Abstract
BackgroundPost-transcriptional regulation by microRNAs is recognized as one of the major pathways for the control of cellular homeostasis. Less well understood is the transcriptional and epigenetic regulation of genes encoding microRNAs. In the present study we addressed the epigenetic regulation of the miR-181c in normal and malignant brain cells.MethodsTo explore the epigenetic regulation of the miR-181c we evaluated its expression using RT-qPCR and the in vivo binding of the CCCTC-binding factor (CTCF) to its regulatory region in different glioblastoma cell lines. DNA methylation survey, chromatin immunoprecipitation and RNA interference assays were used to assess the role of CTCF in the miR-181c epigenetic silencing.ResultsWe found that miR-181c is downregulated in glioblastoma cell lines, as compared to normal brain tissues. Loss of expression correlated with a notorious gain of DNA methylation at the miR-181c promoter region and the dissociation of the multifunctional nuclear factor CTCF. Taking advantage of the genomic distribution of CTCF in different cell types we propose that CTCF has a local and cell type specific regulatory role over the miR-181c and not an architectural one through chromatin loop formation. This is supported by the depletion of CTCF in glioblastoma cells affecting the expression levels of NOTCH2 as a target of miR-181c.ConclusionTogether, our results point to the epigenetic role of CTCF in the regulation of microRNAs implicated in tumorigenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2273-6) contains supplementary material, which is available to authorized users.
Highlights
Post-transcriptional regulation by microRNAs is recognized as one of the major pathways for the control of cellular homeostasis
Differential expression of miR-181c in brain and human glioblastoma cells The human miR-181c is frequently downregulated in Glioblastoma Multiforme (GBM) and its downregulation has been linked to tumour progression [33]
ChIPseq data shows that CCCTC-binding factor (CTCF) binds the promoter region (Fig. 1a)
Summary
Post-transcriptional regulation by microRNAs is recognized as one of the major pathways for the control of cellular homeostasis. MicroRNAs exert their regulatory effect post-transcriptionally by inducing RNA degradation or translation inhibition, and their expression can be deregulated in cancer by genetic and epigenetic mechanisms [2,3,4]. MicroRNAs like miR-101, miR-205 and miR-26a regulate chromatin modifiers in cancer such as the Polycomb associated. DNA methylation can regulate microRNAs gene expression in cancer [8]. Repression of gene expression by DNA methylation of promoter associated CpG islands has been reported for several microRNAs in glioblastoma cells like miR-211, miR-204, miR-145, miR-137 among others [9,10,11,12]. MiR-145 was shown to be downregulated in glioblastoma cells and low expression of miR-145 was found to
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