Aberrant Silencing of Cancer-Related Genes by CpG Hypermethylation Occurs Independently of Their Spatial Organization in the Nucleus

作者：Easwaran Hariharan P; van Neste Leander; Cope Leslie; Sen Subhojit; Mohammad Helai P; Pageau Gayle J; Lawrence Jeanne B; Herman James G; Schuebel Kornel E; Baylin Stephen B^*

来源：Cancer Research, 2010, 70(20): 8015-8024.

DOI：10.1158/0008-5472.CAN-10-0765

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. Cancer Res; 70( 20); 8015-24.

• 出版日期2010-10-15