Oligomeric compounds and compositions for use in modulation of pri-mirnas
Compounds, compositions and methods are provided for modulating the levels expression, processing and function of pri-miRNAs. In particular, methods and compounds are provided for the modulation of the levels, expression, processing or function of polycistronic pri-miRNAs. The compositions comprise oligomeric compounds targeted to small non-coding RNAs and pri-miRNAs. Further provided are methods for selectively modulating pri-miRNA levels in a cell. Also provided are methods for identifying oligomeric compounds that result in increase pri-miRNA levels when contacted with a cell.
1. A method of increasing the amounts of pri-miR-15 and pri-miR-16 in a cell comprising:
contacting the cell with an oligomeric compound comprising an oligonucleotide consisting of 15 to 30 linked nucleosides and having a nucleobase sequence at least 90% complementary to a target region within nucleobases 257 to 308 of SEQ ID NO: 102, whereby the amounts of pri-miR-15 and pri-miR-16 in the cell are increased.
2. The method of claim 1 wherein the nucleobase sequence of the oligonucleotide is at least 95% complementary to a target region within nucleotides 257 to 308 of SEQ ID NO: 102.
3. The method of claim 1 wherein the nucleobase sequence of the oligonucleotide is 100% complementary to a target region within nucleobases 257 to 308 of SEQ ID NO 102.
4. The method of claim 1 wherein the oligonucleotide consists of 17 to 25 linked nucleosides.
5. The method of claim 1 wherein the oligomeric compound consists of an oligonucleotide.
6. The method of claim 1 wherein at least one nucleoside of the oligonucleotide comprises a sugar modification.
7. The method of claim 6 wherein each nucleoside of the oligonucleotide comprises a sugar modification.
8. The method of claim 7 wherein the sugar modification is 2′-O-methoxyethyl.
9. The method of claim 1 wherein at least one internucleoside linkage is a modified internucleoside linkage.
10. The method of claim 1 wherein each internucleoside linkage is a modified internucleoside linkage.
11. The method of claim 10 wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.
12. The method of claim 1 wherein the oligonucleotide comprises at least one cytosine, wherein the cytosine is a 5-methylcytosine.
13. The method of claim 12 wherein each cytosine is a 5-methylcytosine.
14. The method of claim 1 wherein the oligonucleotide has a nucleobase sequence selected from the group consisting of SEQ ID NOs 92, 93, 94, and 95.
15. A method of increasing the amounts of pri-miR-15 and pri-miR-16 in a cell comprising:
contacting the cell with an oligonucleotide consisting of 17 to 25 linked nucleosides and having a nucleobase sequence at least 90% complementary to a target region within nucleobases 257 to 308 of SEQ ID NO: 102, whereby the amounts of pri-miR-15 and pri-miR-16 in the cell are increased.
16. The method of claim 15 wherein each nucleoside comprises a sugar modification.
17. The method of claim 15 wherein each nucleoside comprises a 2′-O-methoxyethyl sugar modification.
18. The method of claim 17 wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
19. The method of claim 18 wherein the oligonucleotide comprises at least one cytosine and the cytosine is a 5-methylcytosine.
20. The method of claim 19 wherein the oligonucleotide has a nucleobase sequence selected from the group consisting of SEQ ID NOs 92, 93, 94, and 95.