Alternative splicing: the pledge, the turn, and the prestige

Abstract

Alternative pre-mRNA splicing is a tightly controlled process conducted by the spliceosome, with the assistance of several regulators, resulting in the expression of different transcript isoforms from the same gene and increasing both transcriptome and proteome complexity. The differences between alternative isoforms may be subtle but enough to change the function or localization of the translated proteins. A fine control of the isoform balance is, therefore, needed throughout developmental stages and adult tissues or physiological conditions and it does not come as a surprise that several diseases are caused by its deregulation. In this review, we aim to bring the splicing machinery on stage and raise the curtain on its mechanisms and regulation throughout several systems and tissues of the human body, from neurodevelopment to the interactions with the human microbiome. We discuss, on one hand, the essential role of alternative splicing in assuring tissue function, diversity, and swiftness of response in these systems or tissues, and on the other hand, what goes wrong when its regulatory mechanisms fail. We also focus on the possibilities that splicing modulation therapies open for the future of personalized medicine, along with the leading techniques in this field. The final act of the spliceosome, however, is yet to be fully revealed, as more knowledge is needed regarding the complex regulatory network that coordinates alternative splicing and how its dysfunction leads to disease.

Cooperation of SRPK2, Numb and p53 in the malignant biology and chemosensitivity of colorectal cancer

“…Alternative splicing is a common phenomenon in mammalian cells that is tightly associated with the post-splicing steps of mRNA transcription, as well as the synthesis of various protein isoforms [19,20]. Abnormal patterns of prem-RNA alternative splicing are prevalent in human malignancies [21,22], yet the molecular mechanisms of these alterations remain poorly defined.…”

Comprehensive profiling of aberrant prognostic alternative splicing signatures in clear cell renal cell carcinoma: a retrospective study based on large-scale sequencing data

“…This process has a signi cant impact on the diversity of both transcriptome and proteome of human [8; 9]. AS plays a vital role in increasing the complexity of functional proteins and regulating of cell metabolism and cell-speci c functions, which provides opportunity for tumorigenesis and progression [10]. Over the last two decades, molecular tools have been developed to correct or redirect AS events.…”

A Deep Learning approach predicts the impact of point mutations in intronic flanking regions on micro-exon splicing definition

“…events involve very precise and specific mechanisms which add another layer of complexity in gene 44 regulation (Pan et al, 2008). About 90-95% of multi-exon genes are estimated to have alternative 45 splicing isoforms, affecting the variability of expression between cells and tissues (Wang et al,46 2008), and modifying cell localization and abundance of various protein isoforms that alter gene 47 regulation of the cell (Gallego-Paez et al, 2017). In order to be a dynamic and well-orchestrated 48 mechanism, several factors influence the splicing process such as spliceosome formation, 49 involvement of RNA-binding proteins (RBPs) and participation of regulatory sequences such as 50 intronic splicing enhancers/silencers (ISE/ISS) and exonic splicing enhancers/silencers (ESE/ESS), 51 among others (Wang et al, 2015).…”