Skip to main content

Advertisement

SpringerLink
Log in

Role of endogenous antisense RNA in cardiac gene regulation

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Endogenous antisense RNA has been detected for a range of eukaryotic genes and now appears to be a common phenomenon in mammalian cells. Its abundance compared to levels of its complementary sense mRNA indicates that antisense RNA may be involved in posttrancriptional regulation of a gene. In general a downregulating effect on gene expression has been demonstrated or suggested. Due to the heterogeneity in origin and character of different antisense transcripts alternative functions such as stabilizing the corresponding sense transcript and being part of gene recombination must be considered. Regulation by endogenous antisense RNA has been shown for a plethora of genes, including cardiac genes, such as myosin heavy chainMHC, atrial light chain, and troponin I. There is now growing evidence that antisense transcription is involved in human disease, and it is reasonable to consider antisense as a target for intervention procedures. Here we review the progress in our understanding of as well as the controversies arising from investigating the regulatory mechanisms of antisense RNA, with special focus on cardiac genes. Finally, links between antisense transcription and heart disease and the possible use of antisense as a target of cardiac intervention procedures are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

ALC :

Atrial light chain

bFGF :

Basic fibroblast growth factor

cTnI :

Cardiac-specific troponin I

ds :

Double-stranded

MLC :

Myosin light chain

MHC :

Myosin heavy chain

RACE :

Rapid amplification of cDNA ends

RNAi :

RNA interference

VLC :

Ventricular light chain

References

  1. Yelin R, Dahary D, Sorek R, Levanon EY, Goldstein O, Shoshan A, Diber A, Biton S, Tamir Y, Khosravi R, Nemzer S, Pinner E, Walach S, Bernstein J, Savitsky K, Rotman G (2003) Widespread occurrence of antisense transcription in the human genome. Nat Biotechnol 21:379–386

    Article  CAS  PubMed  Google Scholar 

  2. Wagner EG, Simons RW (1994) Antisense RNA control in bacteria, phages, and plasmids. Annu Rev Microbiol 48:713–742

    Article  CAS  PubMed  Google Scholar 

  3. Dolfini S, Consonni G, Mereghetti M, Tonelli C (1993) Antiparallel expression of the sense and antisense transcripts of maize alpha-tubulin genes. Mol Gen Genet 241–:161–169

  4. Werner A, Preston-Fayers K, Dehmelt L, Nalbant P (2002) Regulation of the NPT gene by a naturally occurring antisense transcript. Cell Biochem Biophys 36:241–252

    Article  CAS  PubMed  Google Scholar 

  5. Kimelman D, Kirschner MW (1989) An antisense mRNA directs the covalent modification of the transcript encoding fibroblast growth factor in Xenopus oocytes. Cell 59:687–696

    Article  CAS  PubMed  Google Scholar 

  6. Heywood SM, Kennedy DS, Bester AJ (1975) Studies concerning the mechanism by which translational-control RNA regulates protein synthesis in embryonic muscle. Eur J Biochem 58:587–593

    CAS  PubMed  Google Scholar 

  7. Murphy PR, Knee RS (1994) Identification and characterization of an antisense RNA transcript (gfg) from the human basic fibroblast growth factor gene. Mol Endocrinol 8:852–859

    Article  CAS  PubMed  Google Scholar 

  8. Armstrong B, Krystal G (1992) Isolation and characterization of complementary DNA for N-myc, a gene encoded by the DNA strand opposite to N-myc. Cell Growth Differ 3:385–390

    CAS  PubMed  Google Scholar 

  9. Zezza DJ, Heywood SM (1986) Analysis of tcRNA102 associated with myosin heavy chain-mRNPs in control and dystrophic chick pectoralis muscle. J Biol Chem 261:7461–7645

    CAS  PubMed  Google Scholar 

  10. McCarthy TL, Siegel E, Mroczkowski B, Heywood SM (1983) Characterization of translational-control ribonucleic acid isolated from embryonic chick muscle. Biochemistry 22:935–941

