Aberrant silencing of cancer-related genes by CpG hypermethylation occurs independently of their spatial organization in the nucleus

Hariharan P. Easwaran, Leander Van Neste, Leslie Cope, Subhojit Sen, Helai P. Mohammad, Gayle J. Pageau, Jeanne B. Lawrence, James G. Herman, Kornel E. Schuebel, Stephen B. Baylin

Research output: Contribution to journalArticlepeer-review

Abstract

Aberrant promoter DNA-hypermethylation and repressive chromatin constitutes a frequent mechanism of gene inactivation in cancer. There is great interest in dissecting the mechanisms underlying this abnormal silencing. Studies have shown changes in the nuclear organization of chromatin in tumor cells as well as the association of aberrant methylation with long-range silencing of neighboring genes. Furthermore, certain tumors show a high incidence of promoter methylation termed as the CpG island methylator phenotype. Here, we have analyzed the role of nuclear chromatin architecture for genes in hypermethylated inactive versus nonmethylated active states and its relation with long-range silencing and CpG island methylator phenotype. Using combined immunostaining for active/repressive chromatin marks and fluorescence in situ hybridization in colorectal cancer cell lines, we show that aberrant silencing of these genes occurs without requirement for their being positioned at heterochromatic domains. Importantly, hypermethylation, even when associated with long-range epigenetic silencing of neighboring genes, occurs independent of their euchromatic or heterochromatic location. Together, these results indicate that, in cancer, extensive changes around promoter chromatin of individual genes or gene clusters could potentially occur locally without preference for nuclear position and/or causing repositioning. These findings have important implications for understanding relationships between nuclear organization and gene expression patterns in cancer.

Original languageEnglish (US)
Pages (from-to)8015-8024
Number of pages10
JournalCancer Research
Volume70
Issue number20
DOIs
StatePublished - Oct 15 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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