Identification of human RNA editing sites: A historical perspective

Ramaswami, Gokul; Li, Jin Billy

doi:10.1016/j.ymeth.2016.05.011

Cited by 69 publications

(64 citation statements)

References 60 publications

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“…Statistical survey of these A-to-I editing sites indicated that the majority of them were in introns, intergenic regions, or 3' UTRs ( Fig. 1A & Table S1 in Additional file 2), which is consistent with the data from the popular RNA editing databases, such as RADAR and REDIportal (2,3,6).…”

Section: High Concordance Of Adar1 Binding Sites With A-to-i Editing supporting

confidence: 82%

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Widespread interaction between ADAR1 and transcriptional byproducts

Tang

Tan

et al. 2019

Preprint

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Background: ADAR1, an adenosine-to-inosine (A-to-I) RNA editing enzyme, has an emerging role in cancer immunotherapy. ADAR1 presumably works by suppressing cellular innate immunity response to endogenously generated double-stranded RNAs through RNA editing. However, RNA species that are directly regulated by ADAR1 mediated RNA editing processes remain poorly defined. Results:In this study, we used a novel bioinformatics approach to track ADAR1-RNA interactions. By integrating DNA-seq, RNA-seq, and ADAR1 RNA immunoprecipitation sequencing (fRIP-seq) data of K562 cell line, we provided the first in-situ landscape profiling of ADAR1 RNA binding and editing activities. With long RNA fragments captured by ADAR1 immunoprecipitation, we were able to identify exon junctions and genomic boundaries used by ADAR1-associated RNAs and thus we could possibly trace pre-RNA processing steps that had been acting on them. Our methodology allowed us to establish the knowledge of transcriptome-wide scenario of ADAR1 activities. Intriguingly, we found that ADAR1 had a tendency to interact with transcriptional byproducts originated from obscure regions such as introns and intergenic regions. Conclusions:Our observation might shed light on the dual role of ADAR1 proteins not only in diversifying the transcriptome, but also in reigning RNA debris from obscure regions. Moreover, as the functional potential of seemly transcriptional byproducts is just beginning to emerge, this study would bridge ADAR1 with other fields of RNA biology.

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Section: High Concordance Of Adar1 Binding Sites With A-to-i Editing supporting

confidence: 82%

“…Most of A-to-I editing sites are detected in poorly annotated and non-conserved genomic regions, such as introns, intergenic regions (IGRs), and 3' UTRs (5,6). Moreover, RNA editing events are co-transcriptional and rarely happen on mature mRNAs (19).…”

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confidence: 99%

Widespread interaction between ADAR1 and transcriptional byproducts

Tang

Tan

et al. 2019

Preprint

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“…(Desrosiers et al 1974;Perry and Kelley 1974;Dubin and Taylor 1975), technological barriers hindered research into the presence and specific distribution of modified nucleosides within messenger (m)RNAs and other ncRNAs. This changed when next generation sequencing methods were adapted, first to detect RNA editing events, reviewed in (Ramaswami and Li 2016), and soon after to map 5methylcytosine (m 5 C) and N6-methyladenosine (m 6 A) in a transcriptome-wide fashion (Dominissini et al 2012;Meyer et al 2012;Squires et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Multiple links between 5-methylcytosine content of mRNA and translation

Schümann

Zhang²,

Sibbritt

et al. 2020

Preprint

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Abstract5-methylcytosine (m5C) is a prevalent base modification in tRNA and rRNA but it also occurs more broadly in the transcriptome, including in mRNA, where it serves incompletely understood molecular functions. In pursuit of potential links of m5C with mRNA translation, we performed polysome profiling of human HeLa cell lysates and subjected RNA from resultant fractions to efficient bisulfite conversion followed by RNA sequencing (bsRNA-seq). Bioinformatic filters for rigorous site calling were devised to reduce technical noise. We obtained ∼1,000 candidate m5C sites in the wider transcriptome, most of which were found in mRNA. Multiple novel sites were validated by amplicon-specific bsRNA-seq in independent samples of either human HeLa, LNCaP and PrEC cells. Furthermore, RNAi-mediated depletion of either the NSUN2 or TRDMT1 m5C:RNA methyltransferases showed a clear dependence on NSUN2 for the majority of tested sites in both mRNAs and noncoding RNAs. Candidate m5C sites in mRNAs are enriched in 5’UTRs and near start codons, and are commonly embedded in a local context reminiscent of the NSUN2-dependent m5C sites found in the variable loop of tRNA. Analysing mRNA sites across the polysome profile revealed that modification levels, at bulk and for many individual sites, were inversely correlated with ribosome association. Altogether, these findings emphasise the major role of NSUN2 in making this mark transcriptome-wide and further substantiate a functional interdependence of cytosine methylation level with mRNA translation.

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“…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 . Separate laboratories have examined the RNA editome across many tissues or developmental stages in human and other mammals 13–17 .…”

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confidence: 99%

Dynamic landscape and regulation of RNA editing in mammals

Tan

Shanmugam

et al. 2017

Nature

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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 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 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.

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Identification of human RNA editing sites: A historical perspective

Cited by 69 publications

References 60 publications

Widespread interaction between ADAR1 and transcriptional byproducts

Widespread interaction between ADAR1 and transcriptional byproducts

Multiple links between 5-methylcytosine content of mRNA and translation

Dynamic landscape and regulation of RNA editing in mammals

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