Genome-wide methylation and expression profiling identifies promoter characteristics affecting demethylation-induced gene up-regulation in melanoma
<p>Abstract</p> <p>Background</p> <p>Abberant DNA methylation at CpG dinucleotides represents a common mechanism of transcriptional silencing in cancer. Since CpG methylation is a reversible event, tumor supressor genes that have undergone silencing through this mechani...
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| Main Authors: | , , , , |
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| Format: | Book |
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BMC,
2010-02-01T00:00:00Z.
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| Online Access: | Connect to this object online. |
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| Summary: | <p>Abstract</p> <p>Background</p> <p>Abberant DNA methylation at CpG dinucleotides represents a common mechanism of transcriptional silencing in cancer. Since CpG methylation is a reversible event, tumor supressor genes that have undergone silencing through this mechanism represent promising targets for epigenetically active anti-cancer therapy. The cytosine analog 5-aza-2'-deoxycytidine (decitabine) induces genomic hypomethylation by inhibiting DNA methyltransferase, and is an example of an epigenetic agent that is thought to act by up-regulating silenced genes.</p> <p>Methods</p> <p>It is unclear why decitabine causes some silenced loci to re-express, while others remain inactive. By applying data-mining techniques to large-scale datasets, we attempted to elucidate the qualities of promoter regions that define susceptibility to the drug's action. Our experimental data, derived from melanoma cell strains, consist of genome-wide gene expression data before and after treatment with decitabine, as well as genome-wide data on un-treated promoter methylation status, and validation of specific genes by bisulfite sequencing.</p> <p>Results</p> <p>We show that the combination of promoter CpG content and methylation level informs the ability of decitabine treatment to up-regulate gene expression. Promoters with high methylation levels and intermediate CpG content appear most susceptible to up-regulation by decitabine, whereas few of those highly methylated promoters with high CpG content are up-regulated. For promoters with low methylation levels, those with high CpG content are more likely to be up-regulated, whereas those with low CpG content are underrepresented among up-regulated genes.</p> <p>Conclusions</p> <p>Clinically, elucidating the patterns of action of decitabine could aid in predicting the likelihood of up-regulating epigenetically silenced tumor suppressor genes and others from pathways involved with tumor biology. As a first step toward an eventual translational application, we build a classifier to predict gene up-regulation based on promoter methylation and CpG content, which achieves a performance of 0.77 AUC.</p> |
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| Item Description: | 10.1186/1755-8794-3-4 1755-8794 |