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Deciphering the functions and regulation of brain-enriched A-to-I RNA editing

Abstract

Adenosine-to-inosine (A-to-I) RNA editing, in which genomically encoded adenosine is changed to inosine in RNA, is catalyzed by adenosine deaminase acting on RNA (ADAR). This fine-tuning mechanism is critical during normal development and diseases, particularly in relation to brain functions. A-to-I RNA editing has also been hypothesized to be a driving force in human brain evolution. A large number of RNA editing sites have recently been identified, mostly as a result of the development of deep sequencing and bioinformatic analyses. Deciphering the functional consequences of RNA editing events is challenging, but emerging genome engineering approaches may expedite new discoveries. To understand how RNA editing is dynamically regulated, it is imperative to construct a spatiotemporal atlas at the species, tissue and cell levels. Future studies will need to identify the cis and trans regulatory factors that drive the selectivity and frequency of RNA editing. We anticipate that recent technological advancements will aid researchers in acquiring a much deeper understanding of the functions and regulation of RNA editing.

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Figure 1: Overview.
Figure 2: Decreased number of RNA editing sites shared with human sites with increased phylogenetic distance.

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References

  1. Taft, R.J., Pheasant, M. & Mattick, J.S. The relationship between non-protein-coding DNA and eukaryotic complexity. Bioessays 29, 288–299 (2007).

    Article  CAS  Google Scholar 

  2. Nishikura, K. Functions and regulation of RNA editing by ADAR deaminases. Annu. Rev. Biochem. 79, 321–349 (2010).

    Article  CAS  Google Scholar 

  3. Palladino, M.J., Keegan, L.P., O'Connell, M.A. & Reenan, R.A. A-to-I pre-mRNA editing in Drosophila is primarily involved in adult nervous system function and integrity. Cell 102, 437–449 (2000).

    Article  CAS  Google Scholar 

  4. Tonkin, L.A. et al. RNA editing by ADARs is important for normal behavior in Caenorhabditis elegans. EMBO J. 21, 6025–6035 (2002).

    Article  CAS  Google Scholar 

  5. Chen, C.X. et al. A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains. RNA 6, 755–767 (2000).

    Article  CAS  Google Scholar 

  6. Wang, Q., Khillan, J., Gadue, P. & Nishikura, K. Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science 290, 1765–1768 (2000).

    Article  CAS  Google Scholar 

  7. Hartner, J.C. et al. Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J. Biol. Chem. 279, 4894–4902 (2004).

    Article  CAS  Google Scholar 

  8. Higuchi, M. et al. Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature 406, 78–81 (2000).

    Article  CAS  Google Scholar 

  9. Maas, S., Kawahara, Y., Tamburro, K.M. & Nishikura, K. A-to-I RNA editing and human disease. RNA Biol. 3, 1–9 (2006).

    Article  CAS  Google Scholar 

  10. Burns, C.M. et al. Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387, 303–308 (1997).

    Article  CAS  Google Scholar 

  11. Kawahara, Y. et al. Dysregulated editing of serotonin 2C receptor mRNAs results in energy dissipation and loss of fat mass. J. Neurosci. 28, 12834–12844 (2008).

    Article  CAS  Google Scholar 

  12. Silberberg, G., Lundin, D., Navon, R. & Ohman, M. Deregulation of the A-to-I RNA editing mechanism in psychiatric disorders. Hum. Mol. Genet. 21, 311–321 (2012).

    Article  CAS  Google Scholar 

  13. Eran, A. et al. Comparative RNA editing in autistic and neurotypical cerebella. Mol. Psychiatry 18, 1041–1048 (2012).

    Article  Google Scholar 

  14. Chen, L. et al. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat. Med. 19, 209–216 (2013).

    Article  Google Scholar 

  15. Sommer, B., Kohler, M., Sprengel, R. & Seeburg, P.H. RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67, 11–19 (1991).

    Article  CAS  Google Scholar 

  16. Hoopengardner, B., Bhalla, T., Staber, C. & Reenan, R. Nervous system targets of RNA editing identified by comparative genomics. Science 301, 832–836 (2003).

    Article  CAS  Google Scholar 

  17. Levanon, E.Y. et al. Evolutionarily conserved human targets of adenosine to inosine RNA editing. Nucleic Acids Res. 33, 1162–1168 (2005).

    Article  CAS  Google Scholar 

  18. Levanon, E.Y. et al. Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat. Biotechnol. 22, 1001–1005 (2004).

    Article  CAS  Google Scholar 

  19. Kim, D.D. et al. Widespread RNA editing of embedded alu elements in the human transcriptome. Genome Res. 14, 1719–1725 (2004).

    Article  CAS  Google Scholar 

  20. Athanasiadis, A., Rich, A. & Maas, S. Widespread A-to-I RNA editing of Alu-containing mRNAs in the human transcriptome. PLoS Biol. 2, e391 (2004).

    Article  Google Scholar 

  21. Li, J.B. et al. Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science 324, 1210–1213 (2009).

    Article  CAS  Google Scholar 

  22. Li, M. et al. Widespread RNA and DNA sequence differences in the human transcriptome. Science 333, 53–58 (2011).

    Article  CAS  Google Scholar 

  23. Kleinman, C.L. & Majewski, J. Comment on “Widespread RNA and DNA sequence differences in the human transcriptome”. Science 335, 1302; author reply 1302 (2012).

    Article  CAS  Google Scholar 

  24. Pickrell, J.K., Gilad, Y. & Pritchard, J.K. Comment on “Widespread RNA and DNA sequence differences in the human transcriptome”. Science 335, 1302; author reply 1302 (2012).

    Article  CAS  Google Scholar 

  25. Lin, W., Piskol, R., Tan, M.H. & Li, J.B. Comment on “Widespread RNA and DNA sequence differences in the human transcriptome”. Science 335, 1302; author reply 1302 (2012).

