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Nature. 2017 Oct 11;550(7675):249-254. doi: 10.1038/nature24041.

Dynamic landscape and regulation of RNA editing in mammals.

Collaborators (248)

Aguet F, Ardlie KG, Cummings BB, Gelfand ET, Getz G, Hadley K, Handsaker RE, Huang KH, Kashin S, Karczewski KJ, Lek M, Li X, MacArthur DG, Nedzel JL, Nguyen DT, Noble MS, Segrè AV, Trowbridge CA, Tukiainen T, Abell NS, Balliu B, Barshir R, Basha O, Battle A, Bogu GK, Brown A, Brown CD, Castel SE, Chen LS, Chiang C, Conrad DF, Cox NJ, Damani FN, Davis JR, Delaneau O, Dermitzakis ET, Engelhardt BE, Eskin E, Ferreira PG, Frésard L, Gamazon ER, Garrido-Martín D, Gewirtz ADH, Gliner G, Gloudemans MJ, Guigo R, Hall IM, Han B, He Y, Hormozdiari F, Howald C, Kyung Im H, Jo B, Yong Kang E, Kim Y, Kim-Hellmuth S, Lappalainen T, Li G, Li X, Liu B, Mangul S, McCarthy MI, McDowell IC, Mohammadi P, Monlong J, Montgomery SB, Muñoz-Aguirre M, Ndungu AW, Nicolae DL, Nobel AB, Oliva M, Ongen H, Palowitch JJ, Panousis N, Papasaikas P, Park Y, Parsana P, Payne AJ, Peterson CB, Quan J, Reverter F, Sabatti C, Saha A, Sammeth M, Scott AJ, Shabalin AA, Sodaei R, Stephens M, Stranger BE, Strober BJ, Sul JH, Tsang EK, Urbut S, van de Bunt M, Wang G, Wen X, Wright FA, Xi HS, Yeger-Lotem E, Zappala Z, Zaugg JB, Zhou YH, Akey JM, Bates D, Chan J, Chen LS, Claussnitzer M, Demanelis K, Diegel M, Doherty JA, Feinberg AP, Fernando MS, Halow J, Hansen KD, Haugen E, Hickey PF, Hou L, Jasmine F, Jian R, Jiang L, Johnson A, Kaul R, Kellis M, Kibriya MG, Lee K, Li JB, Li Q, Li X, Lin J, Lin S, Linder S, Linke C, Liu Y, Maurano MT, Molinie B, Montgomery SB, Nelson J, Neri FJ, Oliva M, Park Y, Pierce BL, Rinaldi NJ, Rizzardi LF, Sandstrom R, Skol A, Smith KS, Snyder MP, Stamatoyannopoulos J, Stranger BE, Tang H, Tsang EK, Wang L, Wang M, Van Wittenberghe N, Wu F, Zhang R, Nierras CR, Branton PA, Carithers LJ, Guan P, Moore HM, Rao A, Vaught JB, Gould SE, Lockart NC, Martin C, Struewing JP, Volpi S, Addington AM, Koester SE, Little AR, Brigham LE, Hasz R, Hunter M, Johns C, Johnson M, Kopen G, Leinweber WF, Lonsdale JT, McDonald A, Mestichelli B, Myer K, Roe B, Salvatore M, Shad S, Thomas JA, Walters G, Washington M, Wheeler J, Bridge J, Foster BA, Gillard BM, Karasik E, Kumar R, Miklos M, Moser MT, Jewell SD, Montroy RG, Rohrer DC, Valley DR, Davis DA, Mash DC, Undale AH, Smith AM, Tabor DE, Roche NV, McLean JA, Vatanian N, Robinson KL, Sobin L, Barcus ME, Valentino KM, Qi L, Hunter S, Hariharan P, Singh S, Um KS, Matose T, Tomaszewski MM, Barker LK, Mosavel M, Siminoff LA, Traino HM, Flicek P, Juettemann T, Ruffier M, Sheppard D, Taylor K, Trevanion SJ, Zerbino DR, Craft B, Goldman M, Haeussler M, Kent WJ, Lee CM, Paten B, Rosenbloom KR, Vivian J, Zhu J, Craft B, Goldman M, Haeussler M, Kent WJ, Lee CM, Paten B, Rosenbloom KR, Vivian J, Zhu J.

Author information

1
Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
2
School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637459, Singapore.
3
Genome Institute of Singapore, Agency for Science Technology and Research, Singapore 138672, Singapore.
4
The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
5
St Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
6
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
7
Central European Institute of Technology, Masaryk University, Kamenice, Brno 625 00, Czech Republic.
8
Department of Molecular, Cellular and Developmental Biology, University of California-Santa Barbara, Santa Barbara, California 93106, USA.
9
Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63108, USA.
10
Department of Pathology &Immunology, Washington University School of Medicine, St Louis, Missouri 63108, USA.
11
Department of Life Sciences, University of Trieste, 34127 Trieste, Italy and National Laboratory CIB (LNCIB), Area Science Park, 34149 Trieste, Italy.
12
Cardiovascular Research Institute, University of California-San Francisco, San Francisco, California 94158, USA.
13
Department of Anesthesia, Stanford University School of Medicine, Stanford, California 94305, USA.
14
Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria 3065, Australia.

Abstract

Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules. Although many editing sites have recently been discovered, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. Globally, ADAR1 is the primary editor of repetitive sites and ADAR2 is the primary editor of non-repetitive coding sites, whereas the catalytically inactive ADAR3 predominantly acts as an inhibitor of editing. Cross-species analysis of RNA editing in several tissues revealed that species, rather than tissue type, is the primary determinant of editing levels, suggesting stronger cis-directed regulation of RNA editing for most sites, although the small set of conserved coding sites is under stronger trans-regulation. In addition, we curated an extensive set of ADAR1 and ADAR2 targets and showed that many editing sites display distinct tissue-specific regulation by the ADAR enzymes in vivo. Further analysis of the GTEx data revealed several potential regulators of editing, such as AIMP2, which reduces editing in muscles by enhancing the degradation of the ADAR proteins. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing.

PMID:
29022589
PMCID:
PMC5723435
DOI:
10.1038/nature24041
[Indexed for MEDLINE]
Free PMC Article

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