Abstract
BackgroundMicroRNA (miRNA) are small non-coding RNA molecules which function as nucleic acid-based specificity factors in the universal RNA binding complex known as the RNA induced silencing complex (RISC). In the canonical gene-silencing pathway, these activated RISC particles are associated with RNA decay and gene suppression, however, there is evidence to suggest that in some circumstances they may also stabilise their target RNA and even enhance translation. To further explore the role of miRNA in this context, we performed a genome-wide expression analysis to investigate the molecular consequences of bidirectional modulation of the disease-associated miRNAs miR-181b and miR-107 in multiple human cell lines.ResultsThis data was subjected to pathways analysis and correlated against miRNA targets predicted through seed region homology. This revealed a large number of both conserved and non-conserved miRNA target genes, a selection of which were functionally validated through reporter gene assays. Contrary to expectation we also identified a significant proportion of predicted target genes with both conserved and non-conserved recognition elements that were positively correlated with the modulated miRNA. Finally, a large proportion of miR-181b associated genes devoid of the corresponding miRNA recognition element, were enriched with binding motifs for the E2F1 transcription factor, which is encoded by a miR-181b target gene.ConclusionsThese findings suggest that miRNA regulate target genes directly through interactions with both conserved and non-conserved target recognition elements, and can lead to both a decrease and increase in transcript abundance. They also multiply their influence through interaction with transcription factor genes exemplified by the observed miR-181b/E2F1 relationship.
Highlights
MicroRNA are small non-coding RNA molecules which function as nucleic acid-based specificity factors in the universal RNA binding complex known as the RNA induced silencing complex (RISC)
This revealed that a large proportion of target genes are not conserved and that many genes are modified by miRNA-associated secondary influence, exemplified by the relationship between miR-181b E2F transcription factor 1 (E2F1) transcription factor and genes with E2F1 motifs
The analysis of positively associated target genes suggested that a substantial proportion of miRNA associated mRNA are not destabilised and degraded
Summary
MicroRNA (miRNA) are small non-coding RNA molecules which function as nucleic acid-based specificity factors in the universal RNA binding complex known as the RNA induced silencing complex (RISC). MicroRNA (miRNA) encompass a highly conserved class of endogenous small non-coding RNA which function as the nucleic acid-based specificity factor in post-transcriptional gene silencing (PTGS) [1,2,3] In this process miRNA direct a ribonucleoprotein effector complex, known as the RISC, to complementary miRNA recognition elements (MREs) within the 30 untranslated region (30-UTR) of mRNA transcripts. An additional filter is often applied to the interpretation of expression data through the assumption that miRNA-mRNA interactions are associated with a reduction in target stability and steady state transcript levels While this relationship is supported at both the protein [11,12,13] and RNA [14,15,16] level, and more recently in experiments investigating both mRNA target levels and their translation [17], there may be alternative modalities for some RISC associated transcripts, beyond gene suppression, that could give rise to discrete functions during development, in highly specialized cells such as neurons. The existence of these competing endogenous RNA (ceRNA) and their influence on miRNA is supported in a number of recent studies [23,24,25,26]
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