About this Research Topic
Splicing has been extensively studied in recent years both under physiological and pathological conditions. In particular, high-throughput RNA sequencing 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 back-splicing, 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 and, besides being potential therapeutic agents and targets, also represent attractive biomarkers, especially in liquid biopsies.The increasing data from human genomes are providing, for the first time, population-wide data on 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 has been shown to be implicated in drug resistance to chemotherapy. A number of approaches have been 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 the view of these many implications in human diseases and of the tremendous efforts aimed at translating the molecular understanding of splicing into, we are proposing a Research Topic gathering new data on RNA splicing and back-splicing in disease and therapy. Original Research articles and Reviews dedicated to:
• Mechanisms of splicing and back-splicing regulation in physiology and disease;
• Description of functional roles of specific splicing events or circRNAs;
• Identification of RNA markers originating from splicing/back-splicing events;
• Analysis of splicing and back-splicing in cancer, omics-based splicing/back-splicing profiles in disease;
• Splicing correction as a therapeutic strategy for human diseases, and therapeutic routes of targeting
alternative-spliced isoforms are welcome.
Keywords: Linear splicing, Back-splicing, Splicing correction, Circular RNAs, RNA biomarkers
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