    CAS  PubMed  Google Scholar 

  11. Simons RW (1994) The control of prokaryotic and eukaryotic gene expression by naturally occurring antisense RNA. In: Crooke ST, LeBlew B (eds) Antisense research and applications. CRC, Boca Raton, pp 97–124

  12. Vanhee-Brossollet C, Vaquero C (1998) Do natural antisense transcripts make sense in eukaryotes? Gene 211:1–9

    Google Scholar 

  13. Kim JH, McLinden RJ, Mosca JD, Vahey MT, Greene WC, Redfield RR (1996) Inhibition of HIV replication by sense and antisense rev response elements in HIV-based retroviral vectors. J Acquir Immune Defic Syndr Hum Retrovirol 12:343–351

    CAS  PubMed  Google Scholar 

  14. Sharma HW, Narayanan R (1995) The therapeutic potential of antisense oligonucleotides. Bioessays 17:1055–1063

    CAS  PubMed  Google Scholar 

  15. Krystal GW, Armstrong BC, Battey JF (1990) N-myc mRNA forms an RNA-RNA duplex with endogenous antisense transcripts. Mol Cell Biol 10:4180–4191

    CAS  PubMed  Google Scholar 

  16. Podlowski S, Bramlage P, Baumann G, Morano I, Luther HP (2002) Cardiac troponin I sense-antisense RNA duplexes in the myocardium. J Cell Biochem 85:198–207

    CAS  PubMed  Google Scholar 

  17. Fedoroff N, Wellauer PK, Wall R (1977) Intermolecular duplexes in heterogeneous nuclear RNA from HeLa cells. Cell 10:597–610

    Article  CAS  PubMed  Google Scholar 

  18. Kumar M, Carmichael GG (1998) Antisense RNA: function, fate of duplex RNA in cells of higher eukaryotes. Microbiol Mol Biol Rev 62:1415–1434

    CAS  PubMed  Google Scholar 

  19. Wu H, MacLeod AR, Lima WF, Crooke ST (1998) Identification and partial purification of human double strand RNase activity. A novel terminating mechanism for oligoribonucleotide antisense drugs. J Biol Chem 273:2532–2542

    Article  CAS  PubMed  Google Scholar 

  20. Bass BL, Weintraub H (1988) An unwinding activity that covalently modifies its double-stranded RNA substrate. Cell 55:1089–1098

    Article  CAS  PubMed  Google Scholar 

  21. Kumar M, Carmichael GG (1997) Nuclear antisense RNA induces extensive adenosine modifications and nuclear retention of target transcripts. Proc Natl Acad Sci USA 94:3542–3547

    Article  CAS  PubMed  Google Scholar 

  22. Proud CG (1995) PKR: a new name and new roles Trends Biochem Sci 20:241–246

    Google Scholar 

  23. Kerr IM, Brown RE (1978) pppA2’p5’A2’p5’A: an inhibitor of protein synthesis synthesized with an enzyme fraction from interferon-treated cells Proc Natl Acad Sci USA 75:256–260

    Google Scholar 

  24. Wu H, Xu H, Miraglia LJ, Crooke ST (2000) Human RNase III is a 160-kDa protein involved in preribosomal RNA processing. J Biol Chem 275:36957–36965

    Article  CAS  PubMed  Google Scholar 

  25. Crooke ST, Bennett CF (1996) Progress in antisense oligonucleotide therapeutics. Annu Rev Pharmacol Toxicol 36:107–129

    Article  CAS  PubMed  Google Scholar 

  26. Hildebrandt M, Nellen W (1992) Differential antisense transcription from the Dictyostelium EB4 gene locus: implications on antisense-mediated regulation of mRNA stability. Cell 69:197–204

