Abstract
BackgroundMicroRNA (miRNA) target genes tend to have relatively long and conserved 3' untranslated regions (UTRs), but to what degree these characteristics contribute to miRNA targeting is poorly understood. Different high-throughput experiments have, for example, shown that miRNAs preferentially regulate genes with both short and long 3' UTRs and that target site conservation is both important and irrelevant for miRNA targeting.ResultsWe have analyzed several gene context-dependent features, including 3' UTR length, 3' UTR conservation, and messenger RNA (mRNA) expression levels, reported to have conflicting influence on miRNA regulation. By taking into account confounding factors such as technology-dependent experimental bias and competition between transfected and endogenous miRNAs, we show that two factors - target gene expression and competition - could explain most of the previously reported experimental differences. Moreover, we find that these and other target site-independent features explain about the same amount of variation in target gene expression as the target site-dependent features included in the TargetScan model.ConclusionsOur results show that it is important to consider confounding factors when interpreting miRNA high throughput experiments and urge special caution when using microarray data to compare average regulatory effects between groups of genes that have different average gene expression levels.
Highlights
MicroRNA target genes tend to have relatively long and conserved 3’ untranslated regions (UTRs), but to what degree these characteristics contribute to miRNA targeting is poorly understood
We found that two features - the competition effect between endogenous miRNAs and transfected miRNAs, and messenger RNA (mRNA) expression level - have a strong impact on results from high throughput experiments
Target mRNA features: ectopic miRNA expression differentially affects subgroups of genes with differing 3’ UTR length, 3’ UTR conservation, and mRNA expression level As we expected that mRNAs targeted by miRNA have long and conserved 3’ UTRs, we wanted to examine how these characteristics affect miRNA regulation
Summary
MicroRNA (miRNA) target genes tend to have relatively long and conserved 3’ untranslated regions (UTRs), but to what degree these characteristics contribute to miRNA targeting is poorly understood. Different high-throughput experiments have, for example, shown that miRNAs preferentially regulate genes with both short and long 3’ UTRs and that target site conservation is both important and irrelevant for miRNA targeting. Results: We have analyzed several gene context-dependent features, including 3’ UTR length, 3’ UTR conservation, and messenger RNA (mRNA) expression levels, reported to have conflicting influence on miRNA regulation. In addition to 3’ UTR length and conservation, several other gene characteristics affect miRNA regulation. Many miRNAs are known to regulate genes involved in cell development processes [3]. Another example is that miRNAs appear to preferentially target genes with high CpG promoters [14]. As highly expressed genes transcribe a large number of mRNAs, the miRNA regulation of those mRNAs can be different from those of weakly expressed genes, current analyses disagree on whether miRNAs affect highly expressed genes more or less than medium or lowly expressed genes [15,16]
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