Oligomeric compounds and compositions for use in modulation of small non-coding RNAs
Compounds, compositions and methods are provided for modulating the expression and function of small non-coding RNAs. The compositions comprise oligomeric compounds, targeted to small non-coding RNAs. Methods of using these compounds for modulation of small non-coding RNAs as well as downstream targets of these RNAs and for diagnosis and treatment of disease associated with small non-coding RNAs are also provided.
1. A method of modulating the level of a precursor miRNA comprising:
contacting a cell with an oligomeric compound consisting of 15 to 30 monomeric subunits; wherein the oligomeric compound is complementary to the precursor miRNA and at least one monomeric subunit is a modified nucleoside or a nucleoside mimetic; and thereby modulating the level of the precursor miRNA.
2. The method of claim 1 wherein the contacting comprises inhibiting processing of the precursor miRNA.
3. The method of claim 1 wherein the level of the precursor miRNA is decreased.
4. The method of claim 1 wherein the oligomeric compound is complementary to a region flanking a Drosha cleavage site within the precursor miRNA.
5. The method of claim 1 wherein the precursor miRNA is a a pri-miRNA or a pre-miRNA.
6. The method of claim 5 wherein the oligomeric compound is complementary to a region of a pri-miRNA comprising a 5′ Drosha cleavage site.
7. The method of claim 5 wherein the oligomeric compound is complementary to a region of a pri-miRNA comprising a 3′ Drosha cleavage site.
8. The method of claim 1 wherein the oligomeric compound is complementary to a region comprising the miRNA.
9. The method of claim 1 wherein the oligomeric compound is complementary to a region comprising a loop structure.
10. The method of claim 1 wherein the level of a pri-miRNA is increased.
11. The method of claim 1 wherein the precursor miRNA comprises two or more miRNAs.
12. The method of claim 11 wherein the contacting comprises inhibiting the processing of two or more miRNAs.
13. The method of claim 11 wherein the precursor miRNA is a polycistronic precursor, and the polycistronic precursor is contacted with a first oligomeric compound complementary to a first region of the polycistronic precursor and a second oligomeric compound complementary to a second region of the polycistronic precursor.
14. The method of claim 1 wherein at least one monomeric subunit comprises at least one modified sugar moiety.
15. The method of claim 14 wherein the modified sugar moiety is chosen from 2′-F, 2′-O-methyl, 2′-O-methoxyethyl, and a bicyclic sugar moiety.
16. The method of claim 1 wherein the modified nucleoside or nucleoside mimetic comprises at least one modified internucleoside linkage.
17. The method of claim 16 wherein the modified internucleoside linkage is a phosphorothioate linkage.
18. The method of claim 1 wherein each monomeric subunit comprises a modified sugar moiety.
19. The method of claim 18 wherein the modified sugar moiety is 2′-O-methoxyethyl.
20. The method of claim 1 wherein the oligomeric compound consists of 17 to 25 monomeric subunits.
21. The method of claim 1 wherein the oligomeric compound is a single-stranded oligonucleotide.