A small molecule enhances RNA interference and promotes microRNA processing

Ge Shan; Yujing Li; Junliang Zhang; Wendi Li; Keith E. Szulwach; Ranhui Duan; Mohammad A. Faghihi; Ahmad M. Khalil; Lianghua Lu; Zain Paroo; Anthony W S Chan; Zhangjie Shi; Qinghua Liu; Claes Wahlestedt; Chuan He; Peng Jin

doi:10.1038/nbt.1481

A small molecule enhances RNA interference and promotes microRNA processing

Ge Shan, Yujing Li, Junliang Zhang, Wendi Li, Keith E. Szulwach, Ranhui Duan, Mohammad A. Faghihi, Ahmad M. Khalil, Lianghua Lu, Zain Paroo, Anthony W S Chan, Zhangjie Shi, Qinghua Liu, Claes Wahlestedt, Chuan He, Peng Jin

Research output: Contribution to journal › Article › peer-review

214 Scopus citations

Abstract

Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are sequence-specific post-transcriptional regulators of gene expression. Although major components of the RNA interference (RNAi) pathway have been identified, regulatory mechanisms for this pathway remain largely unknown. Here we demonstrate that the RNAi pathway can be modulated intracellularly by small molecules. We have developed a cell-based assay to monitor the activity of the RNAi pathway and find that the small-molecule enoxacin (Penetrex) enhances siRNA-mediated mRNA degradation and promotes the biogenesis of endogenous miRNAs. We show that this RNAi-enhancing activity depends on the trans-activation-responsive region RNA-binding protein. Our results provide a proof-of-principle demonstration that small molecules can be used to modulate the activity of the RNAi pathway. RNAi enhancers may be useful in the development of research tools and therapeutics.

Original language	English (US)
Pages (from-to)	933-940
Number of pages	8
Journal	Nature biotechnology
Volume	26
Issue number	8
DOIs	https://doi.org/10.1038/nbt.1481
State	Published - Aug 2008

ASJC Scopus subject areas

Biotechnology
Bioengineering
Applied Microbiology and Biotechnology
Molecular Medicine
Biomedical Engineering

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10.1038/nbt.1481

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title = "A small molecule enhances RNA interference and promotes microRNA processing",

abstract = "Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are sequence-specific post-transcriptional regulators of gene expression. Although major components of the RNA interference (RNAi) pathway have been identified, regulatory mechanisms for this pathway remain largely unknown. Here we demonstrate that the RNAi pathway can be modulated intracellularly by small molecules. We have developed a cell-based assay to monitor the activity of the RNAi pathway and find that the small-molecule enoxacin (Penetrex) enhances siRNA-mediated mRNA degradation and promotes the biogenesis of endogenous miRNAs. We show that this RNAi-enhancing activity depends on the trans-activation-responsive region RNA-binding protein. Our results provide a proof-of-principle demonstration that small molecules can be used to modulate the activity of the RNAi pathway. RNAi enhancers may be useful in the development of research tools and therapeutics.",

author = "Ge Shan and Yujing Li and Junliang Zhang and Wendi Li and Szulwach, {Keith E.} and Ranhui Duan and Faghihi, {Mohammad A.} and Khalil, {Ahmad M.} and Lianghua Lu and Zain Paroo and Chan, {Anthony W S} and Zhangjie Shi and Qinghua Liu and Claes Wahlestedt and Chuan He and Peng Jin",

note = "Funding Information: We would like to thank S. Warren, S. Chang, K. Garber and C. Strauss for their helpful discussions and critical reading of the manuscript and H. Ju for technical assistance. We thank I. Verma, J. Belasco and G. Hannon for providing us the plasmids. Q.L. is a Damon Runyon Scholar (DRS-43) and is supported by the Welch Foundation (I-1608). P.J. is supported by NIH grants (NS051630 and MH076090). P.J. is the recipient of a Beckman Young Investigator Award and a Basil O{\textquoteright}Connor Scholar Research Award and is an Alfred P. Sloan Research Fellow in Neuroscience.",

year = "2008",

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T1 - A small molecule enhances RNA interference and promotes microRNA processing

AU - Shan, Ge

AU - Li, Yujing

AU - Zhang, Junliang

AU - Li, Wendi

AU - Szulwach, Keith E.

AU - Duan, Ranhui

AU - Faghihi, Mohammad A.

AU - Khalil, Ahmad M.

AU - Lu, Lianghua

AU - Paroo, Zain

AU - Chan, Anthony W S

AU - Shi, Zhangjie

AU - Liu, Qinghua

AU - Wahlestedt, Claes

AU - He, Chuan

AU - Jin, Peng

N1 - Funding Information: We would like to thank S. Warren, S. Chang, K. Garber and C. Strauss for their helpful discussions and critical reading of the manuscript and H. Ju for technical assistance. We thank I. Verma, J. Belasco and G. Hannon for providing us the plasmids. Q.L. is a Damon Runyon Scholar (DRS-43) and is supported by the Welch Foundation (I-1608). P.J. is supported by NIH grants (NS051630 and MH076090). P.J. is the recipient of a Beckman Young Investigator Award and a Basil O’Connor Scholar Research Award and is an Alfred P. Sloan Research Fellow in Neuroscience.

PY - 2008/8

Y1 - 2008/8

N2 - Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are sequence-specific post-transcriptional regulators of gene expression. Although major components of the RNA interference (RNAi) pathway have been identified, regulatory mechanisms for this pathway remain largely unknown. Here we demonstrate that the RNAi pathway can be modulated intracellularly by small molecules. We have developed a cell-based assay to monitor the activity of the RNAi pathway and find that the small-molecule enoxacin (Penetrex) enhances siRNA-mediated mRNA degradation and promotes the biogenesis of endogenous miRNAs. We show that this RNAi-enhancing activity depends on the trans-activation-responsive region RNA-binding protein. Our results provide a proof-of-principle demonstration that small molecules can be used to modulate the activity of the RNAi pathway. RNAi enhancers may be useful in the development of research tools and therapeutics.

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A small molecule enhances RNA interference and promotes microRNA processing

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