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Silencing of microRNAs in vivo with ‘antagomirs’
Abstract
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.
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“Methods have been developed to manipulate miRNA function pharmacologically, facilitating the development of new cancer therapeutic strategies (Hutvagner et al., 2004; Krutzfeldt et al., 2005).”
From Modulation of K-Ras-Dependent Lung Tumorigenesis by MicroRNA-21 (2010) · cites this paper as Krutzfeldt et al., 2005
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Metadata
- Authors
- Krützfeldt, J., Rajewsky, N., Braich, R., Rajeev, K. G., Tuschl, T., Manoharan, M., & Stoffel, M.
- Affiliations
- Rockefeller University (US)
- New York University (US)
- Alnylam Pharmaceuticals (United States) (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Stoffel, Markus
- ORCID
- Venue
- Nature
- Published
- 2005-10-30
- Volume
- 438
- Issue
- 7068
- Pages
- 685-689
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2161693225
- Cited by
- 3,949
- References
- 27
- Citations by year
- 2026: 51 · 2025: 75 · 2024: 98 · 2023: 109 · 2022: 138 · 2021: 148 · 2020: 155 · 2019: 135 · 2018: 169 · 2017: 169 · 2016: 210 · 2015: 249 · 2014: 326 · 2013: 329 · 2012: 318
- FWCI
- 52.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Bristol-Myers Squibb
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Molecular Biology Research
- Keywords
- microRNA, antagomir, microRNA silencing, in vivo gene regulation, miR-122, miR-16, miR-192, miR-194, miR-196, Hoxb8, Sonic hedgehog, embryonic development, non-coding RNA, oligonucleotide therapeutics
- MeSH terms
- Antagomirs, Animals, Cholesterol, Oligonucleotides, Sensitivity and Specificity, Substrate Specificity, Time Factors, Down-Regulation, Up-Regulation, RNA, Complementary, Computational Biology, 3' Untranslated Regions, Gene Silencing, MicroRNAs, Mice
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