Editorial: RNA Splicing and Backsplicing: Disease and Therapy

© 2020 Asselta, Duga, Velasco and Buratti.Splicing has been extensively studied in recent years both under physiological and pathological conditions. In particular, high-throughput RNA sequencing has allowed a much deeper knowledge on the breadth of alternative splicing in gene expression regulation. Besides the multiplicity of transcripts originating from “conventional” linear splicing, an additional layer of complexity is provided by backsplicing, mostly occurring at annotated exon boundaries, which produces circular RNAs (circRNAs). These are covalently closed RNA rings particularly stable compared to their linear counterparts because they are resistant to exonucleolytic decay; besides being potential therapeutic agents and targets, they also represent attractive biomarkers. In parallel, the increasing data from human genomes are providing, for the first time, population-wide landscapes of genetic variants potentially impacting on splicing, both in monogenic and complex diseases. Splicing alterations have been particularly studied in autoimmune diseases, where they can be responsible for the generation of autoantigens, and in cancer, where the neo-antigens originating from splicing derangement can impact on tumor immunogenicity and have important consequences on the efficacy of immunotherapy. Moreover, the generation of alternatively spliced isoforms was shown to be implicated in drug resistance to chemotherapy. As a result, a number of approaches were developed to modulate splicing both to correct splicing mutations and to promote/silence specific splicing events as potential therapies, including antisense oligonucleotides, modified U1 snRNAs, small molecules acting on splicing, and trans-splicing. These post-transcriptional interventions have substantial advantages over traditional gene therapy, including no need to deliver large DNA constructs and no concerns regarding the tissue specificity and expression level of the transgene. In view of these many implications in human diseases and the tremendous efforts aimed at translating the molecular understanding of splicing into the clinic, the purpose of this Research Topic was to provide an overview on new data on RNA splicing and backsplicing in disease and therapy. The articles in this topic range from understanding the mechanisms of splicing regulation, to evaluating the impact of splicing isoforms and circRNA detection on disease diagnosis and prognosis, up to possible therapeutic applications of splicing correction