Abstract
DNA methylation of promoters is linked to transcriptional silencing of protein-coding genes, and its alteration plays important roles in cancer formation. For example, hypermethylation of tumor suppressor genes has been seen in some cancers. Alteration of methylation in the promoters of microRNAs (miRNAs) has also been linked to transcriptional changes in cancers; however, no systematic studies of methylation and transcription of miRNAs have been reported. In the present study, to clarify the relation between DNA methylation and transcription of miRNAs, next-generation sequencing and microarrays were used to analyze the methylation and expression of miRNAs, protein-coding genes, other non-coding RNAs (ncRNAs), and pseudogenes in the human breast cancer cell lines MCF7 and the adriamycin (ADR) resistant cell line MCF7/ADR. DNA methylation in the proximal promoter of miRNAs is tightly linked to transcriptional silencing, as it is with protein-coding genes. In protein-coding genes, highly expressed genes have CpG-rich proximal promoters whereas weakly expressed genes do not. This is only rarely observed in other gene categories, including miRNAs. The present study highlights the epigenetic similarities and differences between miRNA and protein-coding genes.
Highlights
DNA methylation plays important roles in development, differentiation, X inactivation, genomic imprinting, and silencing of transposable elements through the regulation of transcription [1,2,3]
DNA enriched by the methyl-CpG binding domain (MBD) domain of MBD1, using an Illumina sequencer
His-tagged fragment of MBD1 in bacteria. This fragment contains the critical MBD domain required for stable and selective binding to methyl-cytosine-phosphate-guanine dinucleotide (CpG) but no structural elements known to contribute to sequence-specific DNA binding [15]
Summary
DNA methylation plays important roles in development, differentiation, X inactivation, genomic imprinting, and silencing of transposable elements through the regulation of transcription [1,2,3]. The oldest technology for genome-wide analysis of DNA methylation, Restriction Landmark Genomic Scanning, which utilizes two-dimensional gel electrophoresis of genomic DNA, was developed in 1991 [9,10] This technology has been used in the cloning of many imprinted genes [10] and tumor suppressors [11,12]. Differentially methylated regions were found only in the CpG islands just upstream of miRNAs in most reports on the epigenetic silencing of miRNAs because such cases are discovered It has not been clarified whether the transcriptional start sites far upstream of miRNAs are influenced by DNA methylation or not. To clarify the relation between DNA methylation and transcription of miRNAs, here we systematically analyzed the methylation and expression of human genes encoding miRNAs, proteins, other non-coding RNAs (ncRNAs), and pseudogenes using next-generation sequencing and microarray analysis
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