Abstract
Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with trait diversity and disease susceptibility, yet their functional properties often remain unclear. It has been hypothesized that SNPs in microRNA binding sites may disrupt gene regulation by microRNAs (miRNAs), short non-coding RNAs that bind to mRNA and downregulate the target gene. While several studies have predicted the location of SNPs in miRNA binding sites, to date there has been no comprehensive analysis of their impact on miRNA regulation. Here we investigate the functional properties of genetic variants and their effects on miRNA regulation of gene expression in cancer. Our analysis is motivated by the hypothesis that distinct alleles may cause differential binding (from miRNAs to mRNAs or from transcription factors to DNA) and change the expression of genes. We previously identified pathways—systems of genes conferring specific cell functions—that are dysregulated by miRNAs in cancer, by comparing miRNA–pathway associations between healthy and tumor tissue. We draw on these results as a starting point to assess whether SNPs on dysregulated pathways are responsible for miRNA dysregulation of individual genes in tumors. Using an integrative regression analysis that incorporates miRNA expression, mRNA expression, and SNP genotype data, we identify functional SNPs that we term “regulatory QTLs (regQTLs)”: loci whose alleles impact the regulation of genes by miRNAs. We apply the method to breast, liver, lung, and prostate cancer data from The Cancer Genome Atlas, and provide a tool to explore the findings.
Highlights
MicroRNAs are small noncoding RNA molecules that modulate gene expression post-transcriptionally by means of complementary base pairing with mRNA transcripts
We identify regulatory QTLs (regQTLs), genomic variants that influence miRNA regulation of gene expression, by integrating genomic and expression data from The Cancer Genome Atlas (TCGA) data
We test whether different alleles at a single nucleotide polymorphisms (SNPs) locus within a given gene alter how a miRNA modulates the expression of that gene across TCGA tumor samples. regQTLs may provide context to gene regulation in cancer, due to genetic diversity or genetic alterations
Summary
MicroRNAs (miRNAs) are small noncoding RNA molecules that modulate gene expression post-transcriptionally by means of complementary base pairing with mRNA transcripts. Regions flanking the “seed region” of the miRNA typically bind the mRNA, creating a stronger annealing between the two RNA molecules This results in the transcript being prevented from being translated into protein or degraded in the cell [1]. Because these molecular interactions are executed through base pairing, they can be influenced by genetic variation; changes in genome sequence may influence binding energy and the strength of annealing, or may even abrogate miRNA target sites entirely [2]. Polymorphisms in miRNA and target site sequences have been implicated in aberrant miRNA-mRNA interactions and have been associated with multiple cancers [5,6,7], suggesting a link between genetic variation, miRNA regulation, and disease. Several studies [2, 5] have suggested that polymorphisms within miRNA regulatory networks affect clinical outcomes and treatment responses
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