Role of a cluster of long noncoding RNA transcripts in protecting the heart from pathological hypertrophy
Nucleic acids encoding modified myosin heavy-chain-associated RNA transcripts are provided. The modified myosin heavy-chain-associated RNA transcripts belongs to a cluster of long noncoding RNAs (lncRNA) and bind to chromatin remodeler Brg1 to inhibit Brg1's genomic targeting and gene regulation function. The modified myosin heavy-chain-associated RNA transcripts expressed in an individual inhibit Brg1's gene regulation function and protect the heart of the individual from myopathy and failure. One of the modified heavy-chain-associated RNAs is a 400 base pair fragment segmented from a natural 779 base pair sequence of Mhrt (Mhrt779) and has the same cardioprotective effects as the Mhrt779.
1. A composition comprising a nucleic acid encoding a modified myosin heavy-chain-associated RNA transcript, wherein the modified myosin heavy-chain-associated RNA transcript inhibits Brg1's genomic targeting and gene regulation function in a subject to whom the composition is administered,
wherein the modified myosin heavy-chain-associated RNA transcript comprises SEQ ID NO: 2.
2. A composition comprising a nucleic acid encoding a modified myosin heavy-chain-associated RNA transcript, wherein the modified myosin heavy-chain-associated RNA transcript inhibits Brg1's genomic targeting and gene regulation function in a subject to whom the composition is administered,
wherein the modified myosin heavy-chain-associated RNA transcript comprises SEQ ID NO: 4.
3. The composition of claim 1 , wherein the nucleic acid is incorporated into a vector.
4. The composition of claim 3 , wherein the vector comprises an expression cassette comprising a promoter operably linked to the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript, and wherein the promoter directs an expression of the nucleic acid to produce the modified myosin heavy-chain-associated RNA transcript.
5. The composition of claim 4 , wherein the promoter comprises an inducible promoter.
6. The composition of claim 5 , wherein the promoter comprises a tetracycline response element.
7. A non-human organism carrying a transgene comprising a promoter and a nucleic acid encoding a modified myosin heavy-chain-associated RNA transcript,
wherein the promoter regulates an expression of the nucleic acid to produce the modified myosin heavy-chain-associated RNA transcript in the organism, and
wherein the modified myosin heavy-chain-associated RNA transcript inhibits Brg1's genomic targeting and gene regulation function in the organism; and
wherein the modified myosin heavy-chain-associated RNA transcript is selected from the group consisting of: SEQ ID NO: 2 and SEQ ID NO: 4.
8. The non-human organism of claim 7 , wherein the transgene is incorporated into a genome DNA of the organism.
9. The non-human organism of claim 7 , wherein the promoter comprises an inducible promoter.
10. The non-human organism of claim 9 , wherein the promoter comprises a tetracycline response element.
11. The non-human organism of claim 8 , wherein the organism is a transgenic mouse carrying the transgene.
12. The non-human organism of claim 11 , wherein the promoter comprises a tetracycline response element, and wherein the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript expresses the modified myosin heavy-chain-associated RNA transcript in cardiomyocytes of the transgenic mouse in the presence of tetracycline or a tetracycline analog.
13. A method comprising:
administering to a subject a composition comprising a nucleic acid encoding a modified myosin heavy-chain-associated RNA transcript to express the modified myosin heavy-chain-associated RNA transcript in the subject,
wherein the modified myosin heavy-chain-associated RNA transcript inhibits Brg1's genomic targeting and gene regulation function in the subject; and
wherein the modified myosin heavy-chain-associated RNA transcript is selected from the group consisting of: SEQ ID NO: 2 and SEQ ID NO: 4.
14. The method of claim 13 , wherein the composition comprises a vector, and wherein the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript is incorporated in the vector.
15. The method of claim 14 , wherein the vector comprises an expression cassette comprising a promoter operably linked to the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript, and wherein the promoter regulates an expression of the nucleic acid to produce the modified myosin heavy-chain-associated RNA transcript in the subject.
16. The method of claim 13 , wherein the nucleic acid is incorporated into a genome DNA of the subject.
17. The method of claim 15 , wherein the promoter comprises an inducible promoter.
18. The method of claim 17 , wherein the promoter comprises a tetracycline response element.
19. The method of claim 17 , wherein the nucleic acid expresses the modified myosin heavy-chain-associated RNA transcript in cardiomyocytes of the subject under an induction of doxycycline treatment.
20. The method of claim 15 , wherein the composition is administered to the subject with a pharmaceutical carrier.
21. The method of claim 15 , wherein the composition is administered to the subject via injection.
22. The method of claim 21 , wherein the composition is administered to the subject through intravenously injection.
23. The method of claim 21 , wherein the composition is administered to the subject through intracardiac injection.
24. A treatment delivery apparatus comprising a device and at least one dosage of a composition contained in the device,
wherein the composition comprises a nucleic acid encoding a modified myosin heavy-chain-associated RNA transcript,
wherein the modified myosin heavy-chain-associated RNA transcript inhibits Brg1's genomic targeting and gene regulation function in a subject to whom the composition is administered; and
wherein the modified myosin heavy-chain-associated RNA transcript is selected from the group consisting of: SEQ ID NO: 2 and SEQ ID NO: 4.
25. The treatment delivery apparatus of claim 24 , wherein the composition comprises a vector, and wherein the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript is incorporated in the vector.
26. The treatment delivery apparatus of claim 25 , wherein the vector comprises an expression cassette comprising a promoter operably linked to the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript, and wherein the promoter directs an expression of the nucleic acid to produce the modified myosin heavy-chain-associated RNA transcript.
27. A method comprising:
administering to a subject a composition comprising a modified myosin heavy-chain-associated RNA transcript;
wherein the modified myosin heavy-chain-associated RNA transcript inhibits Brg1's genomic targeting and gene regulation function in the subject; and
wherein the modified myosin heavy-chain-associated RNA transcript is selected from the group consisting of: SEQ ID NO: 2 and SEQ ID NO: 4.
28. The method of claim 27 , wherein the composition comprises nanoparticles, and wherein the modified myosin heavy-chain-associated RNA transcript is packaged with the nanoparticles.
29. The composition of claim 2 , wherein the nucleic acid is incorporated into a vector.
30. The composition of claim 29 , wherein the vector comprises an expression cassette comprising a promoter operably linked to the nucleic acid encoding the modified myosin heavy-chain-associated RNA transcript, and wherein the promoter directs an expression of the nucleic acid to produce the modified myosin heavy-chain-associated RNA transcript.
31. The composition of claim 30 , wherein the promoter comprises an inducible promoter.
32. The composition of claim 31 , wherein the promoter comprises a tetracycline response element.