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Pre-mRNA splicing is a fundamental step in mRNA maturation and its discovery in 1977 revolutionized our understanding of gene expression. This collection includes reviews and research articles from across the Nature group of journals to showcase the latest advances in splicing research and the emerging understanding of how splicing regulates gene expression, and through it cell fate, development and physiology. The articles focus on topics that include alternative splicing, the architecture and function of spliceosome complexes, the coordination of splicing with other processes such as transcription and mRNA decay, and splicing-related diseases and therapeutics.
Genome-wide analyses of the effects of U1 snRNP inhibition in human cells shows that telescripting suppresses premature cleavage and polyadenylation in long introns to sustain expression of large genes important for cell cycle and development.
Grelet et al. find that hnRNP E1 release from PNUTS pre-RNA in response to TGFβ generates a lncRNA that acts as competitive sponge for miR-205, promoting epithelial–mesenchymal transition in cancer.
An HDR-independent therapeutic genome-editing approach corrected the splice-site mutation in Lama2 in a mouse model of congenital muscular dystrophy type 1A, and may be applied more broadly to correct splice-site mutations associated with other diseases.
In prostate cancer tumour aggressiveness can be related to race. Here, the authors identify an alternative RNA splice variant of PIK3CD as a potential mechanism to explain racial disparities in the incidence and aggressiveness of prostate cancer between African American and European American men.
After transcription the 3′-end of U6 snRNA is oligo-uridylylated by the terminal uridylyltransferase TUT1. Here the authors present the crystal structure of human TUT1 and give insights into the mechanism of 3′-end uridylylation by the enzyme.
Yuan et al. show that the MBNL3 splicing factor promotes alternative splicing of the lncRNA-PXN-AS1 antisense transcript of PXN, leading to the stabilization of PXN mRNA and increasing its protein levels to promote liver cancer growth.
A number of natural occurring small-molecule splicing modulators are known. Here, the authors combine chemogenomic, structural and biochemical methods and show that these compounds also target the spliceosome-associated protein PHF5A and propose a potential modulator binding site in the PHF5A–SF3B1 complex.
Li et al. show that the c-Myc-dependent splicing switch from ketohexokinase-C (KHK-C) to KHK-A activates phosphoribosyl pyrophosphate synthetase 1 (PRPS1), resulting in enhanced de novo nucleic acid synthesis and hepatocellular carcinoma formation.
While circular RNAs (circRNAs) have been identified in all eukaryotic kingdoms of life, their functions have remained elusive. Now, a study shows that circRNAs can promote alternative splicing of their cognate mRNA, thus driving homeotic phenotypes.
William Fairbrother and colleagues use a massively parallel splicing assay (MaPSy) to analyze 4,964 exonic, disease-causing mutations for splicing defects in vivo and in vitro. They find that 10% of these exonic mutations affect splicing, and they classify these alterations by the stage of spliceosome assembly that is disrupted.
Some circulating avian influenza A viruses can infect humans, but the mechanism enabling species jump is poorly understood. Here, Huanget al. identify a nucleotide in NEP of avian H7N9 viruses that affects splicing efficiency of the NS segment and supports virus replication in avian and mammalian cells.
Alternative splicing of mRNAs occurs in tissue specific manners and may be modulated by genetic variations. Here, Takata and colleagues perform splicing quantitative trait loci analysis (sQTL) of human brain and show significant enrichment of sQTLs among neurological disease-associated loci.
The phosphorylation of serine/arginine-rich proteins by CDC-like kinase is a central regulatory mechanism for RNA splicing reactions. Here, the authors synthesize a novel small molecule CLK inhibitor and map CLK-responsive alternative splicing events and discover an effect on conjoined gene transcription.
The cryo-electron microscopy structure of a yeast spliceosome stalled before mature RNA formation provides insight into the mechanism of exon ligation.
Precursor mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans and defects in global pre-mRNA splicing associated with age are reduced by dietary restriction via splicing factor 1.
Two complementary studies describe how the pervasive N6-methyladenosine modification in mRNA can affect Drosophila sex determination, neuronal function and behaviour.
The chromatin-associated protein AKAP95 is known for its chromatin-related functions including enhancing transcription. Here the authors show that AKAP95 interacts with the splicing regulatory factors as well as RNAs to regulate the inclusion of exons and pre-mRNA splicing.
Comparative analysis of RNA-seq and ribosome profiling data show that a major fraction of exon-skipping events in transcripts with medium-to-high abundance are engaged by ribosomes and therefore are likely to be translated.
Various cis-regulatory functions of genomic loci that produce long non-coding RNAs are revealed, including instances where their promoters have enhancer-like activity and the lncRNA transcripts themselves are not required for activity.
The RNA-binding protein CPEB1 drives post-transcriptional changes in the host transcriptome and poly(A)-tail lengthening of viral RNAs, processes essential for productive HCMV infection.
The observations that introns are acquired in bursts and that exons are often nucleosome-sized can be explained by the generation of introns from DNA transposons, which insert between nucleosomes.
A primate-specific insertion of an Alu element in 5S-OT, a lncRNA transcribed from 5S rRNA loci, allows 5S-OT to regulate alternative splicing via RNA-RNA pairing and recruitment of the splicing factor U2AF65.
Synthetic spike-in standards (‘sequins’), representing spliced mRNA isoforms, provide internal controls for assessing transcript assembly and quantification within and between RNA sequencing libraries. Sequins representing fused genes can be used to determine the sensitivity limit for oncogenic fusions in cancer samples.
The transport of secretory proteins from the endoplasmic reticulum to the Golgi depends on COPII-coated vesicles. Here, the authors show that activation-induced alternative splicing of Sec16 controls adaptation of COPII transport to increased secretory cargo upon T cell activation.
The assembly of the splicesome involves several distinct stages that require the sequential action of DExD/H-box RNA helicases. Here, the authors uncover a new intermediate, the pre-B complex, that accumulates in the presence of an inactive form of the DEAD-box protein Prp28.
Circular RNAs are increasingly understood to have important biological roles and have several subclasses. Here, the authors develop CIRI-AS to analyse sequencing data, identifying the prevalence of alternative splicing and circular RNA isoforms.
Genotype–phenotype landscapes are an important characteristic for understanding the evolution of traits. Here the authors construct the local landscape for the alternative splicing of FAS/CD95 exon 6, revealing the regulation of splicing and the evolution of regulatory information between species.
A 3.8-Å cryo-EM structure of a bacterial group IIA intron in complex with its intron-encoded protein reveals how the reverse transcriptase domain interacts with the mobile intron RNA as well as structural similarities with eukaryotic telomerase and spliceosomal components.
Crystal structures of the reverse transcriptase domains of two group II intron–encoded proteins reveal their similarity to the RT domain of splicing factor Prp8, thus suggesting a common ancestry shared by group II introns and the spliceosome.
Leukemias bearing heterozygous mutations in the SRSF2 splicing-factor-encoding gene can be therapeutically targeted by pharmacologic inhibition of residual spliceosome function.
Structural and cellular analyses reveal that the presence of an isoform-specific α-helix in myosin VI determines whether this motor protein functions in endocytosis or cell migration.
The higher abundance of U1 among snRNPs is explained by the identification of an additional mode of assembly: RBP U1-70K bridges pre-U1 to SMN–Gemin2–Sm, thus establishing a Gemin5-independent assembly pathway.