Anything but Ordinary – Emerging Splicing Mechanisms in Eukaryotic Gene Regulation

Splicing of precursor mRNAs (pre-mRNA) is an important step during eukaryotic gene expression. The identification of the actual splice sites and the proper removal of introns are essential for the production of the desired mRNA isoforms and their encoded proteins. While the basic mechanisms of splicing regulation are well understood, recent work has uncovered a growing number of noncanonical splicing mechanisms that play key roles in the regulation of gene expression. In this review, we summarize the current principles of splicing regulation, including the impact of cis and trans regulatory elements, as well as the influence of chromatin structure, transcription, and RNA modifications. We further discuss the recent development of emerging splicing mechanisms, such as recursive and back splicing, and their impact on gene expression. Recent progress in sequencing methods and computational analyses have led to the discovery of novel splicing isoforms and noncanonical splicing mechanisms.Cotranscriptional splicing enables the fine tuning of gene expression by epigenetic and epitranscriptomics marks.Local condensates formed by intrinsically disordered domains of RNA polymerase II and splicing factors may optimize the splicing reaction.Recursive splicing and the inhibition of cryptic splice sites by the exon junction complex are two related processes with opposite outcome.Splicing of circular RNA is enhanced by the low efficiency splicing of the flanking introns and their ability to form secondary structures.