Alternative Splicing Regulatory Networks: Functions, Mechanisms, and Evolution

Abstract

High-throughput sequencing-based methods and their applications in the study of transcriptomes have revolutionized our understanding of alternative splicing. Networks of functionally coordinated and biologically important alternative splicing events continue to be discovered in an ever-increasing diversity of cell types in the context of physiologically normal and disease states. These studies have been complemented by efforts directed at defining sequence codes governing splicing and their cognate trans-acting factors, which have illuminated important combinatorial principles of regulation. Additional studies have revealed critical roles of position-dependent, multivalent protein-RNA interactions that direct splicing outcomes. Investigations of evolutionary changes in RNA binding proteins, splice variants, and associated cis elements have further shed light on the emergence, mechanisms, and functions of splicing networks. Progress in these areas has emphasized the need for a coordinated, community-based effort to systematically address the functions of individual splice variants associated with normal and disease biology.

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

“…This complex in turn recruits U4/U6-U5 snRNPs and promotes the formation of catalytically active spliceosome complexes that mediate trans-esterification reactions [23]. However, since the sequences recognized by the spliceosome are short and degenerate, and human exons are generally much shorter (~150 bp) than introns (>1000 bp), proper exon recognition is a difficult task that requires additional cis-regulatory RNA elements and trans-acting factors [22,24]. Moreover, competition between trans-acting factors for binding to cis-regulatory RNA elements can result in the alternative selection of exons in the mature mRNA.…”

Small Protein Hidden in lncRNA LOC90024 Promotes “Cancerous” RNA Splicing and Tumorigenesis

“…Aberrant splicing is closely associated with numerous human diseases, such as cancers, and contributes to all the hallmarks of cancer. [ 6,7 ] AS is generally orchestrated by cis ‐RNA elements that recruit splicing factors to enhance or silence the splicing of adjacent exons. Common splicing factors include serine/arginine‐rich proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs).…”

“…Accumulating evidence indicates that aberrant AS controls various hallmarks of cancer. [ 6–9 ] However, the functional roles of the AS of TF RNAs in cancers remain poorly understood.…”

PsiCLIP reveals dynamic RNA binding by DEAH-box helicases before and after exon ligation

“…However, the contribution of individual splicing factors is difficult to discern in such profiles. In addition, iCLIP of individual splicing factors has revealed their position-dependent capacity to control alternative splicing decisions in mammals (Ule & Blencowe, 2019) but has not led to direct insights into step-specific mechanisms of the core spliceosome. A key issue with these methods is that spliceosomes are not stalled at a specific step, therefore the resulting profiles represent an ensemble of spliceosomal snapshots across many splicing steps, with a bias towards those that are ratelimiting.…”