title: 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.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the Johns Hopkins Medical Institutions, Baltimore, MD 21117, USA.
authors.forename: Hariharan
authors.initials: H
authors.lastname: Easwaran
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Johnstone
authors.forename: Leander
authors.initials: L
authors.lastname: Van Neste
authors.forename: Joyce
authors.initials: J
authors.lastname: Ohm
authors.forename: Tim
authors.initials: T
authors.lastname: Mosbruger
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Wang
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Aryee
authors.forename: Patrick
authors.initials: P
authors.lastname: Joyce
authors.forename: Nita
authors.initials: N
authors.lastname: Ahuja
authors.forename: Dan
authors.initials: D
authors.lastname: Weisenberger
authors.forename: Eric
authors.initials: E
authors.lastname: Collisson
authors.forename: Jingchun
authors.initials: J
authors.lastname: Zhu
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Yegnasubramanian
authors.forename: William
authors.initials: W
authors.lastname: Matsui
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D005809:Genes, Regulator; D006657:Histones / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000378:metabolism; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D002843:Chromatin; D006657:Histones; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins