Abstract
BackgroundAbnormal DNA methylation is observed as an early event in breast carcinogenesis. However, how such alterations arise is still poorly understood. microRNAs (miRNAs) regulate gene expression at the post-transcriptional level and play key roles in various biological processes. Here, we integrate miRNA expression and DNA methylation at CpGs to study how miRNAs may affect the breast cancer methylome and how DNA methylation may regulate miRNA expression.MethodsmiRNA expression and DNA methylation data from two breast cancer cohorts, Oslo2 (n = 297) and The Cancer Genome Atlas (n = 439), were integrated through a correlation approach that we term miRNA-methylation Quantitative Trait Loci (mimQTL) analysis. Hierarchical clustering was used to identify clusters of miRNAs and CpGs that were further characterized through analysis of mRNA/protein expression, clinicopathological features, in silico deconvolution, chromatin state and accessibility, transcription factor binding, and long-range interaction data.ResultsClustering of the significant mimQTLs identified distinct groups of miRNAs and CpGs that reflect important biological processes associated with breast cancer pathogenesis. Notably, two major miRNA clusters were related to immune or fibroblast infiltration, hence identifying miRNAs associated with cells of the tumor microenvironment, while another large cluster was related to estrogen receptor (ER) signaling. Studying the chromatin landscape surrounding CpGs associated with the estrogen signaling cluster, we found that miRNAs from this cluster are likely to be regulated through DNA methylation of enhancers bound by FOXA1, GATA2, and ER-alpha. Further, at the hub of the estrogen cluster, we identified hsa-miR-29c-5p as negatively correlated with the mRNA and protein expression of DNA methyltransferase DNMT3A, a key enzyme regulating DNA methylation. We found deregulation of hsa-miR-29c-5p already present in pre-invasive breast lesions and postulate that hsa-miR-29c-5p may trigger early event abnormal DNA methylation in ER-positive breast cancer.ConclusionsWe describe how miRNA expression and DNA methylation interact and associate with distinct breast cancer phenotypes.
Highlights
Abnormal DNA methylation is observed as an early event in breast carcinogenesis
We identified 89,118 significant correlations with the same sign in both cohorts, pointing to consistent associations between miRNA expression and DNA methylation (Additional file 2), hereafter referred to as miRNA-methylation Quantitative Trait Loci
We identified hsa-miR-29c-5p as a potential epigenetic hub in estrogen receptor (ER)-positive breast cancer as it was the miRNA in cluster C with most CpG associations, positively correlated with the Global methylation alteration (GMA) score, upregulated in ER-positive tumors compared to both ER-negative tumors and normal breast tissue, in silico predicted to target DNMT3A and negatively correlated to DNMT3A messenger RNA (mRNA) and protein levels
Summary
Abnormal DNA methylation is observed as an early event in breast carcinogenesis. how such alterations arise is still poorly understood. microRNAs (miRNAs) regulate gene expression at the posttranscriptional level and play key roles in various biological processes. It is essential to understand the crosstalk between the genome and the epigenome and its role in defining tumor phenotypes Key enzymes, such as DNA methyltransferases (DNMTs) and ten-eleven translocation enzymes (TETs), regulate the DNA methylation machinery, and alterations of their expressions have been described in cancers with serious consequences in terms of cancer cell phenotype [5, 6]. How such enzymes may be early deregulated during carcinogenesis is still unclear
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