Regulation of alternative mRNA splicing: old players and new perspectives

Abstract

Nearly all human multiexon genes are subject to alternative splicing in one or more cell types. The splicing machinery therefore has to select between multiple splice sites in a context-dependent manner, relying on sequence features in cis- and trans-acting splicing regulators that either promote or repress splice site recognition and spliceosome assembly. However, the functional coupling between multiple gene regulatory layers signifies that splicing can also be modulated by transcriptional or epigenetic characteristics. Other, less obvious, aspects of alternative splicing have come to light in recent years, often involving core components of the spliceosome previously thought to perform a basal rather than a regulatory role in splicing. Together this paints a highly dynamic picture of splicing regulation, where the final splice site choice is governed by the entire transcriptional environment of a gene and its cellular context.

Gallop Racing Shifts Mature mRNA towards Introns: Does Exercise-Induced Stress Enhance Genome Plasticity?

“…AS is a highly regulated process with a complex interactions network between sequence features within the pre-mRNA [39] and trans-active splicing factor proteins [40]. This process can occur physiologically for steady state cell protein production, but also in case of response to developmental cues and external stimuli, including stress [41,42].…”

Splicing Players Are Differently Expressed in Sporadic Amyotrophic Lateral Sclerosis Molecular Clusters and Brain Regions

“…Unlike many enzymes, the spliceosome does not have a preformed catalytic center. Instead, it is constructed de novo on the pre-mRNA in a stepwise manner for each round of splicing and undergoes multiple rearrangements to configure the catalytic core [8]. The major spliceosome machine is composed of five small nuclear ribonucleoprotein complexes, (snRNPs), U1, U2, U4, U5, and U6, each containing a cognate U-rich noncoding small nuclear RNA (snRNA).…”

“…A small subset of unusual introns containing non-consensus termini are processed by a much less abundant spliceosomal machine (minor spliceosome) which contains the U5 snRNP and analogs of the remaining snRNPs (U11, U12, U4atac, and U6atac) [8][9][10][11][12]. Following transcription, snRNAs are exported through the nuclear pore complex (NPC) into the cytoplasm where snRNPs maturate inside a large assemblysome (the survival motor neuron (SMN) complex); core snRNPs are then imported into the nucleus, assembled in Cajal bodies and are ready to be recruited by the nascent pre-mRNA for splicing [8,13]. The basepairing of snRNPs with pre-mRNA relies on a series of conserved regulatory sequence elements (the splice donor site, the splice acceptor site, the branch site, and the polypyrimidine tract) [14].…”

“…Additional layers of regulation are introduced by some auxiliary motifs (exon and intron splicing enhancers or silencers) that may stimulate exon inclusion or inhibit splicing with the mediation of RNA-binding proteins (RBPs), mainly of which belong to the families of serine/arginine-rich splicing factor (SRSF) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs), acting as splicing enhancers or repressors, respectively [15,16]. For a complete overview of splicing machinery, intermediated complexes and auxiliary regulatory factors, readers are invited to refer to some complete reviews [8,[17][18][19].…”

RNA splicing analysis in genomic medicine

“…These are recognised and bound by various RNA-binding proteins such as serine-arginine-rich (SR) proteins and heterogeneous ribonucleoproteins (hnRNPs) that are trans-acting splicing factors. The spliceosome complex itself is composed of small nuclear RNAs (snRNAs) plus various proteins (forming snRNPs) and accessory factors (Dvinge, 2018). In addition to snRNPs, long non-coding RNAs have also been reported to be involved in splicing (Romero-Barrios et al, 2018).…”