Alternative splicing

  • Article
    | Open Access

    UNC5B is a Netrin-1 receptor expressed in endothelial cells that in the absence of ligand induces apoptosis. Here the authors identify an UNC5B splicing isoform that is insensitive to the pro-survival ligand Netrin-1 and is required for apoptosis-dependent blood vessel development.

    • Davide Pradella
    • , Gianluca Deflorian
    •  & Claudia Ghigna
  • Article
    | Open Access

    We know that most splicing reactions take place co-transcriptionally, but how the transcription machinery facilitate splicing of introns is unknown. Here the authors show that the 5′ splice site remains associated with the transcription machinery during intron synthesis through U1 snRNP, providing a basis for the rapid splicing reaction of introns.

    • Yodfat Leader
    • , Galit Lev Maor
    •  & Gil Ast
  • Article
    | Open Access

    The Argonaute protein CSR-1 is essential for fertility and viability in C. elegans. Here the authors show that CSR-1A isoform associates preferentially with small RNAs mapping to spermatogenesis-specific genes while CSR-1B isoform binds small RNAs mapping to oogenesis-specific genes. Arginine methylation of CSR-1A promotes small RNA-binding specificity.

    • Dieu An H. Nguyen
    •  & Carolyn M. Phillips
  • Article
    | Open Access

    Functional RNA secondary structure is important for the pre-mRNA processing including splicing, cleavage and polyadenylation, and RNA editing. Here the authors present a catalog of conserved long-range RNA structures in the human transcriptome by defining pairs of conserved complementary regions (PCCR) in pre-aligned evolutionarily conserved regions.

    • Svetlana Kalmykova
    • , Marina Kalinina
    •  & Dmitri Pervouchine
  • Article
    | Open Access

    Circular RNAs have been identified using short-read RNA sequencing. Here, the authors report isoCirc, a long-read sequencing method to characterize full-length circRNA isoforms and generate a catalogue of full-length circRNA isoforms in 12 human tissues and one human cell line.

    • Ruijiao Xin
    • , Yan Gao
    •  & Yi Xing
  • Article
    | Open Access

    Control over splicing could be used for both therapeutic and engineering applications. Here the authors create artificial splicing factors using RNA-targeting CRISPR systems under small molecule control.

    • Menghan Du
    • , Nathaniel Jillette
    •  & Albert Wu Cheng
  • Article
    | Open Access

    The extracellular regions (ECRs) of adhesion GPCRs have diverse biological functions, but their structures and mechanisms of action remain unclear. Here, the authors solve the ECR structure of the Gpr126 receptor and show that ECR conformation and signaling functions are regulated by alternative splicing.

    • Katherine Leon
    • , Rebecca L. Cunningham
    •  & Demet Araç
  • Article
    | Open Access

    CTCF plays key roles in gene regulation, chromatin insulation and organizing the higher-order chromatin architecture of mammalian genomes. Here the authors investigate the function an alternatively spliced shorter CTCF isoform, finding that this isoform antagonizes canonical CTCF occupancy and changes chromatin architecture to promote apoptosis.

    • Jiao Li
    • , Kaimeng Huang
    •  & Hongjie Yao
  • Article
    | Open Access

    Cytoplasmic PTEN is a tumor suppressor that antagonises PI3K signalling. Here, the authors show that nuclear PTEN can interact with the spliceosomal proteins and drive pre-mRNA splicing in a phosphatase-independent manner, in particular, PTEN depletion promotes Golgi extension and secretion through GOLGA2 exon skipping.

    • Shao-Ming Shen
    • , Yan Ji
    •  & Guo-Qiang Chen
  • Article
    | Open Access

    Alternative splicing of influenza A virus (IAV) M transcript is regulated by hnRNP K and NS1-BP, but mechanistic details are unknown. Here, Thompson et al. show how hnRNP K and NS1-BP bind M mRNA and that these proteins regulate splicing of host transcripts in both the absence and presence of IAV infection.

    • Matthew G. Thompson
    • , Raquel Muñoz-Moreno
    •  & Kristen W. Lynch
  • Article
    | Open Access

    The precise timing of neurodevelopmental splicing switches and the underlying regulatory mechanisms remain poorly understood. This study identifies two major waves of developmental switches under the control of distinct combinations of RNA-binding proteins in central and peripheral nervous systems.

    • Sebastien M. Weyn-Vanhentenryck
    • , Huijuan Feng
    •  & Chaolin Zhang
  • Article
    | Open Access

    Myotonic dystrophy (DM) type 2 is a neuromuscular pathology caused by large expansions of CCTG repeats. Here the authors find that rbFOX1 RNA binding protein binds to CCUG RNA repeats and competes with MBNL1 for the binding to CCUG repeats, releasing MBNL1 from sequestration in DM2 muscle cells.

    • Chantal Sellier
    • , Estefanía Cerro-Herreros
    •  & Nicolas Charlet-Berguerand
  • Article
    | Open Access

    Intron retention (IR) can increase protein diversity and function, and yet unregulated IR may be detrimental to cellular health. This study shows that aberrant IR occurs in ALS and finds nuclear loss of an RNA-binding protein called SFPQ as a new molecular hallmark in this devastating condition.

    • Raphaelle Luisier
    • , Giulia E. Tyzack
    •  & Rickie Patani
  • Article
    | Open Access

    Type I interferon signaling is critical for the control of infection. Here the authors show that zinc finger RNA-binding protein (ZFR) can control type I interferon responses, and that this control is itself regulated by distinct ZFR truncation patterns that differ between monocytes and macrophages.

    • Nazmul Haque
    • , Ryota Ouda
    •  & J. Robert Hogg
  • Article
    | Open Access

    Small molecules correcting the splicing deficit of the survival of motor neuron 2 (SMN2) gene have been identified as having therapeutic potential. Here, the authors provide evidence that SMN2 mRNA forms a ribonucleoprotein complex that can be specifically targeted by these small molecules.

    • Manaswini Sivaramakrishnan
    • , Kathleen D. McCarthy
    •  & Friedrich Metzger
  • Article
    | Open Access

    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.

    • Ilka Wilhelmi
    • , Regina Kanski
    •  & Florian Heyd
  • Article
    | Open Access

    Alternative splicing and alternative polyadenylation (APA) contribute to mRNA diversity but are difficult to assess using short read RNA-seq data. Here, the authors use single molecule long-read isoform sequencing and develop a computational pipeline to identify full-length splice isoforms and APA sites in sorghum.

    • Salah E. Abdel-Ghany
    • , Michael Hamilton
    •  & Anireddy S. N. Reddy
  • Article
    | Open Access

    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.

    • Philippe Julien
    • , Belén Miñana
    •  & Ben Lehner
  • Article
    | Open Access

    MALT1 regulates NFκB signalling both as a scaffolding protein and as a protease. Here the authors show that during T cell activation the expression of MALT1 gene switches to an alternatively spliced variant, which increases TCR signal transduction due to enhanced TRAF6 binding.

    • Isabel Meininger
    • , Richard A. Griesbach
    •  & Daniel Krappmann
  • Article
    | Open Access

    Patients with myotonic dystrophy (MD) suffer from severe cardiac issues of unknown aetiology. Freyermuth et al. show that fatal changes in cardiac electrophysiological properties in humans and mice with MD may arise from misregulation of the alternative splicing of the cardiac Na+ channel SCN5Atranscript, resulting in expression of its fetal form.

    • Fernande Freyermuth
    • , Frédérique Rau
    •  & Nicolas Charlet-Berguerand
  • Article
    | Open Access

    The alternative splicing factor Nova2 is best known for its pivotal function in the brain. Giampietro et al. reveal an important role for Nova2 in the regulation of alternative splicing of transcripts in the vascular endothelium that are crucial for the maintenance of endothelial cell polarity and vessel lumen formation in zebrafish.

    • Costanza Giampietro
    • , Gianluca Deflorian
    •  & Claudia Ghigna
  • Article |

    Protein arginine methylation is an abundant post-translational modification often associated with RNA-binding proteins. Here the authors show that the previously uncharacterized PRMT9 enzyme catalyses the symmetrical methylation of SAP145, which promotes its association with the SMN complex and regulates splicing.

    • Yanzhong Yang
    • , Andrea Hadjikyriacou
    •  & Mark T. Bedford
  • Article
    | Open Access

    RNA binding proteins are key regulators of alternative splicing. Here, Best et al. show that the human Tra2α and Tra2ß RNA binding proteins jointly contribute to the control of constitutive and alternative splicing events to regulate essential biological processes including the response to DNA damage.

    • Andrew Best
    • , Katherine James
    •  & David J. Elliott
  • Article
    | Open Access

    RNA sequencing has enabled the global analysis of both gene expression levels and splicing events. Here, the authors develop a multivariate approach that is able to identify SNPs that influence splicing, and investigate the overlap of these with functional domains across the genome, including previously identified GWAS signals.

    • Jean Monlong
    • , Miquel Calvo
    •  & Roderic Guigó
  • Article |

    Frameshift mutations in the protein polyglutamine tract-binding protein 1 (PQBP1) are believed to cause X-linked mental retardation. Here, Mizuguchi et al.present the crystal structure of a C-terminal fragment of PQBP1 in complex with the spliceosomal protein U5–15kD, and show details of this interaction that can lead to mechanistic insights into the disease.

    • Mineyuki Mizuguchi
    • , Takayuki Obita
    •  & Hitoshi Okazawa
  • Article
    | Open Access

    Telomerase activity can be regulated by alternative splicing of its catalytic subunit TERT. Here, Wong et al. demonstrate that TERTsplicing is regulated via RNA:RNA pairing of repetitive intronic sequences with the pre-mRNA, thus revealing a new function for conserved elements embedded within introns.

    • Mandy S. Wong
    • , Jerry W. Shay
    •  & Woodring E. Wright
  • Article
    | Open Access

    Alternative splicing at the Drosophila Down syndrome cell adhesion molecule gene generates 38,016 isoforms, and underlies self-avoidance of growing neurons. Wang et al. identify a structure in the DSCAM mRNA that ensures mutually exclusive splicing and observe expansion of the structure with increasing number of exons during arthropod evolution.

    • Xuebin Wang
    • , Guoli Li
    •  & Yongfeng Jin
  • Article
    | Open Access

    Synaptic GTPase-activating protein, SynGAP, is a postsynaptic signalling protein that can regulate synaptic function. McMahonet al. express different SynGAP isoforms in neurons and find that the effect on synaptic strength depends on alternative promoter usage and alternative splicing of the C-terminus.

    • A.C. McMahon
    • , M.W. Barnett
    •  & P.C. Kind