Specificity, duplex degradation and subcellular localization of antagomirs

Krützfeldt, Jan; Kuwajima, Satoru; Braich, Ravi; Rajeev, Kallanthottathil G; Pena, John; Tuschl, Thomas; Manoharan, Muthiah; Stoffel, Markus (2007). Specificity, duplex degradation and subcellular localization of antagomirs. Nucleic acids research, 35(9), pp. 2885-92. London: Information Retrieval Ltd. 10.1093/nar/gkm024

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MicroRNAs (miRNAs) are an abundant class of 20-23-nt long regulators of gene expression. The study of miRNA function in mice and potential therapeutic approaches largely depend on modified oligonucleotides. We recently demonstrated silencing miRNA function in mice using chemically modified and cholesterol-conjugated RNAs termed 'antagomirs'. Here, we further characterize the properties and function of antagomirs in mice. We demonstrate that antagomirs harbor optimized phosphorothioate modifications, require >19-nt length for highest efficiency and can discriminate between single nucleotide mismatches of the targeted miRNA. Degradation of different chemically protected miRNA/antagomir duplexes in mouse livers and localization of antagomirs in a cytosolic compartment that is distinct from processing (P)-bodies indicates a degradation mechanism independent of the RNA interference (RNAi) pathway. Finally, we show that antagomirs, although incapable of silencing miRNAs in the central nervous system (CNS) when injected systemically, efficiently target miRNAs when injected locally into the mouse cortex. Our data further validate the effectiveness of antagomirs in vivo and should facilitate future studies to silence miRNAs for functional analysis and in clinically relevant settings.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Endocrinology, Diabetology and Clinical Nutrition

UniBE Contributor:

Krützfeldt, Jan

ISSN:

0305-1048

ISBN:

17439965

Publisher:

Information Retrieval Ltd.

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:06

Last Modified:

17 Mar 2015 22:20

Publisher DOI:

10.1093/nar/gkm024

PubMed ID:

17439965

Web of Science ID:

000247350800007

URI:

https://boris.unibe.ch/id/eprint/28605 (FactScience: 122003)

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