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Genome Res. 2019 Sep;29(9):1453-1463. doi: 10.1101/gr.242636.118. Epub 2019 Aug 19.

A high resolution A-to-I editing map in the mouse identifies editing events controlled by pre-mRNA splicing.

Author information

1
Center for Anatomy and Cell Biology, Medical University of Vienna, A-1090 Vienna, Austria.
2
Institute of Theoretical Biochemistry, University of Vienna, A-1090 Vienna, Austria.
3
Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, I-70126 Bari, Italy.
4
Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, I-70126 Bari, Italy.
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Contributed equally

Abstract

Pre-mRNA-splicing and adenosine to inosine (A-to-I) RNA-editing occur mostly cotranscriptionally. During A-to-I editing, a genomically encoded adenosine is deaminated to inosine by adenosine deaminases acting on RNA (ADARs). Editing-competent stems are frequently formed between exons and introns. Consistently, studies using reporter assays have shown that splicing efficiency can affect editing levels. Here, we use Nascent-seq and identify ∼90,000 novel A-to-I editing events in the mouse brain transcriptome. Most novel sites are located in intronic regions. Unlike previously assumed, we show that both ADAR (ADAR1) and ADARB1 (ADAR2) can edit repeat elements and regular transcripts to the same extent. We find that inhibition of splicing primarily increases editing levels at hundreds of sites, suggesting that reduced splicing efficiency extends the exposure of intronic and exonic sequences to ADAR enzymes. Lack of splicing factors NOVA1 or NOVA2 changes global editing levels, demonstrating that alternative splicing factors can modulate RNA editing. Finally, we show that intron retention rates correlate with editing levels across different brain tissues. We therefore demonstrate that splicing efficiency is a major factor controlling tissue-specific differences in editing levels.

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