RNA editing in nascent RNA affects pre-mRNA splicing

Abstract

In eukaryotes, nascent RNA transcripts undergo an intricate series of RNA processing steps to achieve mRNA maturation. RNA editing and alternative splicing are two major RNA processing steps that can introduce significant modifications to the final gene products. By tackling these processes in isolation, recent studies have enabled substantial progress in understanding their global RNA targets and regulatory pathways. However, the interplay between individual steps of RNA processing, an essential aspect of gene regulation, remains poorly understood. By sequencing the RNA of different subcellular fractions, we examined the timing of adenosine-to-inosine (A-to-I) RNA editing and its impact on alternative splicing. We observed that >95% A-to-I RNA editing events occurred in the chromatin-associated RNA prior to polyadenylation. We report about 500 editing sites in the 3 ′ acceptor sequences that can alter splicing of the associated exons. These exons are highly conserved during evolution and reside in genes with important cellular function. Furthermore, we identified a second class of exons whose splicing is likely modulated by RNA secondary structures that are recognized by the RNA editing machinery. The genome-wide analyses, supported by experimental validations, revealed remarkable interplay between RNA editing and splicing and expanded the repertoire of functional RNA editing sites.

Cis- and trans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancer development

“…It is expected that RNA editing and splicing have extensive crosstalk, as they share the largest overlap in time and space during processing of pre-mRNA 19 . Editing occurs cotranscriptionally on nascent RNA, suggesting that editing precedes splicing and may cause widespread effects on splicing 20 . As proposed by previous studies, A-to-I editing may modulate splicing through disrupting branch point sequence (BPS) 21 , creating novel 3′ splice site (3′ss) 17,20,22 , modifying auxiliary cis-acting elements 23,24 as well as affecting RNA secondary structure 25,26 .…”

Widespread interaction between ADAR1 and transcriptional byproducts

“…It has been reported that A-to-I editing events predominantly happen on nascent transcripts (19) and RNA editing events may affect splicing regulation or vice versa (19,26,27) . In this study, we demonstrated that ADAR1 was likely involved in splicing indirectly via regulating splicesome genes.…”

“…A small proportion of RNA editing events have been reported to affect splicing regulation or vice versa (19,26,27). Moreover, global splicing changes have been observed after ADAR knockdown (28).…”

“…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). Gene annotations (i.e., GENCODE, UCSC genes, or RefSeq genes) contain only mature RNA structures and thus cannot be directly used for associating editing sites with the RNA properties.…”

Landscape of Dysregulated Placental RNA Editing Associated with Preeclampsia

“…suggesting that this DES in RHOA may play a role in the development of EOSPE. Chr, chromosome; b) Pos, position; c) D, damaging; d) B, benign; e) P, possibly damaging It is reported that RNA editing tends to occur in introns (Athanasiadis et al 2004), and some intronic RNA editing sites are known to regulate gene expression by influencing circRNA biogenesis and alternative splicing (Rueter et al 1999;Laurencikiene et al 2006;Ivanov et al 2015;Hsiao et al 2018). We speculated that there might be an association between intronic DESs and intron retention (IR).…”