    Article  CAS  PubMed  Google Scholar 

  27. Merino E, Balbas P, Puente J, Bolivar F (1994) Antisense overlapping openreading frames in genes from bacteria to humans. Nucleic Acids Res 22:1903–1908

    CAS  PubMed  Google Scholar 

  28. Fire A (1999) RNA-triggered gene silencing. Trends Genet 15:358–363

    Google Scholar 

  29. Korneev SA, Park JH, O’Shea M (1999) Neuronal expression of neural nitric oxide synthase (nNOS) protein is suppressed by an antisense RNA transcribed from an NOS pseudogene. J Neurosci 19:7711–7720

    CAS  PubMed  Google Scholar 

  30. Lewin B (1990) Genes IV. Oxford University Press, New York

  31. Tommasi S, Pfeifer GP (1999) In vivo structure of two divergent promoters at the human PCNA locus. Synthesis of antisense RNA and S phase-dependent binding of E2F complexes in intron 1. J Biol Chem 274:27829–27838

    Article  CAS  PubMed  Google Scholar 

  32. Volloch V, Schweitzer B, Rits S (1996) Antisense globin RNA in mouse erythroid tissues: structure, origin, and possible function. Proc Natl Acad Sci USA 93:2476–2481

    Article  CAS  PubMed  Google Scholar 

  33. Merzendorfer H, Harvey WR, Wieczorek H (1997) Sense and antisense RNA for the membrane associated 40 kDa subunit M40 of the insect V-ATPase. FEBS Lett 411:239–244

    Article  CAS  PubMed  Google Scholar 

  34. Røsok O, Sioud M (2004) Systematic identification of sense-antisense transcripts in mammalian cells. Nat Biotechnol 22:104–108

    Article  PubMed  Google Scholar 

  35. Leinwand LA, Saez L, McNally E, Nadal-Ginard B (1983) Isolation and characterization of human myosin heavy chain genes. Proc Natl Acad Sci USA 80:3716–3720

    CAS  PubMed  Google Scholar 

  36. Lompre AM, Nadal-Ginard B, Mahdavi V (1984) Expression of the cardiac ventricular alpha- and beta-myosin heavy chain genes is developmentally and hormonally regulated J Biol Chem 259:6437–6446

    Google Scholar 

  37. Lompre AM, Schwartz K, d’Albis A, Lacombe G, Van Thiem N, Swynghedauw B (1979) Myosin isoenzyme redistribution in chronic heart overload. Nature 282:105–107

    CAS  PubMed  Google Scholar 

  38. Boheler KR, Chassagne C, Martin X, Wisnewsky C, Schwartz K (1992) Cardiac expressions of alpha- and beta-myosin heavy chains and sarcomeric alpha-actins are regulated through transcriptional mechanisms. Results from nuclear run-on assays in isolated rat cardiac nuclei. J Biol Chem 267:12979–12985

    CAS  PubMed  Google Scholar 

  39. Luther HP, Morwinski R, Wallukat G, Haase H, Morano (1997) Expression of sense and naturally occurring antisense mRNA of myosin heavy chain in rat heart tissue and cultivated cardiomyocytes. J Mol Cell Cardiol 29:27–35

    Article  CAS  PubMed  Google Scholar 

  40. Luther HP, Haase H, Hohaus A, Beckmann G, Reich J, Morano I (1998) Characterization of naturally occurring myosin heavy chain antisense mRNA in rat heart. J Cell Biochem 70:110–120

    CAS  PubMed  Google Scholar 

  41. Haddad F, Bodell PW, Qin AX, Giger JM, Baldwin KM (2003) Role of antisense RNA in coordinating cardiac myosin heavy chain gene switching. J Biol Chem 278:37132–37138

    Article  CAS  PubMed  Google Scholar 

  42. Mercadier JJ, Bouveret P, Gorza L, Schiaffino S, Clark WA, Zak R, Swynghedauw B, Schwartz K (1983) Myosin isoenzymes in normal and hypertrophied human ventricular myocardium. Circ Res 53:52–62

