Genome-wide methylation and expression profiling identifies promoter characteristics affecting demethylation-induced gene up-regulation in melanoma. Rubinstein, J. C, Tran, N., Ma, S., Halaban, R., & Krauthammer, M. BMC medical genomics, 3:4, feb, 2010.
doi  abstract   bibtex   
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. 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. 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. 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.
@article{Rubinstein2010,
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. 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. 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. 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.},
author = {Rubinstein, Jill C and Tran, Nam and Ma, Shuangge and Halaban, Ruth and Krauthammer, Michael},
doi = {10.1186/1755-8794-3-4},
issn = {1755-8794 (Electronic)},
journal = {BMC medical genomics},
keywords = {Aged,Antimetabolites, Antineoplastic,Azacitidine,Cell Line, Tumor,CpG Islands,DNA Methylation,DNA Modification Methylases,Decitabine,Enzyme Inhibitors,Epigenesis, Genetic,Female,Gene Expression Profiling,Genome, Human,Humans,Male,Melanoma,Middle Aged,Promoter Regions, Genetic,Tumor Suppressor Proteins,Up-Regulation,analogs {\&} derivatives,antagonists {\&} inhibitors,drug effects,genetics,metabolism,pharmacology},
language = {eng},
month = {feb},
pages = {4},
pmid = {20144234},
title = {{Genome-wide methylation and expression profiling identifies promoter characteristics affecting demethylation-induced gene up-regulation in melanoma.}},
volume = {3},
year = {2010}
}

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