Aberrant silencing of cancer-related genes by CpG hypermethylation occurs independently of their spatial organization in the nucleus
AuthorsEaswaran, Hariharan P.
Van Neste, Leander
Mohammad, Helai P.
Pageau, Gayle Jeannette
Lawrence, Jeanne B.
Herman, James G.
Schuebel, Kornel E.
Baylin, Stephen B.
UMass Chan AffiliationsDepartment of Cell Biology
Document TypeJournal Article
KeywordsAdaptor Proteins, Signal Transducing
Cell Line, Tumor
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genome-Wide Association Study
In Situ Hybridization
In Situ Hybridization, Fluorescence
Intercellular Adhesion Molecule-1
Reverse Transcriptase Polymerase Chain Reaction
MetadataShow full item record
AbstractAberrant 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.
SourceCancer Res. 2010 Oct 15;70(20):8015-24. Epub 2010 Aug 24. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/36035
Related ResourcesLink to Article in PubMed