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

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

doi:10.1007/s00018-017-2656-0

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 journal › Review article › peer-review

68 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	797-814
Number of pages	18
Journal	Cellular and Molecular Life Sciences
Volume	75
Issue number	5
DOIs	https://doi.org/10.1007/s00018-017-2656-0
Publication status	Published - 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.

Keywords

Abasic pivot
Ago HITS-CLIP
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

Access to Document

10.1007/s00018-017-2656-0

Cite this

@article{f912dad513174a3dab87dbead62886e2,

title = "Evaluation and control of miRNA-like off-target repression for RNA interference",

abstract = "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.",

keywords = "Abasic pivot, Ago HITS-CLIP, Chemical modification, Noncanonical target sites, Off-target effects, RNA-Seq, RNAi therapeutics, Ribo-Seq, miRNA seed sites",

author = "Heeyoung Seok and Haejeong Lee and Jang, {Eun Sook} and Chi, {Sung Wook}",

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: {\textcopyright} 2017, Springer International Publishing AG.",

year = "2018",

month = mar,

day = "1",

doi = "10.1007/s00018-017-2656-0",

language = "English",

volume = "75",

pages = "797--814",

journal = "Cellular and Molecular Life Sciences",

issn = "1420-682X",

publisher = "Birkhauser Verlag Basel",

number = "5",

}

TY - JOUR

T1 - Evaluation and control of miRNA-like off-target repression for RNA interference

AU - Seok, Heeyoung

AU - Lee, Haejeong

AU - Jang, Eun Sook

AU - Chi, Sung Wook

N1 - 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.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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.

KW - Abasic pivot

KW - Ago HITS-CLIP

KW - Chemical modification

KW - Noncanonical target sites

KW - Off-target effects

KW - RNA-Seq

KW - RNAi therapeutics

KW - Ribo-Seq

KW - miRNA seed sites

UR - http://www.scopus.com/inward/record.url?scp=85029428006&partnerID=8YFLogxK

U2 - 10.1007/s00018-017-2656-0

DO - 10.1007/s00018-017-2656-0

M3 - Review article

C2 - 28905147

AN - SCOPUS:85029428006

SN - 1420-682X

VL - 75

SP - 797

EP - 814

JO - Cellular and Molecular Life Sciences

JF - Cellular and Molecular Life Sciences

IS - 5

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this