Silencing of microRNA families by seed-targeting tiny LNAs
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Silencing of microRNA families by seed-targeting tiny LNAs. / Obad, Susanna; dos Santos, Camila O; Petri, Andreas; Heidenblad, Markus; Broom, Oliver; Ruse, Cristian; Fu, Cexiong; Lindow, Morten; Stenvang, Jan; Straarup, Ellen Marie; Hansen, Henrik Frydenlund; Koch, Troels; Pappin, Darryl; Hannon, Gregory J; Kauppinen, Sakari.
In: Nature Genetics, Vol. 43, No. 4, 2011, p. 371-8.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Silencing of microRNA families by seed-targeting tiny LNAs
AU - Obad, Susanna
AU - dos Santos, Camila O
AU - Petri, Andreas
AU - Heidenblad, Markus
AU - Broom, Oliver
AU - Ruse, Cristian
AU - Fu, Cexiong
AU - Lindow, Morten
AU - Stenvang, Jan
AU - Straarup, Ellen Marie
AU - Hansen, Henrik Frydenlund
AU - Koch, Troels
AU - Pappin, Darryl
AU - Hannon, Gregory J
AU - Kauppinen, Sakari
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - 3' Untranslated Regions
KW - Animals
KW - Base Sequence
KW - Cell Line, Tumor
KW - Female
KW - Gene Knockdown Techniques
KW - Gene Silencing
KW - Genes, Reporter
KW - Genetic Techniques
KW - HeLa Cells
KW - Humans
KW - Liver
KW - Luciferases, Renilla
KW - Mammary Neoplasms, Experimental
KW - Mice
KW - Mice, Inbred BALB C
KW - MicroRNAs
KW - Oligonucleotides
U2 - 10.1038/ng.786
DO - 10.1038/ng.786
M3 - Journal article
C2 - 21423181
VL - 43
SP - 371
EP - 378
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 4
ER -
ID: 59320376