Silencing of microRNAs in vivo with 'antagomirs'

Krützfeldt, Jan; Rajewsky, Nikolaus; Braich, Ravi; Rajeev, Kallanthottathil G; Tuschl, Thomas; Manoharan, Muthiah; Stoffel, Markus (2005). Silencing of microRNAs in vivo with 'antagomirs'. Nature, 438(7068), pp. 685-9. London: Macmillan Journals Ltd. 10.1038/nature04303

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MicroRNAs (miRNAs) are an abundant class of non-coding RNAs that are believed to be important in many biological processes through regulation of gene expression. The precise molecular function of miRNAs in mammals is largely unknown and a better understanding will require loss-of-function studies in vivo. Here we show that a novel class of chemically engineered oligonucleotides, termed 'antagomirs', are efficient and specific silencers of endogenous miRNAs in mice. Intravenous administration of antagomirs against miR-16, miR-122, miR-192 and miR-194 resulted in a marked reduction of corresponding miRNA levels in liver, lung, kidney, heart, intestine, fat, skin, bone marrow, muscle, ovaries and adrenals. The silencing of endogenous miRNAs by this novel method is specific, efficient and long-lasting. The biological significance of silencing miRNAs with the use of antagomirs was studied for miR-122, an abundant liver-specific miRNA. Gene expression and bioinformatic analysis of messenger RNA from antagomir-treated animals revealed that the 3' untranslated regions of upregulated genes are strongly enriched in miR-122 recognition motifs, whereas downregulated genes are depleted in these motifs. Analysis of the functional annotation of downregulated genes specifically predicted that cholesterol biosynthesis genes would be affected by miR-122, and plasma cholesterol measurements showed reduced levels in antagomir-122-treated mice. Our findings show that antagomirs are powerful tools to silence specific miRNAs in vivo and may represent a therapeutic strategy for silencing miRNAs in disease.

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:

0028-0836

ISBN:

16258535

Publisher:

Macmillan Journals Ltd.

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:06

Last Modified:

04 May 2014 23:20

Publisher DOI:

10.1038/nature04303

PubMed ID:

16258535

Web of Science ID:

000233593100054

URI:

https://boris.unibe.ch/id/eprint/28594 (FactScience: 121981)

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