title: Nuclear RNAi contributes to the silencing of off-target genes and repetitive sequences in Caenorhabditis elegans.
abstract: Small RNAs recognize, bind, and regulate other complementary cellular RNAs. The introduction of small RNAs to eukaryotic cells frequently results in unintended silencing of related, but not identical, RNAs: a process termed off-target gene silencing. Off-target gene silencing is one of the major concerns during the application of small RNA-based technologies for gene discovery and the treatment of human disease. Off-target gene silencing is commonly thought to be due to inherent biochemical limitations of the RNAi machinery. Here we show that following the introduction of exogenous sources of double-stranded RNA, the nuclear RNAi pathway, but not its cytoplasmic counterparts, is the primary source of off-target silencing in Caenorhabditis elegans. In addition, we show that during the normal course of growth and development the nuclear RNAi pathway regulates repetitive gene families. Therefore, we speculate that RNAi off-target effects might not be "mistakes" but rather an intentional and genetically programmed aspect of small RNA-mediated gene silencing, which might allow small RNAs to silence rapidly evolving parasitic nucleic acids. Finally, reducing off-target effects by manipulating the nuclear RNAi pathway in vivo might improve the efficacy of small RNA-based technologies.
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, People's Republic of China.
authors.forename: Xufei
authors.initials: X
authors.lastname: Zhou
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.forename: Hui
authors.initials: H
authors.lastname: Mao
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Ji
authors.forename: Meng
authors.initials: M
authors.lastname: Yin
authors.forename: Xuezhu
authors.initials: X
authors.lastname: Feng
authors.forename: Shouhong
authors.initials: S
authors.lastname: Guang
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*
chemical_list: D029742:Caenorhabditis elegans Proteins; D034741:RNA, Small Interfering
keywords: Nrde; off target; repetitive sequence; silencing