Global gene expression profiling of mouse liver tissue samples after treated with various anti-HCV shRNAs
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE55131 | GEO | 2014/10/03
SECONDARY ACCESSION(S): PRJNA238589
REPOSITORIES: GEO
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Project description:RNA interference (RNAi) is becoming routine in scientific discovery and treating human disease. However, its applications are hampered by unwanted effects. The RNA-Seq analyses from mouse liver samples expressing various anti-HCV shRNAs show that weak base-pairing in both seed and 3’ regions is required to achieve minimal off-targeting effect. We created nine shRNAs against the HCV genome, and transfected shRNA-expressing plasmids into mouse liver via a hydrodynamic tail vein infusion. A plasmid backbone lacking the shRNA sequence was used as a negative control. After 7 days, mouse liver RNAs were harvested and subject to RNA-Seq analysis (two biological repeats).
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Project description:Short-hairpin RNA (shRNA)-induced RNAi is used for biological discovery and therapeutics. Dicer, whose normal role is to liberate endogenous miRNAs from their precursors, processes shRNAs into different biologically active siRNAs, affecting their efficacy and potential for off-targeting. We found that in cells, Dicer induced imprecise cleavage events around the expected sites based on the previously described 5'/3'-counting rules. These promiscuous non-canonical cleavages were abrogated when the cleavage site was positioned 2 nt from a bulge or loop. Interestingly, we observed that the ~1/3 of mammalian endogenous pre-miRNAs that contained such structures were more precisely processed by Dicer. Implementing a new "loop-counting rule", we designed potent anti-HCV shRNAs with substantially reduced off-target effects. Our results suggest that Dicer recognizes the loop/bulge structure in addition to the ends of shRNAs/pre-miRNAs for accurate processing. This has important implications for both miRNA processing and future design of shRNAs for RNAi-based genetic screens and therapies.
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