Dataset Information

The impact of miRNA target sites in coding sequences and in 3'UTRs.

ABSTRACT: Animal miRNAs are a large class of small regulatory RNAs that are known to directly and negatively regulate the expression of a large fraction of all protein encoding genes. The identification and characterization of miRNA targets is thus a fundamental problem in biology. miRNAs regulate target genes by binding to 3' untranslated regions (3'UTRs) of target mRNAs, and multiple binding sites for the same miRNA in 3'UTRs can strongly enhance the degree of regulation. Recent experiments have demonstrated that a large fraction of miRNA binding sites reside in coding sequences. Overall, miRNA binding sites in coding regions were shown to mediate smaller regulation than 3'UTR binding. However, possible interactions between target sites in coding sequences and 3'UTRs have not been studied. Using transcriptomics and proteomics data of ten miRNA mis-expression experiments as well as transcriptome-wide experimentally identified miRNA target sites, we found that mRNA and protein expression of genes containing target sites both in coding regions and 3'UTRs were in general mildly but significantly more regulated than those containing target sites in 3'UTRs only. These effects were stronger for conserved target sites of length 7-8 nt in coding regions compared to non-conserved sites. Combined with our other finding that miRNA target sites in coding regions are under negative selection, our results shed light on the functional importance of miRNA targeting in coding regions.

SUBMITTER: Fang Z

PROVIDER: S-EPMC3062573 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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The impact of miRNA target sites in coding sequences and in 3'UTRs.

Fang Zhuo Z Rajewsky Nikolaus N

PloS one 20110322 3

Animal miRNAs are a large class of small regulatory RNAs that are known to directly and negatively regulate the expression of a large fraction of all protein encoding genes. The identification and characterization of miRNA targets is thus a fundamental problem in biology. miRNAs regulate target genes by binding to 3' untranslated regions (3'UTRs) of target mRNAs, and multiple binding sites for the same miRNA in 3'UTRs can strongly enhance the degree of regulation. Recent experiments have demonst ...[more]

PMID: 21445367

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Project description:Traditional mutation assessment methods generally focus on predicting disruptive changes in protein-coding regions rather than non-coding regulatory regions like untranslated regions (UTRs) of mRNAs. The UTRs, however, are known to have many sequence and structural motifs that can regulate translational and transcriptional efficiency and stability of mRNAs through interaction with RNA-binding proteins and other non-coding RNAs like microRNAs (miRNAs). In a recent study, transcriptomes of tumor cells harboring mutant and wild-type KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) genes in patients with non-small cell lung cancer (NSCLC) have been sequenced to identify single nucleotide variations (SNVs). About 40% of the total SNVs (73,717) identified were mapped to UTRs, but omitted in the previous analysis. To meet this obvious demand for analysis of the UTRs, we designed a comprehensive pipeline to predict the effect of SNVs on two major regulatory elements, secondary structure and miRNA target sites. Out of 29,290 SNVs in 6462 genes, we predict 472 SNVs (in 408 genes) affecting local RNA secondary structure, 490 SNVs (in 447 genes) affecting miRNA target sites and 48 that do both. Together these disruptive SNVs were present in 803 different genes, out of which 188 (23.4%) were previously known to be cancer-associated. Notably, this ratio is significantly higher (one-sided Fisher's exact test p-value = 0.032) than the ratio (20.8%) of known cancer-associated genes (n = 1347) in our initial data set (n = 6462). Network analysis shows that the genes harboring disruptive SNVs were involved in molecular mechanisms of cancer, and the signaling pathways of LPS-stimulated MAPK, IL-6, iNOS, EIF2 and mTOR. In conclusion, we have found hundreds of SNVs which are highly disruptive with respect to changes in the secondary structure and miRNA target sites within UTRs. These changes hold the potential to alter the expression of known cancer genes or genes linked to cancer-associated pathways.

Dataset Information

The impact of miRNA target sites in coding sequences and in 3'UTRs.

Publications

The impact of miRNA target sites in coding sequences and in 3'UTRs.

Similar Datasets

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