The importance of RNA editing in vascular disease was demonstrated in a recent study 18. Unexpectedly, the artery was the most highly edited tissue type ( Fig. The different brain regions clustered together, as did heart and skeletal muscle. When we examined non-repetitive sites in coding regions only, the editing levels became more distinct among the various tissues ( Fig. 1b), possibly owing to higher expression of ADAR2 (also known as ADARB1) ( Extended Data Fig. Within the brain, the cerebellum was clearly segregated from other brain parts ( Extended Data Fig. Nevertheless, principal component analysis (PCA) showed that the brain regions could still be resolved from non-brain tissues ( Extended Data Fig. 1a) and the overall editing activities were also generally similar, except for skeletal muscle, in which editing was significantly lower than in other tissues ( P < 2.2 × 10 −16, Wilcoxon rank sum test Fig. Notably, the editing profiles across different tissues were highly correlated ( Fig. To construct a mammalian reference atlas of A-to-I editing, we first compiled a comprehensive list of editing sites in human and mouse ( Supplementary Note 1) and then examined the RNA editome across tissues using 8,551 RNA-sequencing (RNA-seq) samples derived from 552 donors in the GTEx project ( Supplementary Information 1). In this work, we performed multidimensional analyses of thousands of new and publicly available sequencing libraries to address major gaps in our fundamental knowledge of A-to-I editing. However, the published studies are limited in the number of samples and tissues examined and do not systematically compare the editing landscape across species or thoroughly dissect the regulation of editing. Separate laboratories have examined the RNA editome across many tissues or developmental stages in human and other mammals 13, 14, 15, 16, 17. The prevalence and importance of A-to-I RNA editing have been illuminated in recent years largely owing to the rapid adoption of high-throughput sequencing technologies 11, 12. Collectively, our work provides insights into the complex cis- and trans-regulation of A-to-I editing. 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. 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. 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. 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. We show that editing levels in non-repetitive coding regions vary more between tissues than editing levels in repetitive regions. 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. Although many editing sites have recently been discovered 2, 3, 4, 5, 6, 7, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood 8, 9, 10. 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 1.
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