MicroRNA-like off-target transcript regulation by siRNAs is species specific

siRNAs mediate sequence-specific gene silencing in cultured mammalian cells but also silence unintended transcripts. Many siRNA off-target transcripts match the guide-strand "seed region," similar to the way microRNAs match their target sites. The extent to which this seed-matched, microRN...

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Bibliographic Details
Published in:RNA (Cambridge) 2009-02, Vol.15 (2), p.308-315
Main Authors: Burchard, Julja, Jackson, Aimee L, Malkov, Vladislav, Needham, Rachel H V, Tan, Yejun, Bartz, Steven R, Dai, Hongyue, Sachs, Alan B, Linsley, Peter S
Format: Article
Language:English
Subjects:
3' Untranslated Regions - genetics
3' Untranslated Regions - metabolism
Animals
Apolipoproteins B - genetics
Cell Line, Tumor
Cells, Cultured
Gene Expression Profiling
Gene Silencing
Humans
Mice
MicroRNAs - genetics
MicroRNAs - metabolism
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
Selection, Genetic
Species Specificity
Transcription, Genetic
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Summary:siRNAs mediate sequence-specific gene silencing in cultured mammalian cells but also silence unintended transcripts. Many siRNA off-target transcripts match the guide-strand "seed region," similar to the way microRNAs match their target sites. The extent to which this seed-matched, microRNA-like, off-target silencing affects the specificity of therapeutic siRNAs in vivo is currently unknown. Here, we compare microRNA-like off-target regulations in mouse liver in vivo with those seen in cell culture for a series of therapeutic candidate siRNAs targeting Apolipoprotein B (APOB). Each siRNA triggered regulation of consistent microRNA-like off-target transcripts in mouse livers and in cultured mouse liver tumor cells. In contrast, there was only random overlap between microRNA-like off-target transcripts from cultured human and mouse liver tumor cells. Therefore, siRNA therapeutics may trigger microRNA-like silencing of many unintended targets in vivo, and the potential toxicities caused by these off-target gene regulations cannot be accurately assessed in rodent models.
ISSN:1355-8382
1469-9001
DOI:10.1261/rna.1326809