Abstract
BackgroundThe nuclear transcription factor estrogen receptor alpha (ER-alpha) is the target of several antiestrogen therapeutic agents for breast cancer. However, many ER-alpha positive patients do not respond to these treatments from the beginning, or stop responding after being treated for a period of time. Because of the association of gene transcription alteration and drug resistance and the emerging evidence on the role of DNA methylation on transcription regulation, understanding of these relationships can facilitate development of approaches to re-sensitize breast cancer cells to treatment by restoring DNA methylation patterns.MethodsWe constructed a hierarchical empirical Bayes model to investigate the simultaneous change of gene expression and promoter DNA methylation profiles among wild type (WT) and OHT/ICI resistant MCF7 breast cancer cell lines.ResultsWe found that compared with the WT cell lines, almost all of the genes in OHT or ICI resistant cell lines either do not show methylation change or hypomethylated. Moreover, the correlations between gene expression and methylation are quite heterogeneous across genes, suggesting the involvement of other factors in regulating transcription. Analysis of our results in combination with H3K4me2 data on OHT resistant cell lines suggests a clear interplay between DNA methylation and H3K4me2 in the regulation of gene expression. For hypomethylated genes with alteration of gene expression, most (~80%) are up-regulated, consistent with current view on the relationship between promoter methylation and gene expression.ConclusionsWe developed an empirical Bayes model to study the association between DNA methylation in the promoter region and gene expression. Our approach generates both global (across all genes) and local (individual gene) views of the interplay. It provides important insight on future effort to develop therapeutic agent to re-sensitize breast cancer cells to treatment.
Highlights
The nuclear transcription factor estrogen receptor alpha (ER-alpha) is the target of several antiestrogen therapeutic agents for breast cancer
The distribution of CpG dinucleotides in the genome is highly asymmetric with a high concentration of DNA segments 200bp to several kb in length called “CpG islands”, residing in the promoter region and first exon for approximately 60% of genes [6]
Since we are interested in the correlation of the differentiation of gene expression and DNA methylation, we focus on the posterior distribution of ( GEi, Mi )t = ( i2 − i1, i2 − i1)t, (9)
Summary
The nuclear transcription factor estrogen receptor alpha (ER-alpha) is the target of several antiestrogen therapeutic agents for breast cancer. Because of the association of gene transcription alteration and drug resistance and the emerging evidence on the role of DNA methylation on transcription regulation, understanding of these relationships can facilitate development of approaches to re-sensitize breast cancer cells to treatment by restoring DNA methylation patterns. The term epigenetics in general refers to heritable pattern of gene expression that is mechanistically regulated through processes other than alteration in the primary DNA sequences [1,2]. DNA methylation is mostly common on cytosines that precede a guanosine (the CpG dinucleotide). The distribution of CpG dinucleotides in the genome is highly asymmetric with a high concentration of DNA segments 200bp to several kb in length called “CpG islands”, residing in the promoter region and first exon for approximately 60% of genes [6]. While the relationship between CpG island methylation and gene silencing is well established, the mechanisms underlying this phenomena are less clear but thought to include physical blocking of transcription factor binding [9,10] and/or recruitment of transcriptional repressors to the methylated sites [11]
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