New class of microRNA targets containing simultaneous 5′-UTR and 3′-UTR interaction sites

Abstract

MicroRNAs (miRNAs) are known to post-transcriptionally regulate target mRNAs through the 39-UTR, which interacts mainly with the 59-end of miRNA in animals. Here we identify many endogenous motifs within human 59-UTRs specific to the 39-ends of miRNAs. The 39-end of conserved miRNAs in particular has significant interaction sites in the humanenriched, less conserved 59-UTR miRNA motifs, while human-specific miRNAs have significant interaction sites only in the conserved 59-UTR motifs, implying both miRNA and 59-UTR are actively evolving in response to each other. Additionally, many miRNAs with their 39-end interaction sites in the 59-UTRs turn out to simultaneously contain 59-end interaction sites in the 39-UTRs. Based on these findings we demonstrate combinatory interactions between a single miRNA and both end regions of an mRNA using model systems. We further show that genes exhibiting large-scale protein changes due to miRNA overexpression or deletion contain both UTR interaction sites predicted. We provide the predicted targets of this new miRNA target class, miBridge, as an efficient way to screen potential targets, especially for nonconserved miRNAs, since the target search space is reduced by an order of magnitude compared with the 39-UTR alone. Efficacy is confirmed by showing SEC24D regulation with hsa-miR-605, a miRNA identified only in primate, opening the door to the study of nonconserved miRNAs. Finally, miRNAs (and associated proteins) involved in this new targeting class may prevent 40S ribosome scanning through the 59-UTR and keep it from reaching the start-codon, preventing 60S association.

MicroRNAs and post-transcriptional regulation of skeletal development

“…Nevertheless, there is usually an imperfect complementarity, and the final effect of miRNA activity is a decrease in protein expression due to translational suppression. Interestingly, miRNAs have also been found to target the 5 0 -UTRs of mRNAs (Lytle et al 2007, Lee et al 2009) and to induce target translation (Vasudevan et al 2007).…”

miR-20b, miR-98, miR-125b-1*, and let-7e* as new potential diagnostic biomarkers in ulcerative colitis

“…It is generally believed that the mature miRNA then incorporates into the RNA-induced silencing complex, and guides this complex to the 3'-untranslated region (3'-UTR) of specific target mRNA transcripts to suppress translation or induce their degradation [1,2,[10][11][12][13] . However, miRNAbinding sites in coding regions as well as in the 5'-UTRs have also been reported [14][15][16][17][18][19] .…”

microRNA-17 regulates the expression of ATG7 and modulates the autophagy process, improving the sensitivity to temozolomide and low-dose ionizing radiation treatments in human glioblastoma cells

“…11 However, several evidences indicate that they act also on different mRNA regions and different cellular compartments, including nucleus, either enhancing or suppressing gene expression. [12][13][14][15] Recently, an increasing number of miRNAs are being characterized to modulate the expression of ATG genes and their regulators at different autophagic stages: induction, vesicle nucleation, elongation, and completion. 16,17 Nonetheless, despite recent advances in understanding miRNA regulation of the autophagy process, several gaps remain.…”