    Article  CAS  Google Scholar 

  26. Ramaswami, G. et al. Accurate identification of human Alu and non-Alu RNA editing sites. Nat. Methods 9, 579–581 (2012).

    Article  CAS  Google Scholar 

  27. Piskol, R., Peng, Z., Wang, J. & Li, J.B. Lack of evidence for existence of noncanonical RNA editing. Nat. Biotechnol. 31, 19–20 (2013).

    Article  CAS  Google Scholar 

  28. Ramaswami, G. et al. Identifying RNA editing sites using RNA sequencing data alone. Nat. Methods 10, 128–132 (2013).

    Article  CAS  Google Scholar 

  29. Paz-Yaacov, N. et al. Adenosine-to-inosine RNA editing shapes transcriptome diversity in primates. Proc. Natl. Acad. Sci. USA 107, 12174–12179 (2010).

    Article  CAS  Google Scholar 

  30. Lomeli, H. et al. Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science 266, 1709–1713 (1994).

    Article  CAS  Google Scholar 

  31. Brusa, R. et al. Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice. Science 270, 1677–1680 (1995).

    Article  CAS  Google Scholar 

  32. Olaghere da Silva, U.B. et al. Impact of RNA editing on functions of the serotonin 2C receptor in vivo. Front. Neurosci. 4, 26 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Gaj, T., Gersbach, C.A. & Barbas, C.F. III ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 31, 397–405 (2013).

    Article  CAS  Google Scholar 

  34. Mizrahi, R.A., Schirle, N.T. & Beal, P.A. Potent and selective inhibition of A-to-I RNA editing with 2′-O-methyl/locked nucleic acid–containing antisense oligoribonucleotides. ACS Chem. Biol. 8, 832–839 (2013).

    Article  CAS  Google Scholar 

  35. Wahlstedt, H., Daniel, C., Enstero, M. & Ohman, M. Large-scale mRNA sequencing determines global regulation of RNA editing during brain development. Genome Res. 19, 978–986 (2009).

    Article  CAS  Google Scholar 

  36. Sanjana, N.E., Levanon, E.Y., Hueske, E.A., Ambrose, J.M. & Li, J.B. Activity-dependent A-to-I RNA editing in rat cortical neurons. Genetics 192, 281–287 (2012).

    Article  CAS  Google Scholar 

  37. Peng, Z. et al. Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome. Nat. Biotechnol. 30, 253–260 (2012).

    Article  CAS  Google Scholar 

  38. Heiman, M. et al. A translational profiling approach for the molecular characterization of CNS cell types. Cell 135, 738–748 (2008).

    Article  CAS  Google Scholar 

  39. Steiner, F.A., Talbert, P.B., Kasinathan, S., Deal, R.B. & Henikoff, S. Cell type–specific nuclei purification from whole animals for genome-wide expression and chromatin profiling. Genome Res. 22, 766–777 (2012).

    Article  CAS  Google Scholar 

  40. Ke, R. et al. In situ sequencing for RNA analysis in preserved tissue and cells. Nat. Methods 10, 857–860 (2013).

    Article  CAS  Google Scholar 

  41. Jepson, J.E., Savva, Y.A., Jay, K.A. & Reenan, R.A. Visualizing adenosine-to-inosine RNA editing in the Drosophila nervous system. Nat. Methods 9, 189–194 (2012).

    Article  CAS  Google Scholar 

  42. Eggington, J.M., Greene, T. & Bass, B.L. Predicting sites of ADAR editing in double-stranded RNA. Nat. Commun. 2, 319 (2011).

    Article  Google Scholar 

  43. Daniel, C., Veno, M.T., Ekdahl, Y., Kjems, J. & Ohman, M. A distant cis acting intronic element induces site-selective RNA editing. Nucleic Acids Res. 40, 9876–9886 (2012).

    Article  CAS  Google Scholar 

  44. Peng, P.L. et al. ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia. Neuron 49, 719–733 (2006).

    Article  CAS  Google Scholar 

  45. Marcucci, R. et al. Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects. EMBO J. 30, 4211–4222 (2011).

    Article  CAS  Google Scholar 

  46. Bhogal, B. et al. Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein. Nat. Neurosci. 14, 1517–1524 (2011).

    Article  CAS  Google Scholar 

  47. Hughes, M.E., Grant, G.R., Paquin, C., Qian, J. & Nitabach, M.N. Deep sequencing the circadian and diurnal transcriptome of Drosophila brain. Genome Res. 22, 1266–1281 (2012).

    Article  CAS  Google Scholar 

  48. Garncarz, W., Tariq, A., Handl, C., Pusch, O. & Jantsch, M.F. A high-throughput screen to identify enhancers of ADAR-mediated RNA-editing. RNA Biol. 10, 192–204 (2013).

    Article  CAS  Google Scholar 

  49. Tariq, A. et al. RNA-interacting proteins act as site-specific repressors of ADAR2-mediated RNA editing and fluctuate upon neuronal stimulation. Nucleic Acids Res. 41, 2581–2593 (2013).

    Article  CAS  Google Scholar 

  50. Alivisatos, A.P. et al. Neuroscience. The brain activity map. Science 339, 1284–1285 (2013).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank members of the Li laboratory for discussions and critical reading of the manuscript, and particularly R. Zhang for making Figure 2. This work was funded by US National Institutes of Health (GM102484) and the Ellison Medical Foundation (to J.B.L.).

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Correspondence to Jin Billy Li.

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Li, J., Church, G. Deciphering the functions and regulation of brain-enriched A-to-I RNA editing. Nat Neurosci 16, 1518–1522 (2013). https://doi.org/10.1038/nn.3539

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