Evaluation and control of miRNA-like off-target repression for RNA interference

Heeyoung Seok, Haejeong Lee, Eun Sook Jang, Sung Wook Chi

Research output: Contribution to journalReview articlepeer-review

68 Citations (Scopus)


RNA interference (RNAi) has been widely adopted to repress specific gene expression and is easily achieved by designing small interfering RNAs (siRNAs) with perfect sequence complementarity to the intended target mRNAs. Although siRNAs direct Argonaute (Ago), a core component of the RNA-induced silencing complex (RISC), to recognize and silence target mRNAs, they also inevitably function as microRNAs (miRNAs) and suppress hundreds of off-targets. Such miRNA-like off-target repression is potentially detrimental, resulting in unwanted toxicity and phenotypes. Despite early recognition of the severity of miRNA-like off-target repression, this effect has often been overlooked because of difficulties in recognizing and avoiding off-targets. However, recent advances in genome-wide methods and knowledge of Ago–miRNA target interactions have set the stage for properly evaluating and controlling miRNA-like off-target repression. Here, we describe the intrinsic problems of miRNA-like off-target effects caused by canonical and noncanonical interactions. We particularly focus on various genome-wide approaches and chemical modifications for the evaluation and prevention of off-target repression to facilitate the use of RNAi with secured specificity.

Original languageEnglish
Pages (from-to)797-814
Number of pages18
JournalCellular and Molecular Life Sciences
Issue number5
Publication statusPublished - 2018 Mar 1

Bibliographical note

Funding Information:
Acknowledgements We apologize to researchers whose works were not cited in this review because of space limitations. This work was supported by a grant from Korea University to S.W.C, a grant from the Science Research Center Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning to S.W.C (NRF-2015R1A5A1009024), a grant from NRF funded by the Ministry of Science, ICT & Future Planning to H.S (NRF-2017R1D1A1B03030852), and a grant from NRF funded by the Ministry of Education to E.-S. J (NRF-2016R1A6A3A11931948).

Publisher Copyright:
© 2017, Springer International Publishing AG.


  • Abasic pivot
  • Chemical modification
  • Noncanonical target sites
  • Off-target effects
  • RNA-Seq
  • RNAi therapeutics
  • Ribo-Seq
  • miRNA seed sites

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology


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