Dataset Information

RegQTLs: Single nucleotide polymorphisms that modulate microRNA regulation of gene expression in tumors.

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.

SUBMITTER: Wilk G

PROVIDER: S-EPMC6343932 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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regQTLs: Single nucleotide polymorphisms that modulate microRNA regulation of gene expression in tumors.

Wilk Gary G Braun Rosemary R

PLoS genetics 20181217 12

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 n ...[more]

PMID: 30557297

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Project description:We previously showed that prototype macaque-tropic human immunodeficiency virus type 1 (HIV-1) acquired nonsynonymous growth-enhancing mutations within a narrow genomic region during the adaptation process in macaque cells. These adaptive mutations were clustered in the 3' region of the pol gene, encoding a small portion of the C-terminal domain of integrase (IN). Mutations in HIV-1 IN have been reported to have pleiotropic effects on both the early and late phases in viral replication. cis-acting functions in the IN-coding sequence for viral gene expression have also been reported. We here demonstrated that the adaptive mutations promoted viral growth by increasing virion production with no positive effects on the early replication phase. Synonymous codon alterations in one of the adaptive mutations influenced virion production levels, which suggested nucleotide-dependent regulation. Indeed, when the single-nucleotide natural polymorphisms observed in the 3' regions of 196 HIV-1/simian immunodeficiency virus (SIVcpz) pol genes (nucleotides [nt] 4895 to 4929 for HIV-1 NL4-3) were introduced into macaque- and human-tropic HIV-1 clones, more than half exhibited altered replication potentials. Moreover, single-nucleotide mutations caused parallel increases or decreases in the expression levels of viral late proteins and viral replication potentials. We also showed that the overall expression profiles of viral mRNAs were markedly changed by single-nucleotide mutations. These results demonstrate that the 3' region of the HIV-1 pol gene (nt 4895 to 4929) can alter viral replication potential by modulating the expression pattern of viral mRNAs in a nucleotide-dependent manner.Viruses have the plasticity to adapt themselves under various constraints. HIV-1 can mutate and evolve in growth-restrictive cells by acquiring adaptive changes in its genome. We have previously identified some growth-enhancing mutations in a narrow region of the IN-coding sequence, in which a number of cis-acting elements are located. We now focus on the virological significance of this pol gene region and the mechanistic basis underlying its effects on viral replication. We have found several naturally occurring synonymous mutations within this region that alter viral replication potentials. The effects caused by these natural single-nucleotide polymorphisms are linked to the definite expression patterns of viral mRNAs. We show here that the nucleotide sequence of the pol gene (nucleotides 4895 to 4929 for HIV-1 NL4-3) plays an important role in HIV-1 replication by modulating viral gene expression.

Dataset Information

RegQTLs: Single nucleotide polymorphisms that modulate microRNA regulation of gene expression in tumors.

Publications

regQTLs: Single nucleotide polymorphisms that modulate microRNA regulation of gene expression in tumors.

Similar Datasets

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