Dynamic landscape and regulation of RNA editing in mammals

GTEx Consortium

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

Adenosine-to-inosine (A-to-I) RNA editing is a conserved posttranscriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules1. Although many editing sites have recently been discovered2-7, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood8-10. 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 nonrepetitive 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.

Original languageEnglish (US)
Pages (from-to)249-254
Number of pages6
JournalNature
Volume550
Issue number7675
DOIs
StatePublished - Oct 11 2017
Externally publishedYes

Fingerprint

RNA Editing
Mammals
Inosine
Adenosine
Genotype
Nucleic Acid Repetitive Sequences
Enzymes
Transcriptome
Primates
Proteolysis
Nucleotides
RNA
Muscles

ASJC Scopus subject areas

  • General

Cite this

Dynamic landscape and regulation of RNA editing in mammals. / GTEx Consortium.

In: Nature, Vol. 550, No. 7675, 11.10.2017, p. 249-254.

Research output: Contribution to journalArticle

GTEx Consortium. / Dynamic landscape and regulation of RNA editing in mammals. In: Nature. 2017 ; Vol. 550, No. 7675. pp. 249-254.
@article{16217f5b242b4d258d1c242eff40e75e,
title = "Dynamic landscape and regulation of RNA editing in mammals",
abstract = "Adenosine-to-inosine (A-to-I) RNA editing is a conserved posttranscriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules1. Although many editing sites have recently been discovered2-7, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood8-10. 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 nonrepetitive 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.",
author = "{GTEx Consortium} and Tan, {Meng How} and Qin Li and Raghuvaran Shanmugam and Robert Piskol and Jennefer Kohler and Young, {Amy N.} and Liu, {Kaiwen Ivy} and Rui Zhang and Gokul Ramaswami and Kentaro Ariyoshi and Ankita Gupte and Keegan, {Liam P.} and George, {Cyril X.} and Avinash Ramu and Ni Huang and Pollina, {Elizabeth A.} and Leeman, {Dena S.} and Alessandra Rustighi and Goh, {Y. P.Sharon} and Fran{\cc}ois Aguet and Ardlie, {Kristin G.} and Cummings, {Beryl B.} and Gelfand, {Ellen T.} and Gad Getz and Kane Hadley and Handsaker, {Robert E.} and Huang, {Katherine H.} and Seva Kashin and Karczewski, {Konrad J.} and Monkol Lek and Xiao Li and MacArthur, {Daniel G.} and Nedzel, {Jared L.} and Nguyen, {Duyen T.} and Noble, {Michael S.} and Segr{\`e}, {Ayellet V.} and Trowbridge, {Casandra A.} and Taru Tukiainen and Abell, {Nathan S.} and Brunilda Balliu and Ruth Barshir and Omer Basha and Alexis Battle and Bogu, {Gireesh K.} and Andrew Brown and Brown, {Christopher D.} and Castel, {Stephane E.} and Chen, {Lin S.} and Colby Chiang and Don Conrad",
year = "2017",
month = "10",
day = "11",
doi = "10.1038/nature24041",
language = "English (US)",
volume = "550",
pages = "249--254",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7675",

}

TY - JOUR

T1 - Dynamic landscape and regulation of RNA editing in mammals

AU - GTEx Consortium

AU - Tan, Meng How

AU - Li, Qin

AU - Shanmugam, Raghuvaran

AU - Piskol, Robert

AU - Kohler, Jennefer

AU - Young, Amy N.

AU - Liu, Kaiwen Ivy

AU - Zhang, Rui

AU - Ramaswami, Gokul

AU - Ariyoshi, Kentaro

AU - Gupte, Ankita

AU - Keegan, Liam P.

AU - George, Cyril X.

AU - Ramu, Avinash

AU - Huang, Ni

AU - Pollina, Elizabeth A.

AU - Leeman, Dena S.

AU - Rustighi, Alessandra

AU - Goh, Y. P.Sharon

AU - Aguet, François

AU - Ardlie, Kristin G.

AU - Cummings, Beryl B.

AU - Gelfand, Ellen T.

AU - Getz, Gad

AU - Hadley, Kane

AU - Handsaker, Robert E.

AU - Huang, Katherine H.

AU - Kashin, Seva

AU - Karczewski, Konrad J.

AU - Lek, Monkol

AU - Li, Xiao

AU - MacArthur, Daniel G.

AU - Nedzel, Jared L.

AU - Nguyen, Duyen T.

AU - Noble, Michael S.

AU - Segrè, Ayellet V.

AU - Trowbridge, Casandra A.

AU - Tukiainen, Taru

AU - Abell, Nathan S.

AU - Balliu, Brunilda

AU - Barshir, Ruth

AU - Basha, Omer

AU - Battle, Alexis

AU - Bogu, Gireesh K.

AU - Brown, Andrew

AU - Brown, Christopher D.

AU - Castel, Stephane E.

AU - Chen, Lin S.

AU - Chiang, Colby

AU - Conrad, Don

PY - 2017/10/11

Y1 - 2017/10/11

N2 - Adenosine-to-inosine (A-to-I) RNA editing is a conserved posttranscriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules1. Although many editing sites have recently been discovered2-7, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood8-10. 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 nonrepetitive 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.

AB - Adenosine-to-inosine (A-to-I) RNA editing is a conserved posttranscriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules1. Although many editing sites have recently been discovered2-7, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood8-10. 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 nonrepetitive 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.

UR - http://www.scopus.com/inward/record.url?scp=85031298074&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85031298074&partnerID=8YFLogxK

U2 - 10.1038/nature24041

DO - 10.1038/nature24041

M3 - Article

C2 - 29022589

AN - SCOPUS:85031298074

VL - 550

SP - 249

EP - 254

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7675

ER -