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
Identifieur interne : 002C06 ( Main/Exploration ); précédent : 002C05; suivant : 002C07Antagonism 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
Auteurs : Joacim Elmén [Danemark] ; Morten Lindow [Danemark] ; Asli Silahtaroglu [Danemark] ; Mads Bak [Danemark] ; Mette Christensen [Danemark] ; Allan Lind-Thomsen [Danemark] ; Maj Hedtj Rn [Danemark] ; Jens Bo Hansen [Danemark] ; Henrik Frydenlund Hansen [Danemark] ; Ellen Marie Straarup [Danemark] ; Keith Mccullagh [Danemark] ; Phil Kearney [Danemark] ; Sakari Kauppinen [Danemark]Source :
- Nucleic Acids Research [ 0305-1048 ] ; 2008.
Abstract
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.
Url:
DOI: 10.1093/nar/gkm1113
Affiliations:
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last="Kauppinen">Sakari Kauppinen</name><affiliation wicri:level="1"><country xml:lang="fr">Danemark</country><wicri:regionArea>Santaris Pharma, Bøge Allé 3, DK-2970 Hørsholm and Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N</wicri:regionArea><wicri:noRegion>DK-2200 Copenhagen N</wicri:noRegion></affiliation><affiliation></affiliation><affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Nucleic Acids Research</title><idno type="ISSN">0305-1048</idno><idno type="eISSN">1362-4962</idno><imprint><publisher>Oxford University Press</publisher><date type="published">2008</date><date type="e-published">2007</date><biblScope unit="vol">36</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="1153">1153</biblScope><biblScope unit="page" to="1162">1162</biblScope></imprint><idno type="ISSN">0305-1048</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0305-1048</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">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.</div></front></TEI><affiliations><list><country><li>Danemark</li></country></list><tree><country name="Danemark"><noRegion><name sortKey="Elmen, Joacim" sort="Elmen, Joacim" uniqKey="Elmen J" first="Joacim" last="Elmén">Joacim Elmén</name></noRegion><name sortKey="Bak, Mads" sort="Bak, Mads" uniqKey="Bak M" first="Mads" last="Bak">Mads Bak</name><name sortKey="Christensen, Mette" sort="Christensen, Mette" uniqKey="Christensen M" first="Mette" last="Christensen">Mette Christensen</name><name sortKey="Hansen, Henrik Frydenlund" sort="Hansen, Henrik Frydenlund" uniqKey="Hansen H" first="Henrik Frydenlund" last="Hansen">Henrik Frydenlund Hansen</name><name sortKey="Hansen, Jens Bo" sort="Hansen, Jens Bo" uniqKey="Hansen J" first="Jens Bo" last="Hansen">Jens Bo Hansen</name><name sortKey="Hedtj Rn, Maj" sort="Hedtj Rn, Maj" uniqKey="Hedtj Rn M" first="Maj" last="Hedtj Rn">Maj Hedtj Rn</name><name sortKey="Kauppinen, Sakari" sort="Kauppinen, Sakari" uniqKey="Kauppinen S" first="Sakari" last="Kauppinen">Sakari Kauppinen</name><name sortKey="Kearney, Phil" sort="Kearney, Phil" uniqKey="Kearney P" first="Phil" last="Kearney">Phil Kearney</name><name sortKey="Lind Thomsen, Allan" sort="Lind Thomsen, Allan" uniqKey="Lind Thomsen A" first="Allan" last="Lind-Thomsen">Allan Lind-Thomsen</name><name sortKey="Lindow, Morten" sort="Lindow, Morten" uniqKey="Lindow M" first="Morten" last="Lindow">Morten Lindow</name><name sortKey="Mccullagh, Keith" sort="Mccullagh, Keith" uniqKey="Mccullagh K" first="Keith" last="Mccullagh">Keith Mccullagh</name><name sortKey="Silahtaroglu, Asli" sort="Silahtaroglu, Asli" uniqKey="Silahtaroglu A" first="Asli" last="Silahtaroglu">Asli Silahtaroglu</name><name sortKey="Straarup, Ellen Marie" sort="Straarup, Ellen Marie" uniqKey="Straarup E" first="Ellen Marie" last="Straarup">Ellen Marie Straarup</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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