Abstract
BackgroundmicroRNAs (miRNAs) are believed to regulate their targets through posttranscriptional gene regulation and have the potential to silence gene expression via multiple mechanisms. Despite previous advances on miRNA regulation of gene expression, little has been investigated from a genome scale.ResultsTo gain new insight into miRNA regulation in humans, we used large scale data and carried out a series of studies to compare various features of miRNA target genes to that of non-miRNA target genes. We observed significant differences between miRNA and non-miRNA target genes for a number of characteristics, including higher and broader mRNA expression, faster mRNA decay rate, longer protein half-life, and longer gene structures. Based on these features and by analyzing their relationships we found that miRNA target genes, other than having miRNA repression, were most likely under more complex regulation than non-miRNA target genes, which was evidenced by their higher and broader gene expression but longer gene structures. Our results of higher and broader gene expression but fast mRNA decay rates also provide evidence that miRNA dampening of the output of preexisting transcripts facilitates a more rapid and robust transition to new expression programs. This could be achieved by enhancing mRNA degradation through an additive effect from multiple miRNA targeting.ConclusionGenome-scale analysis on the nature of miRNA target genes has revealed a general mechanism for miRNA regulation of human gene expression. The results of this study also indicate that miRNA target genes, other than having miRNA repression, are under more complex gene regulation than non-miRNA target genes. These findings provide novel insight into miRNA regulation of human gene expression.
Highlights
MicroRNAs are believed to regulate their targets through posttranscriptional gene regulation and have the potential to silence gene expression via multiple mechanisms
The higher and broader gene expression but fast mRNA decay rates suggests that miRNA dampening of the output of preexisting but unwanted transcripts to facilitate transition to new expression programs [32,33,34] is a general mechanism for miRNA regulation of human gene expression
The results indicate that miRNA target genes are significantly different from non-miRNA target genes as shown in Figure 1a, where the median expression signals from miRNA target genes derived from PicTar are significantly higher than those from (a) Expression intensity miRNA target gene Non−miRNA target gene p−value
Summary
MicroRNAs (miRNAs) are believed to regulate their targets through posttranscriptional gene regulation and have the potential to silence gene expression via multiple mechanisms. MiRNAs, which were first discovered in Caenorhabditis elegans as post-transcriptional regulators of genes involved in developmental timing [1,2], are small non-coding RNAs of ~23 nucleotides They are recognized as one of the major regulatory gene families, playing important roles in almost every cellular process in animals, plants and viruses [3,4,5]. Whereas miRNAs repress translation of target mRNAs by inhibiting translation initiation [12,13,14], blocking translation elongation [15,16], or promoting premature dissociation of ribosomes [16], they induce significant degradation of mRNA targets by mRNA deadenylation, decapping, and 5' → 3' exonucleolytic degradation The latter have been widely demonstrated from animal studies [17,18], cultured cells [19,20,21], and microarray analysis [19,20,22,23]. Contradicting these mechanisms, it has been recently discovered that miRNA have the potential to activate translation under certain conditions [24,25,26] and the ability to switch from translational repression to translational activation in cell-cycle-arrested cells [27,28,29]
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