Control of Cardiogenesis by microRNA Editing

Summary

Principal Investigator: Kazuko Nishikura
Abstract: DESCRIPTION (provided by applicant): This application addresses broad Challenge Areas (15): Translational Science and Specific Challenge Topic 15-HL-102: Develop therapeutic strategies for heart, lung, and blood diseases based on microRNA technology. One type of RNA editing involves the conversion of adenosine residues into inosine in double-stranded RNA by the action of ADAR (adenosine deaminase acting on RNA). The A?I RNA editing recodes and diversifies the function of important mammalian genes such as glutamate receptor subunits and serotonin receptor 2C. However, the most common targets for A?I editing are non-coding RNAs that contain inverted repeats of repetitive elements such as Alu and LINE located within introns and 3'UTRs. The biological significance of non-coding, repetitive RNA editing is largely unknown. Recently, we found that primary transcripts of certain miRNA genes (pri-miRNAs) are edited. Editing of pri-miRNAs results in inhibition of their processing or expression of edited mature miRNAs that silence genes different from those targeted by unedited miRNAs. Our findings revealed a previously unknown role for A?I RNA editing in miRNA-mediated gene silencing. The heart is the embryonic tissue where ADAR1 is first detected, at stage E10. ADAR2 expression is detected in the aortic sac at E10.5 and selected regions of embryonic heart including aortic valve at E14.5. ADAR1 null mutant mice have embryonic lethal phenotypes including heart malformation possibly due to hypoproliferation or increased apoptosis of cardiomyocytes. Editing of an unknown target dsRNA(s) by ADAR1 and ADAR2 may play a critical role in the regulation of embryonic heart development. The miRNA-mediated RNA interference recently emerged as a previously unsuspected mechanism to regulate cardiogenesis during development. A select set of miRNAs have been shown to repress genes that regulate proliferation/differentiation of cardiomyocytes during development of embryonic heart. Furthermore, aberrant expression of these miRNAs is associated with congenital ventricular septal defects or pathological conditions of adult heart such as ventricular hypertrophy, hyperplasia and arrhythmias. Our preliminary studies indicate that primary transcripts of miRNA-1, miRNA-133a and miR-208 genes undergo A?I editing. In this Challenge Grant application, we will investigate whether RNA editing of primary transcripts of these miRNAs play a role in the regulation of cardiomyocyte proliferation/differentiation and embryonic heart development. The effects of the RNA editing will be investigated in vitro by a miRNA processing assay and during in vitro induced differentiation of P19CL6 mouse embryonic stem cells to cardiomyocytes. Information obtained in this proposal will be essential for the future development of miRNA-based therapy of various cardiovascular diseases. Public Health Relevance: Our research proposal, based on previously unexplored paradigms, will reveal critical information for better understanding of the mechanisms underlying normal and defective development of heart, and function and disease of adult heart. Information obtained through this research proposal is essential for the future development of a new miRNA-based intervention for prevention of congenital heart defects and pathological cardiac conditions such as cardiac hypertrophy and arrhythmias.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Antagonistic and stimulative roles of ADAR1 in RNA silencing
    Kazuko Nishikura
    The Wistar Institute Philadelphia, PA USA
    RNA Biol 10:1240-7. 2013
  2. pmc Human endonuclease V is a ribonuclease specific for inosine-containing RNA
    Yoko Morita
    Graduate School of Engineering Science, Osaka University, 1 3 Machikaneyama, Toyonaka, Osaka 560 8531, Japan
    Nat Commun 4:2273. 2013
  3. pmc ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing
    Hiromitsu Ota
    The Wistar Institute, Philadelphia, PA 19104, USA
    Cell 153:575-89. 2013
  4. ncbi A-to-I editing of protein coding and noncoding RNAs
    Arka Mallela
    The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
    Crit Rev Biochem Mol Biol 47:493-501. 2012
  5. pmc Elucidating the inosinome: global approaches to adenosine-to-inosine RNA editing
    Bjorn Erik Wulff
    The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA
    Nat Rev Genet 12:81-5. 2011
  6. pmc Substitutional A-to-I RNA editing
    Bjorn Erik Wulff
    Gene Expression and Regulation, The Wistar Institute, Philadelphia, PA, USA
    Wiley Interdiscip Rev RNA 1:90-101. 2010
  7. pmc Adenosine-to-inosine RNA editing
    Boris Zinshteyn
    The Wistar Institute, Gene Expression and Regulation, Philadelphia, PA 19104, USA
    Wiley Interdiscip Rev Syst Biol Med 1:202-9. 2009
  8. pmc Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency
    Hisashi Iizasa
    The Wistar Institute, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 285:33358-70. 2010
  9. pmc Functional relevance of serotonin 2C receptor mRNA editing in antidepressant- and anxiety-like behaviors
    Cedric Mombereau
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Neuropharmacology 59:468-73. 2010
  10. pmc Functions and regulation of RNA editing by ADAR deaminases
    Kazuko Nishikura
    Department of Gene Expression and Regulation, The Wistar Institute, Philadelphia, Pennsylvania 19104 4268, USA
    Annu Rev Biochem 79:321-49. 2010

