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

Journal name:
Nature Neuroscience
Volume:
16,
Pages:
1518–1522
Year published:
DOI:
doi:10.1038/nn.3539
Received
Accepted
Published online

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.

At a glance

Figures

  1. Overview.
    Figure 1: Overview.

    We highlight the major, but not all, discussion topics.

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

    Phylogenetic relationships between human, chimpanzee, rhesus macaque and mouse are shown on the left. Myr, million years ago. Numbers of A-to-I editing sites that are conserved between human and each of the other three species are shown on the right, with the numbers in non-Alu regions magnified at the bottom. The number of editing sites conserved in human (indicated in the scales) is based on the analysis of the same number of reads from each species28. Figure is adapted from ref. 28.

References

  1. Taft, R.J., Pheasant, M. & Mattick, J.S. The relationship between non-protein-coding DNA and eukaryotic complexity. Bioessays 29, 288299 (2007).
  2. Nishikura, K. Functions and regulation of RNA editing by ADAR deaminases. Annu. Rev. Biochem. 79, 321349 (2010).
  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, 437449 (2000).
  4. Tonkin, L.A. et al. RNA editing by ADARs is important for normal behavior in Caenorhabditis elegans. EMBO J. 21, 60256035 (2002).
  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, 755767 (2000).
  6. Wang, Q., Khillan, J., Gadue, P. & Nishikura, K. Requirement of the RNA editing deaminase ADAR1 gene for embryonic erythropoiesis. Science 290, 17651768 (2000).
  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, 48944902 (2004).
  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, 7881 (2000).
  9. Maas, S., Kawahara, Y., Tamburro, K.M. & Nishikura, K. A-to-I RNA editing and human disease. RNA Biol. 3, 19 (2006).
  10. Burns, C.M. et al. Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 387, 303308 (1997).
  11. Kawahara, Y. et al. Dysregulated editing of serotonin 2C receptor mRNAs results in energy dissipation and loss of fat mass. J. Neurosci. 28, 1283412844 (2008).
  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, 311321 (2012).
  13. Eran, A. et al. Comparative RNA editing in autistic and neurotypical cerebella. Mol. Psychiatry 18, 10411048 (2012).
  14. Chen, L. et al. Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. Nat. Med. 19, 209216 (2013).
  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, 1119 (1991).
  16. Hoopengardner, B., Bhalla, T., Staber, C. & Reenan, R. Nervous system targets of RNA editing identified by comparative genomics. Science 301, 832836 (2003).
  17. Levanon, E.Y. et al. Evolutionarily conserved human targets of adenosine to inosine RNA editing. Nucleic Acids Res. 33, 11621168 (2005).
  18. Levanon, E.Y. et al. Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nat. Biotechnol. 22, 10011005 (2004).
  19. Kim, D.D. et al. Widespread RNA editing of embedded alu elements in the human transcriptome. Genome Res. 14, 17191725 (2004).
  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).
  21. Li, J.B. et al. Genome-wide identification of human RNA editing sites by parallel DNA capturing and sequencing. Science 324, 12101213 (2009).
  22. Li, M. et al. Widespread RNA and DNA sequence differences in the human transcriptome. Science 333, 5358 (2011).
  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).
  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).
  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).
  26. Ramaswami, G. et al. Accurate identification of human Alu and non-Alu RNA editing sites. Nat. Methods 9, 579581 (2012).
  27. Piskol, R., Peng, Z., Wang, J. & Li, J.B. Lack of evidence for existence of noncanonical RNA editing. Nat. Biotechnol. 31, 1920 (2013).
  28. Ramaswami, G. et al. Identifying RNA editing sites using RNA sequencing data alone. Nat. Methods 10, 128132 (2013).
  29. Paz-Yaacov, N. et al. Adenosine-to-inosine RNA editing shapes transcriptome diversity in primates. Proc. Natl. Acad. Sci. USA 107, 1217412179 (2010).
  30. Lomeli, H. et al. Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science 266, 17091713 (1994).
  31. Brusa, R. et al. Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice. Science 270, 16771680 (1995).
  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).
  33. Gaj, T., Gersbach, C.A. & Barbas, C.F. III ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 31, 397405 (2013).
  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, 832839 (2013).
  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, 978986 (2009).
  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, 281287 (2012).
  37. Peng, Z. et al. Comprehensive analysis of RNA-Seq data reveals extensive RNA editing in a human transcriptome. Nat. Biotechnol. 30, 253260 (2012).
  38. Heiman, M. et al. A translational profiling approach for the molecular characterization of CNS cell types. Cell 135, 738748 (2008).
  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, 766777 (2012).
  40. Ke, R. et al. In situ sequencing for RNA analysis in preserved tissue and cells. Nat. Methods 10, 857860 (2013).
  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, 189194 (2012).
  42. Eggington, J.M., Greene, T. & Bass, B.L. Predicting sites of ADAR editing in double-stranded RNA. Nat. Commun. 2, 319 (2011).
  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, 98769886 (2012).
  44. Peng, P.L. et al. ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 determines vulnerability of neurons in forebrain ischemia. Neuron 49, 719733 (2006).
  45. Marcucci, R. et al. Pin1 and WWP2 regulate GluR2 Q/R site RNA editing by ADAR2 with opposing effects. EMBO J. 30, 42114222 (2011).
  46. Bhogal, B. et al. Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein. Nat. Neurosci. 14, 15171524 (2011).
  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, 12661281 (2012).
  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, 192204 (2013).
  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, 25812593 (2013).
  50. Alivisatos, A.P. et al. Neuroscience. The brain activity map. Science 339, 12841285 (2013).

Download references

Author information

Affiliations

  1. Department of Genetics, Stanford University, Stanford, California, USA.

    • Jin Billy Li
  2. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • George M Church

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Author details

Additional data