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Genome-wide methylation and expression profiling identifies promoter characteristics affecting demethylation-induced gene up-regulation in melanoma.
- Source :
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BMC medical genomics [BMC Med Genomics] 2010 Feb 09; Vol. 3, pp. 4. Date of Electronic Publication: 2010 Feb 09. - Publication Year :
- 2010
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Abstract
- Background: 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.<br />Methods: 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.<br />Results: 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.<br />Conclusions: 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.
- Subjects :
- Aged
Azacitidine pharmacology
Cell Line, Tumor
CpG Islands drug effects
DNA Modification Methylases antagonists & inhibitors
Decitabine
Epigenesis, Genetic
Female
Genome, Human
Humans
Male
Middle Aged
Promoter Regions, Genetic
Tumor Suppressor Proteins genetics
Tumor Suppressor Proteins metabolism
Up-Regulation
Antimetabolites, Antineoplastic pharmacology
Azacitidine analogs & derivatives
DNA Methylation drug effects
Enzyme Inhibitors pharmacology
Gene Expression Profiling
Melanoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1755-8794
- Volume :
- 3
- Database :
- MEDLINE
- Journal :
- BMC medical genomics
- Publication Type :
- Academic Journal
- Accession number :
- 20144234
- Full Text :
- https://doi.org/10.1186/1755-8794-3-4