Alternative Splicing and RNA Editing in Physiology and Disease

Dear Colleagues,

Alternative splicing, first proposed by Gilbert in 1978, allows multi-exon genes to produce several distinct transcripts. Several of the linear transcripts encode protein isoforms with distinct amino acid sequence, structure, and function(s). Alternatively spliced transcripts are generated from a single gene through selection of cassette exons, mutually exclusive exons, retained introns, alternative 3′ or 5′ splice sites, and/or usage of alternative promoters or polyadenylation sites. High-throughput sequencing has revolutionized transcriptomics, revealing that the post-transcriptional maturation of primary transcripts from more than 95% of human multi-exon genes involves alternative splicing. Examples of hundreds of alternative splicing events from a single gene have also been described. Moreover, back-splicing produces circular RNAs (circRNAs). These circular transcripts were initially discovered in RNA viroid analysis during the 1970s but were then characterized as by-products of alternative splicing. Alternative splice variants may contribute to the etiology of many human diseases, including cancer, since protein isoforms that arise by translation of splice variants often contain additional functional domains or lack some of the structural motifs of the classical protein isoform and consequently acquire new properties or are deprived of some of them, respectively. circRNAs have also been shown to play a pivotal role in the initiation and progression of cancer.

Besides somatic mutations and alternative splicing, RNA editing can be a further source for recoding events. The results of RNA editing have been detected in many solid cancers and leukemia, as well as in normal tissues. Global RNA editing measurements from hundreds of cancer samples revealed millions of editing sites, most of them occurring in transcribed noncoding Alu sites. However, editing in coding regions has also been detected and some recurrent editing sites affecting coding regions were reported to influence cancer development and progression. Epitranscriptomics plays essential roles in alternative splicing, nuclear export, transcript stability, and translation of RNAs. Adenosine-to-Inosine (A-to-I) modification and mRNA methylation constitute two of the most common mRNA modifications and have been shown – along with alternative splicing - to significantly affect cancer drug resistance. For instance, the process of “reading” and “erasing” of m⁶A methylation marks are essential for regulation of genes that are responsible for drug resistance.

This Special Issue, entitled “Alternative Splicing and RNA Editing in Physiology and Disease”, is the second issue in a series that previously studied alternative splicing in human physiology and disease. The first issue, published in 2021, comprised 22 manuscripts and can be found at: https://www.mdpi.com/journal/genes/topical_collections/Alt_Splicing .

This Special Issue aims to provide information to the readers regarding the mechanisms and/or products of alternative splicing and RNA editing in physiological and pathological states, with emphasis on cancer, neurodegenerative and cardiovascular diseases, and other pathologies. Authors are encouraged to submit their original research studies concerning this topic. Review articles will also be taken into consideration. The Guest Editor is also willing to evaluate manuscripts describing other aspects of alternative splicing and post-transcriptional RNA modifications proposed by the authors. I hope that this Special Issue regarding the identity, biological role, and/or clinical utility of alternatively spliced, linear and circular transcripts of human genes will attract the interest of the readers of this journal.

Dr. Christos K. Kontos
Guest Editor

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