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Nucleic Acids Research Advance Access originally published online on December 23, 2007
Nucleic Acids Research 2008 36(4):1153-1162; doi:10.1093/nar/gkm1113
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Nucleic Acids Research, 2008, Vol. 36, No. 4 1153-1162
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver

Joacim Elmén1, Morten Lindow1, Asli Silahtaroglu2, Mads Bak2, Mette Christensen2, Allan Lind-Thomsen2, Maj Hedtjärn1, Jens Bo Hansen1, Henrik Frydenlund Hansen1, Ellen Marie Straarup1, Keith McCullagh1, Phil Kearney1 and Sakari Kauppinen1,2,*

1Santaris Pharma, Bøge Allé 3, DK-2970 Hørsholm and 2Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark

*To whom correspondence should be addressed. Tel: +45 45 17 98 38; Fax: +45 45 17 98 98; Email: sk{at}santaris.com

Received June 28, 2007. Revised November 27, 2007. Accepted November 28, 2007.

MicroRNA-122 (miR-122) is an abundant liver-specific miRNA, implicated in fatty acid and cholesterol metabolism as well as hepatitis C viral replication. Here, we report that a systemically administered 16-nt, unconjugated LNA (locked nucleic acid)-antimiR oligonucleotide complementary to the 5' end of miR-122 leads to specific, dose-dependent silencing of miR-122 and shows no hepatotoxicity in mice. Antagonism of miR-122 is due to formation of stable heteroduplexes between the LNA-antimiR and miR-122 as detected by northern analysis. Fluorescence in situ hybridization demonstrated uptake of the LNA-antimiR in mouse liver cells, which was accompanied by markedly reduced hybridization signals for mature miR-122 in treated mice. Functional antagonism of miR-122 was inferred from a low cholesterol phenotype and de-repression within 24 h of 199 liver mRNAs showing significant enrichment for miR-122 seed matches in their 3' UTRs. Expression profiling extended to 3 weeks after the last LNA-antimiR dose revealed that most of the changes in liver gene expression were normalized to saline control levels coinciding with normalized miR-122 and plasma cholesterol levels. Combined, these data suggest that miRNA antagonists comprised of LNA are valuable tools for identifying miRNA targets in vivo and for studying the biological role of miRNAs and miRNA-associated gene-regulatory networks in a physiological context.


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