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- W577293753 abstract "RNA interference (RNAi) technology using short hairpin RNAs (shRNAs) expressed via RNA polymerase (pol) III promoters has been widely exploited to modulate gene expression in a variety of mammalian cell types. For certain applications, such as lineage-specific knockdown, embedding targeting sequences into pol II-driven microRNA (miRNA) architecture is required. Here, using the potential therapeutic target BCL11A, we demonstrate that pol III-driven shRNAs lead to significantly increased knockdown but also increased cytotoxcity in comparison to pol II-driven miRNA adapted shRNAs (shRNA(miR)) in multiple hematopoietic cell lines. We show that the two expression systems yield mature guide strand sequences that differ by a 4 bp shift. This results in alternate seed sequences and consequently influences the efficacy of target gene knockdown. Incorporating a corresponding 4 bp shift into the guide strand of shRNA(miR)s resulted in improved knockdown efficiency of BCL11A. This was associated with a significant de-repression of the hemoglobin target of BCL11A, human γ-globin or the murine homolog Hbb-y. Our results suggest the requirement for optimization of shRNA sequences upon incorporation into a miRNA backbone. These findings have important implications in future design of shRNA(miR)s for RNAi-based therapy in hemoglobinopathies and other diseases requiring lineage-specific expression of gene silencing sequences." @default.
- W577293753 created "2016-06-24" @default.
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- W577293753 date "2015-09-01" @default.
- W577293753 modified "2023-10-17" @default.
- W577293753 title "miRNA-embedded shRNAs for Lineage-specific BCL11A Knockdown and Hemoglobin F Induction" @default.
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- W577293753 doi "https://doi.org/10.1038/mt.2015.113" @default.
- W577293753 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4817887" @default.
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- W577293753 hasPublicationYear "2015" @default.
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