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

TLDR

DNA‑hypermethylated genes in cancer are frequently marked by Polycomb in embryonic stem cells, and bivalent chromatin confers a poised transcriptional state that supports stemness, yet the prevalence of this phenomenon across cancers remains unclear. Genome‑wide analysis shows that about 75 % of hypermethylated genes are Polycomb‑marked bivalent chromatin in embryonic and adult stem cells, many of which are developmental regulators forming a DNA hypermethylation module that is down‑regulated in cancer and whose methylation patterns can cluster colon and breast cancer subtypes, suggesting that selective hypermethylation of PcG targets contributes to a stem‑like state and offers a potential biomarker for tumor phenotyping and therapeutic targeting.

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.