and aging (Easwaran et al., 2012; Rakyan et al., 2010). On the other hand, DNA hypomethylation in cancer was mainly associated with functions identified with cellular signaling, and much lower enrichments in gene functions were found for hypomethylated CpGs in aging.…”

“…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).…”

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

“…These data sets compared primary cultured human bone marrow-derived MSC versus in vitro differentiated osteoblasts (OB) differentiated with dexamethasone 100 nM (Dex) and 10 mM b-glycerophosphate and with the addition of 50 mg/mL ascorbic acid for 28 days (GSE9451 [27]; [26]) or 50 nM ascorbic acid for 16 days (GSE27900 [28]). GSE9451 data set contained three independent MSC lines.…”

“…ChIP-on-chip data for genes bound by EZH2 in undifferentiated MSC and not bound by EZH2 in OB were obtained from Wei et al [26]. H3K27me3 and H3K4me3 ChIP-Seq data were obtained from GEO (Gene Expression Omnibus, www.ncbi.nlm.nih.gov.geo/, NCBI; data set GSE35573) [28]. A list of all genes identified in either of these studies was generated to generate a results profile for each gene.…”

Targeting the epigenome in malignant pleural mesothelioma

“…This "DNA methylation paradox", recapitulates epigenomic states in normal germ cells, and provides the rationale for the development of epigenetic regimens that induce growth arrest/apoptosis via restoration of tumor suppressor gene expression (106)(107)(108), while simultaneously augmenting antitumor immunity by up-regulation of CTAs (79), induction of viral mimicry by de-repression of endogenous retroviruses (109,110), and modulation of the tumor microenvironment (111)(112)(113).…”