Silencing of microRNA families by seed-targeting tiny LNAs

Obad, S., Dos Santos, C. O., Petri, A., Heidenblad, M., Broom, O., Ruse, C., Fu, C., Lindow, M., Stenvang, J., Straarup, E. M., Hansen, H. F., Koch, T., Pappin, D., Hannon, G. J., Kauppinen, S. (2011) Silencing of microRNA families by seed-targeting tiny LNAs. Nature Genetics, 43 (4). pp. 371-380. ISSN 10614036 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/21423181
DOI: 10.1038/ng.786

Abstract

The challenge of understanding the widespread biological roles of animal microRNAs (miRNAs) has prompted the development of genetic and functional genomics technologies for miRNA loss-of-function studies. However, tools for exploring the functions of entire miRNA families are still limited. We developed a method that enables antagonism of miRNA function using seed-targeting 8-mer locked nucleic acid (LNA) oligonucleotides, termed tiny LNAs. Transfection of tiny LNAs into cells resulted in simultaneous inhibition of miRNAs within families sharing the same seed with concomitant upregulation of direct targets. In addition, systemically delivered, unconjugated tiny LNAs showed uptake in many normal tissues and in breast tumors in mice, coinciding with long-term miRNA silencing. Transcriptional and proteomic profiling suggested that tiny LNAs have negligible off-target effects, not significantly altering the output from mRNAs with perfect tiny LNA complementary sites. Considered together, these data support the utility of tiny LNAs in elucidating the functions of miRNA families in vivo. © 2011 Nature America, Inc. All rights reserved.

Item Type: Paper
Uncontrolled Keywords: locked nucleic acid microRNA oligonucleotide animal cell animal tissue article breast tumor controlled study female gene silencing genetic transfection human human cell mouse nonhuman priority journal proteomics upregulation 3' Untranslated Regions Animals Base Sequence Cell Line, Tumor Gene Knockdown Techniques Genes, Reporter Genetic Techniques Hela Cells Humans Liver Luciferases, Renilla Mammary Neoplasms, Experimental Mice Mice, Inbred BALB C MicroRNAs Oligonucleotides Animalia Mus
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > miRNA
CSHL Authors:
Communities: CSHL Cancer Center Program > Cancer Genetics
CSHL Cancer Center Program > Signal Transduction
CSHL Cancer Center Shared Resources > Bioinformatics Service
CSHL Cancer Center Shared Resources > Flow Cytometry Service
CSHL Cancer Center Shared Resources > Proteomics Service
CSHL labs > Hannon lab
CSHL Cancer Center Shared Resources > Mass Spectrometry Service
Depositing User: Matt Covey
Date: 2011
Date Deposited: 09 Jan 2013 16:16
Last Modified: 05 Jan 2017 19:34
PMCID: PMC3541685
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26427

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