Argonaute 2-dependent Regulation of Gene Expression by Single-stranded miRNA Mimics

Molecular Therapy : the Journal of the American Society of Gene Therapy
Masayuki MatsuiDavid R Corey

Abstract

MicroRNAs (miRNAs) are small noncoding transcripts that regulate gene expression. Aberrant expression of miRNAs can affect development of cancer and other diseases. Synthetic miRNA mimics can modulate gene expression and offer an approach to therapy. Inside cells, mature miRNAs are produced as double-stranded RNAs and miRNA mimics typically retain both strands. This need for two strands has the potential to complicate drug development. Recently, synthetic chemically modified single-stranded silencing RNAs (ss-siRNA) have been shown to function through the RNAi pathway to induce gene silencing in cell culture and animals. Here, we test the hypothesis that single-stranded miRNA (ss-miRNA) can also mimic the function of miRNAs. We show that ss-miRNAs can act as miRNA mimics to silence the expression of target genes. Gene silencing requires expression of argonaute 2 (AGO2) protein and involves recruitment of AGO2 to the target transcripts. Chemically modified ss-miRNAs function effectively inside cells through endogenous RNAi pathways and broaden the options for miRNA-based oligonucleotide drug development.

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Citations

Dec 23, 2016·Nucleic Acid Therapeutics·Jiaxin HuDavid R Corey
Aug 28, 2019·Communications Biology·Katia AquilanoDaniele Lettieri-Barbato
Sep 26, 2019·Neural Regeneration Research·Chuan QinJian-Jun Li
Jul 18, 2018·Frontiers in Cardiovascular Medicine·Anindita DasFadi N Salloum
May 20, 2020·Chemistry & Biodiversity·Mathias BolzMichael W Göbel
Jan 12, 2020·Communications Biology·Katia AquilanoDaniele Lettieri-Barbato
May 21, 2021·Journal of the Neurological Sciences·Gayatri GandhiWendy Wai Yeng Yeo

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Methods Mentioned

BETA
PCR
chemical modifications
antisense oligonucleotides
transfection
immunoprecipitation
gene knockdown
chemical modification
protein assay
Reverse Transcription Polymerase Chain Reaction
scraping

Software Mentioned

KaleidaGraph
Synergy

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