Journal
RNA
Volume 19, Issue 2, Pages 280-293Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1261/rna.034850.112
Keywords
miRNA inhibition; Tough Decoy; TuD; lentiviral vectors
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Funding
- Lundbeck Foundation
- Novo Nordisk Foundation
- Danish Heart Foundation
- Kgl. Hofbuntmager Aage Bangs Fond
- Grosserer A. V. Lykfeldts Legat
- Agnes og Poul Friis Fond
- Aase og Ejnar Danielsens Fond
- Faculty of Health Sciences at Aarhus University
- Aarhus University
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MicroRNAs( miRNAs) are key regulators of gene expression and modulators of diverse biological pathways. Analyses of miRNA function as well as therapeutic managing of miRNAs rely on cellular administration of miRNA inhibitors which may be achieved by the use of viral vehicles. This study explores the miRNA-suppressive capacity of inhibitors expressed intracellularly from lentivirus-derived gene vectors. Superior activity of two decoy-type inhibitors, a Bulged Sponge with eight miRNA recognition sites and a hairpin-shaped Tough Decoy containing two miRNA recognition sites, is demonstrated in a side-by-side comparison of seven types of miRNA inhibitors transcribed as short RNAs from an RNA Pol III promoter. We find that lentiviral vectors expressing Tough Decoy inhibitors are less vulnerable than Bulged Sponge-encoding vectors to targeting by the cognate miRNA and less prone, therefore, to reductions in transfer efficiency. Importantly, it is demonstrated that Tough Decoy inhibitors retain their miRNA suppression capacity in the context of longer RNA transcripts expressed from an RNA Pol II promoter. Such RNA Pol II-transcribed Tough Decoy inhibitors are new tools in managing of miRNAs and may have potential for temporal and spatial regulation of miRNA activity as well as for therapeutic targeting of miRNAs that are aberrantly expressed in human disease.
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