ADAR-deficiency perturbs the global splicing landscape in mouse tissues

Abstract

Adenosine-to-inosine RNA editing and pre-mRNA splicing largely occur cotranscriptionally and influence each other. Here, we use mice deficient in either one of the two editing enzymes ADAR (ADAR1) or ADARB1 (ADAR2) to determine the transcriptome-wide impact of RNA editing on splicing across different tissues. We find that ADAR has a 100× higher impact on splicing than ADARB1, although both enzymes target a similar number of substrates with a large common overlap. Consistently, differentially spliced regions frequently harbor ADAR editing sites. Moreover, catalytically dead ADAR also impacts splicing, demonstrating that RNA binding of ADAR affects splicing. In contrast, ADARB1 editing sites are found enriched 5 ′ of differentially spliced regions. Several of these ADARB1-mediated editing events change splice consensus sequences, therefore strongly influencing splicing of some mRNAs. A significant overlap between differentially edited and differentially spliced sites suggests evolutionary selection toward splicing being regulated by editing in a tissue-specific manner.

Chemical probe-based Nanopore Sequencing to Selectively Assess the RNA modifications

“…Owing to the high reactivity of acrylonitrile towards I than Ψ, we primarily focused only on I in the transcriptome analysis. We retrieved chromosome coordinates of A-I sites through RADAR 20 , REDI portal database 21 and published literatures 22 . From the above A-I sites, we further removed sites overlapping with the latest version of the SNP database (dSNP 142).…”

REDIportal: millions of novel A-to-I RNA editing events from thousands of RNAseq experiments

“…As a consequence, A-to-I RNA editing can increase the transcriptome and proteome diversity, generate or destroy splice sites, alter codon identity or base-pairing interactions within higher-order RNA structures. Several evidences indicate that ADAR mediated RNA editing plays pivotal functional roles, tuning gene expression ( 5 , 6 ) or modulating the innate immune response through the MDA5-MAVS axis ( 2 , 7 ). Additionally, its deregulation is under active investigation being linked to different human disorders ( 8 ) including neurological ( 9 , 10 ), autoimmune ( 11 ), cardiovascular diseases ( 12 ) and cancer ( 13 , 14 ).…”

Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution

“…Moreover, a recent study showed that ADAR1 loss reduces induced pluripotent stem cell (iPSC) reprogramming efficiency by inducing ER stress (Guallar et al, 2020). Additionally, alternatively spliced regions frequently harbor A-to-I editing sites whereby ADAR1 deficiency impairs alternative splicing in mouse tissues (Kapoor et al, 2020). Deregulation of ADAR1mediated A-to-I editing alters stem cell survival and self-renewal regulatory mRNA and miRNA stability (Chen et al, 2013;Han et al, 2015;Jiang et al, 2017Jiang et al, , 2019Lazzari et al, 2017;Zipeto et al, 2016).…”