    CAS  PubMed  Google Scholar 

  43. Ritter O, Luther HP, Haase H, Baltas LG, Baumann G, Schulte HD, Morano I (1999) Expression of atrial myosin light chains but not alpha-myosin heavy chains is correlated in vivo with increased ventricular function in patients with hypertrophic obstructive cardiomyopathy. J Mol Med 77:677–685

    Article  CAS  PubMed  Google Scholar 

  44. Luther HP, Podlowski S, Hetzer R, Baumann G (2001) Analysis of sense and naturally occurring antisense transcripts of myosin heavy chain in the human myocardium J Cell Biochem 80:596–605

    CAS  Google Scholar 

  45. Nakao K, Minobe W, Roden R, Bristow M, Leinwand L (1997) Myosin heavy chain gene expression in human heart failure. J Clin Invest 100:2362–2370

    CAS  PubMed  Google Scholar 

  46. Miyata S, Minobe W, Bristow M, Leinwand L (2000) Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ Res 86:386–390

    CAS  PubMed  Google Scholar 

  47. Lowey S, Risby D (1971) Light chains from fast and slow muscle myosins. Nature 234:81–85

    CAS  PubMed  Google Scholar 

  48. Morano M, Zacharzowski U, Maier M, Lange PE, Alexi-Meskishvili V, Haase H, Morano I (1996) Regulation of human heart contractility by essential myosin light chain isoforms. J Clin Invest 98:467–473

    CAS  PubMed  Google Scholar 

  49. Sutsch G, Brunner U, von Schulthess C, Hirzel H, Hess O, Turina M, Krayenbuehl H, Schaub M (1992) Hemodynamic performance and myosin light chain-1 expression of the hypertrophied left ventricle in aortic valve disease before and after valve replacement. Circ Res 70:1035–1043

    CAS  PubMed  Google Scholar 

  50. Morano I (1999) Tuning the human heart molecular motors by myosin light chains. J Mol Med 77:544–555

    Article  CAS  PubMed  Google Scholar 

  51. Ritter O, Haase H, Schulte HD, Lange PE, Morano I (1999) Remodeling of the hypertrophied human myocardium by cardiac bHLH transcription factors. J Cell Biochem 74:551–561

    CAS  PubMed  Google Scholar 

  52. Bartsch H, Voigtsberger S, Baumann G, Morano I, Luther HP (2004) Detection of a novel sense-antisense RNA-hybrid structure by RACE experiments on endogenous Troponin I antisense RNA. RNA 10:1215–1224

    Article  CAS  PubMed  Google Scholar 

  53. Stein P, Svobode P, Anger M, Schultz RM (2003) RNAi: mammalian oocytes do it without RNA-dependent RNA polymerase. RNA 9:187–192

    Article  CAS  PubMed  Google Scholar 

  54. Herbert A (2004) The four Rs of RNA-directed evolution. Nat Genetics 36:19–25

    Article  CAS  Google Scholar 

  55. Morelli, S, Delia D, Capacioli S, Quattrone, Schiavone N, Bevilacqua A, Tomasini S, Nicolin A (1997) The antisense bcl-2-IgH transcript is an optimal target for synthetic oligonucleotides. Proc Natl Acad Sci USA 94:8150–8155

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Our original work on endogenous antisense RNA was supported by the Deutsche Forschungsgemeinschaft Lu 694/1-1.

Author information

Authors and Affiliations

  1. Medical Clinic I, Department of Cardiology, Humboldt University, Charité Hospital, Ziegelstrasse 5–9, 10117, Berlin, Germany

    Hans Peter Luther

Authors
  1. Hans Peter Luther
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans Peter Luther.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luther, H.P. Role of endogenous antisense RNA in cardiac gene regulation. J Mol Med 83, 26–32 (2005). https://doi.org/10.1007/s00109-004-0613-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-004-0613-5

Keywords

Search

Navigation