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Research Paper
DNA Methylation-Dependent Epigenetic Regulation of Gene Expression in MCF-7 Breast Cancer Cells
Ashley G. Rivenbark, Wendell D. Jones, J. Devon Risher and William B. Coleman
volume 1 | issue 1
january/february/march 2006Pages: 32 - 44
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To identify epigenetically-regulated genes in breast cancer, MCF-7 cells were exposed to 250nM
5-aza or 5-aza + 50nM TSA for 3 weeks followed by a 5 week recovery period after treatment
withdrawal and gene expression patterns were examined by microarray analysis. We identified
20 genes that are associated with a >2-fold increase in expression in response to the
demethylating treatment but returned to control levels after treatment withdrawal. RT-PCR
verified that the genes identified were expressed at low or undetectable levels in control MCF-7
cells, but increased expression in treated cells. Most of these putative epigentically-regulated
genes in MCF-7 cells do not contain CpG islands. In fact, these genes could be classified based
upon their promoter CpG features, including genes with: (i) typical CpG features (CpG islands),
(ii) intermediate CpG features (weak CpG islands), and (iii) atypical CpG features (no CpG
islands). Prototype genes from each class (including CpG-deficient genes) were shown to be
methylation-sensitive (subject to CpG methylation and responsive to demethylating agents),
suggesting that not all gene targets of DNA methylation in breast cancer will contain a CpG
island. Based upon the results of the current study and observations from the literature, we
propose expansion of the current model for methylation-dependent regulation of gene expression
to include genes lacking typical CpG islands. The expanded model we propose recognizes that
all promoter CpG dinucleotides represent legitimate targets for DNA methylation and that the
methylation of specific CpG dinucleotides in critical domains of regulatory regions can result in
gene silencing.
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