Scientific Experts

  • Bjorn Erik Wulff
  • Kazuko Nishikura
  • Boris Zinshteyn
  • Hisashi Iizasa
  • Yoko Morita
  • Hiromitsu Ota
  • Arka Mallela
  • Cedric Mombereau
  • Masayuki Sakurai
  • Nozomi Nakanishi
  • Isao Kuraoka
  • Louis Valente
  • Kentaro Ariyoshi
  • Toshihiro Shibutani
  • Ravi Gupta
  • Ramana V Davuluri
  • Shigenori Iwai
  • Artemis Hatzigeorgiou
  • Paul Lieberman
  • Kenzo Takada
  • Yukio Kawahara
  • Andreas Wiedmer
  • Molly Megraw
  • Brigitta B Gundersen
  • Dai Iwakiri
  • Julie A Blendy
  • Louise Showe
  • Manolis Maragkakis
  • Nageswara R Alla

Detail Information

Publications10

  1. pmc Antagonistic and stimulative roles of ADAR1 in RNA silencing
    Kazuko Nishikura
    The Wistar Institute Philadelphia, PA USA
    RNA Biol 10:1240-7. 2013
    ..Expression of miRNAs is globally inhibited in ADAR1-null mouse embryos, which, in turn, alters expression of their target genes and may contribute to their embryonic lethal phenotype. ..
  2. pmc Human endonuclease V is a ribonuclease specific for inosine-containing RNA
    Yoko Morita
    Graduate School of Engineering Science, Osaka University, 1 3 Machikaneyama, Toyonaka, Osaka 560 8531, Japan
    Nat Commun 4:2273. 2013
    ..These results demonstrate that hEndoV controls the fate of inosine-containing RNA in humans. ..
  3. pmc ADAR1 forms a complex with Dicer to promote microRNA processing and RNA-induced gene silencing
    Hiromitsu Ota
    The Wistar Institute, Philadelphia, PA 19104, USA
    Cell 153:575-89. 2013
    ..As expected, the expression of miRNAs is globally inhibited in ADAR1(-/-) mouse embryos, which, in turn, alters the expression of their target genes and might contribute to their embryonic lethal phenotype...
  4. ncbi A-to-I editing of protein coding and noncoding RNAs
    Arka Mallela
    The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
    Crit Rev Biochem Mol Biol 47:493-501. 2012
    ..Such editing has a wide range of physiological effects, including modification of targets in the brain and in disease states...
  5. pmc Elucidating the inosinome: global approaches to adenosine-to-inosine RNA editing
    Bjorn Erik Wulff
    The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA
    Nat Rev Genet 12:81-5. 2011
    ..This Progress article reviews some of these recent global studies and their results...
  6. pmc Substitutional A-to-I RNA editing
    Bjorn Erik Wulff
    Gene Expression and Regulation, The Wistar Institute, Philadelphia, PA, USA
    Wiley Interdiscip Rev RNA 1:90-101. 2010
    ..This includes microRNAs, small interfering RNAs, viral RNAs, and messenger RNAs with potential for recoding events and splice site modifications...
  7. pmc Adenosine-to-inosine RNA editing
    Boris Zinshteyn
    The Wistar Institute, Gene Expression and Regulation, Philadelphia, PA 19104, USA
    Wiley Interdiscip Rev Syst Biol Med 1:202-9. 2009
    ..The vast majority of editing sites are in noncoding sequences. This includes microRNAs, as well as the introns and 3' untranslated regions of messenger RNAs, which play important roles in the RNA-mediated regulation of gene expression...
  8. pmc Editing of Epstein-Barr virus-encoded BART6 microRNAs controls their dicer targeting and consequently affects viral latency
    Hisashi Iizasa
    The Wistar Institute, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 285:33358-70. 2010
    ..Mutation and A-to-I editing appear to be adaptive mechanisms that antagonize miR-BART6 activities...
  9. pmc Functional relevance of serotonin 2C receptor mRNA editing in antidepressant- and anxiety-like behaviors
    Cedric Mombereau
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Neuropharmacology 59:468-73. 2010
    ..These data constitute the first in vivo demonstration of a role for 5-HT(2C)R mRNA editing in anxiety- and depression-related behaviors...
  10. pmc Functions and regulation of RNA editing by ADAR deaminases
    Kazuko Nishikura
    Department of Gene Expression and Regulation, The Wistar Institute, Philadelphia, Pennsylvania 19104 4268, USA
    Annu Rev Biochem 79:321-49. 2010
    ..Here, I review the recent findings that indicate new functions for A-->I editing in the regulation of noncoding RNAs and for interactions between RNA editing and RNA interference mechanisms...