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  • Transcriptional gene silencing using small RNAs. 19495692

    RNA interference is a potent gene silencing pathway initiated by short molecules of double-stranded RNA. Small interfering RNAs (siRNAs) with full sequence complementarity to mRNAs induce cleavage of their target transcripts in the cytoplasm. Recent evidence has shown, however, that siRNAs can also function in the nucleus of mammalian cells to affect changes in chromatin structure. When targeted to promoter regions, siRNAs load into the effector protein Argonaute-1 (AGO1) and direct the formation of silent chromatin domains. This mechanism is known as transcriptional gene silencing (TGS), and the development of TGS as a novel therapeutic modality would be applicable to chronic diseases where long-term, heritable silencing of target genes is warranted. Here we discuss how small RNAs can be used to direct TGS in mammalian cells.
    Document Type:
    Reference
    Product Catalog Number:
    07-599

  • Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. 21423189

    To realize the therapeutic potential of RNA drugs, efficient, tissue-specific and nonimmunogenic delivery technologies must be developed. Here we show that exosomes-endogenous nano-vesicles that transport RNAs and proteins-can deliver short interfering (si)RNA to the brain in mice. To reduce immunogenicity, we used self-derived dendritic cells for exosome production. Targeting was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide. Purified exosomes were loaded with exogenous siRNA by electroporation. Intravenously injected RVG-targeted exosomes delivered GAPDH siRNA specifically to neurons, microglia, oligodendrocytes in the brain, resulting in a specific gene knockdown. Pre-exposure to RVG exosomes did not attenuate knockdown, and non-specific uptake in other tissues was not observed. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated by the strong mRNA (60%) and protein (62%) knockdown of BACE1, a therapeutic target in Alzheimer's disease, in wild-type mice.
    Document Type:
    Reference
    Product Catalog Number:
    07-599

  • CRM1 mediates nuclear-cytoplasmic shuttling of mature microRNAs. 19955415

    Drosha-processed microRNAs (miRNAs) have been shown to be exported from the nucleus to the cytoplasm by Exportin 5, where they are processed a second time to generate mature miRNAs. In this work we show that miRNAs also use CRM1 for nuclear-cytoplasmic shuttling. Inhibition of CRM1 by Leptomycin B results in nuclear accumulation of miRNA guide sequences. Nuclear to cytoplasmic transport can be actively competed by synthetic small interfering RNAs, indicating that this pathway is shared by different classes of processed small RNAs. We also find that CRM1 coimmunoprecipitates with Ago-1, Ago-2, Topo2alpha, EzH2, and Mta, consistent with a role of Argonautes and small RNAs in chromatin remodeling.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple