scholarly journals Elav-mediated exon skipping and alternative polyadenylation of the Dscam1 gene is required for axon outgrowth

2019 ◽  
Author(s):  
Z. Zhang ◽  
K. So ◽  
R. Peterson ◽  
M. Bauer ◽  
H. Ng ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Neural Development ◽  
Rna Binding ◽  
Axon Growth ◽  
Alternative Polyadenylation ◽  
Axon Outgrowth ◽  
List Type ◽  
Long Read ◽  
Upstream Exon ◽  
Exon 19

SummaryMany metazoan genes express alternative long 3′ UTR isoforms in the nervous system, but their functions remain largely unclear. In Drosophila melanogaster, the Dscam1 gene generates short and long (Dscam1-L) 3′ UTR isoforms due to alternative polyadenylation (APA). Here, we found that the RNA-binding protein Embryonic Lethal Abnormal Visual System (Elav) impacts Dscam1 biogenesis at two levels, including regulation of long 3′ UTR biogenesis and skipping of an upstream exon (exon 19). MinION long-read sequencing confirmed the connectivity of this alternative splicing event to the long 3′ UTR. Knockdown or CRISPR deletion of Dscam1-L impaired axon growth in Drosophila. The Dscam1 long 3′ UTR was found to be required for correct Elav-mediated skipping of exon 19. Elav thus co-regulates APA and alternative splicing to generate specific Dscam1 transcripts that are essential for neural development. This coupling of APA to alternative splicing might represent a new class of regulated RNA processing. Graphical AbstractHighlightsElav regulates Dscam1 long 3′ UTR (Dscam1-L) biogenesisLong-read sequencing reveals connectivity of long 3′ UTR to skipping of upstream exon 19Loss of Dscam1-L impairs axon outgrowthDscam1 long 3′ UTR is required for correct splicing of exon 19

scholarly journals Regulation of FXR1 by alternative splicing is required for muscle development and controls liquid-like condensates in muscle cells

2019 ◽  
Author(s):  
Jean A. Smith ◽  
Ennessa G. Curry ◽  
R. Eric Blue ◽  
Christine Roden ◽  
Samantha E. R. Dundon ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Muscle Development ◽  
Rna Binding ◽  
Fragile X ◽  
Protein Isoforms ◽  
List Type ◽  
Tissue Specific ◽  
Intrinsically Disordered ◽  
Multiple Protein

SUMMARYFragile-X mental retardation autosomal homolog-1 (FXR1) is a muscle-enriched RNA-binding protein. FXR1 depletion is perinatally lethal in mice, Xenopus, and zebrafish; however, the mechanisms driving these phenotypes remain unclear. The FXR1 gene undergoes alternative splicing, producing multiple protein isoforms and mis-splicing has been implicated in disease. Furthermore, mutations that cause frameshifts in muscle-specific isoforms result in congenital multi-minicore myopathy. We observed that FXR1 alternative splicing is pronounced in the serine and arginine-rich intrinsically-disordered domain; these domains are known to promote biomolecular condensation. Here, we show that tissue-specific splicing of fxr1 is required for Xenopus development and alters the disordered domain of FXR1. FXR1 isoforms vary in the formation of RNA-dependent biomolecular condensates in cells and in vitro. This work shows that regulation of tissue-specific splicing can influence FXR1 condensates in muscle development and how mis-splicing promotes disease.HIGHLIGHTSThe muscle-specific exon 15 impacts FXR1 functionsAlternative splicing of FXR1 is tissue- and developmental stage specificFXR1 forms RNA-dependent condensatesSplicing regulation changes FXR1 condensate properties

scholarly journals NOVA regulates Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Janelle C Leggere ◽  
Yuhki Saito ◽  
Robert B Darnell ◽  
Marc Tessier-Lavigne ◽  
Harald J Junge ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Alternative Splicing ◽  
Axon Guidance ◽  
Neural Development ◽  
Neuronal Migration ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Splice Variants ◽  
Commissural Neurons

RNA-binding proteins (RBPs) control multiple aspects of post-transcriptional gene regulation and function during various biological processes in the nervous system. To further reveal the functional significance of RBPs during neural development, we carried out an in vivo RNAi screen in the dorsal spinal cord interneurons, including the commissural neurons. We found that the NOVA family of RBPs play a key role in neuronal migration, axon outgrowth, and axon guidance. Interestingly, Nova mutants display similar defects as the knockout of the Dcc transmembrane receptor. We show here that Nova deficiency disrupts the alternative splicing of Dcc, and that restoring Dcc splicing in Nova knockouts is able to rescue the defects. Together, our results demonstrate that the production of DCC splice variants controlled by NOVA has a crucial function during many stages of commissural neuron development.

Nanopore long-read transcriptome data of fungal pathogen of chalkbrood disease, Ascosphaera apis

2020 ◽  
Author(s):  
Yu Du ◽  
Huazhi Chen ◽  
Jie Wang ◽  
Zhiwei Zhu ◽  
Cuiling Xiong ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Fungal Pathogen ◽  
Length Distribution ◽  
Full Length ◽  
List Type ◽  
Transcriptome Data ◽  
Ascosphaera Apis ◽  
Oxford Nanopore ◽  
Long Read ◽  
Colony Productivity

ABSTRACTAscosphaera apis is a fungal pathogen that exclusively infects honeybee larvae, leading to chalkbrood disease, which damages the number of adult honeybees and colony productivity. In this article, A. apis mecylia and spores were respectively purified followed by Oxford Nanopore sequencing via PromethION platform. In total, 6,321,704 and 6,259,727 raw reads were generated from Aam and Aas, with a length distribution among 1 kb~10 kb. The quality (Q) scores of majority of raw reads were Q9 (Aam) and Q11 (Aas). Additionally, 5,669,436 and 6,233,159 clean reads were gained, among them 79.32% and 79.62% were identified as being full-length. The lengths of redundant reads-removed full-length transcripts were among 1 kb~8 kb and 1 kb~9 kb, and most abundant length for both was 1 kb. Furthermore, the length of redundant transcripts-removed clean reads was ranged from 1 kb~7 kb, with the largest group of 1 kb. The data reported here provides a beneficial genetic resource for improving genome and transcriptome annotations of A. apis and for exploring alternative splicing and polyadenylation of A. apis mRNAs.Value of the resultCurrent dataset enables better understanding of the complexity of A. apis transcriptome.The long-read transcriptome data can be used to identify of genes and transcripts associated with A. apis infection mechanism.The accessible data provides full-length transcripts for improving gene structure and functional annotation of A. apis transcriptome.This dataset could be utilized for investigation of alternative splicing and polyadenylation of A. apis mRNAs.

scholarly journals The RNA-Binding Protein HuD Regulates Alternative Splicing and Alternative Polyadenylation in the Mouse Neocortex

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2836
Author(s):  
Rebecca M. Sena ◽  
Jeffery L. Twiss ◽  
Amy S. Gardiner ◽  
Michela Dell’Orco ◽  
David N. Linsenbardt ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Alternative Polyadenylation ◽  
Untranslated Regions ◽  
Sequencing Data ◽  
Hu Proteins ◽  
Nuclear Events ◽  
Neuronal Functions ◽  
Polyadenylation Signals

The neuronal Hu/ELAV-like proteins HuB, HuC and HuD are a class of RNA-binding proteins that are crucial for proper development and maintenance of the nervous system. These proteins bind to AU-rich elements (AREs) in the untranslated regions (3′-UTRs) of target mRNAs regulating mRNA stability, transport and translation. In addition to these cytoplasmic functions, Hu proteins have been implicated in alternative splicing and alternative polyadenylation in the nucleus. The purpose of this study was to identify transcriptome-wide effects of HuD deletion on both of these nuclear events using RNA sequencing data obtained from the neocortex of Elavl4–/– (HuD KO) mice. HuD KO affected alternative splicing of 310 genes, including 17 validated HuD targets such as Cbx3, Cspp1, Snap25 and Gria2. In addition, deletion of HuD affected polyadenylation of 53 genes, with the majority of significantly altered mRNAs shifting towards usage of proximal polyadenylation signals (PAS), resulting in shorter 3′-UTRs. None of these genes overlapped with those showing alternative splicing events. Overall, HuD KO had a greater effect on alternative splicing than polyadenylation, with many of the affected genes implicated in several neuronal functions and neuropsychiatric disorders.

scholarly journals Coding and non-coding drivers of mantle cell lymphoma identified through exome and genome sequencing

2019 ◽  
Author(s):  
Prasath Pararajalingam ◽  
Krysta M. Coyle ◽  
Sarah E. Arthur ◽  
Nicole Thomas ◽  
Miguel Alcaide ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Mantle Cell Lymphoma ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cell Lymphoma ◽  
Hot Spot ◽  
Self Regulation ◽  
List Type ◽  
Recurrent Mutations ◽  
Mantle Cell

AbstractMantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features known to contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes alongside previously published exome cohorts. To confirm our findings, we re-sequenced the genes identified in the exome cohort in 212 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association ofTP53andNOTCH1mutations and further nominate two additional genes,EWSR1andMEF2B, whose mutation respectively associated with poor and good outcome. Our sequencing revealed novel recurrent mutations including a unique missense hot spot inMEF2Band a pattern of non-coding mutations surrounding a single exon of theHNRNPH1gene. We sequenced the whole genomes of 34 MCLs to confirm the focal nature ofHNRNPH1mutations. Using RNA-seq data from 110 of these cases, we identified a functional role for recurrent non-codingHNRNPH1mutations in disrupting an auto-regulatory feedback mechanism. Overall, we identified three novel MCL-related genes with roles in RNA trafficking or splicing, namelyDAZAP1, EWSR1, andHNRNPH1. Taken together, these data strongly implicate a role for aberrant regulation of splicing in MCL pathobiology.Key pointsRNA-binding proteins with roles in regulating alternative splicing,DAZAP1, EWSR1, HNRNPH1, are frequently mutated in MCLThe majority of recurrent somaticHNRNPH1mutations are intronic and HNRNPH1 exhibits self-regulation through alternative splicing

scholarly journals Precise temporal regulation of alternative splicing during neural development

2018 ◽  
Author(s):  
Sebastien M. Weyn-Vanhentenryck ◽  
Huijuan Feng ◽  
Dmytro Ustianenko ◽  
Rachel Duffié ◽  
Qinghong Yan ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Neural Development ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulatory Mechanisms ◽  
Combinatorial Regulation ◽  
Temporal Regulation ◽  
Maturation Stages

AbstractAlternative splicing (AS) is a crucial step of gene expression that must be tightly controlled, but the precise timing of dynamic splicing switches during neural development and the underlying regulatory mechanisms are poorly understood. Here we systematically analyzed the temporal regulation of AS in a large number of transcriptome profiles of developing mouse cortices, in vivo purified neuronal subtypes, and neurons differentiated in vitro. Our analysis revealed early- and late-switch exons in genes with distinct functions, and these switches accurately define neuronal maturation stages. Integrative modeling suggests that these switches are under direct and combinatorial regulation by distinct sets of neuronal RNA-binding proteins including Nova, Rbfox, Mbnl and Ptbp. Surprisingly, various neuronal subtypes in the sensory systems lack Nova and/or Rbfox expression. These neurons retain the “immature” splicing program in early-switch exons, affecting numerous synaptic genes. These results provide new insights into the organization and regulation of the neurodevelopmental transcriptome.

scholarly journals Splicing-associated chromatin signatures: a combinatorial and position-dependent role for histone marks in splicing definition

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
E. Agirre ◽  
A. J. Oldfield ◽  
N. Bellora ◽  
A. Segelle ◽  
R. F. Luco
Keyword(s):  
Alternative Splicing ◽  
Rna Binding ◽  
Embryonic Stem ◽  
Chromatin Modifications ◽  
Histone Marks ◽  
Splicing Regulators ◽  
Machine Learning Approach ◽  
Alternatively Spliced ◽  
Rna Motif ◽  
Regulation Changes

AbstractAlternative splicing relies on the combinatorial recruitment of splicing regulators to specific RNA binding sites. Chromatin has been shown to impact this recruitment. However, a limited number of histone marks have been studied at a global level. In this work, a machine learning approach, applied to extensive epigenomics datasets in human H1 embryonic stem cells and IMR90 foetal fibroblasts, has identified eleven chromatin modifications that differentially mark alternatively spliced exons depending on the level of exon inclusion. These marks act in a combinatorial and position-dependent way, creating characteristic splicing-associated chromatin signatures (SACS). In support of a functional role for SACS in coordinating splicing regulation, changes in the alternative splicing of SACS-marked exons between ten different cell lines correlate with changes in SACS enrichment levels and recruitment of the splicing regulators predicted by RNA motif search analysis. We propose the dynamic nature of chromatin modifications as a mechanism to rapidly fine-tune alternative splicing when necessary.

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