scholarly journals The minor and major spliceosome interact to regulate alternative splicing around minor introns

2020 ◽  
Author(s):  
Anouk M. Olthof ◽  
Alisa K. White ◽  
Madisen F. Lee ◽  
Almahdi Chakroun ◽  
Alice K. Abdel Aleem ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Intron Retention ◽  
Radial Glial Cell ◽  
Disease Pathogenesis ◽  
Exon Definition ◽  
Cell Divisions ◽  
Alternatively Spliced ◽  
Radial Glial ◽  
Dorsal Telencephalon ◽  
Assembly Activity

AbstractMutations in minor spliceosome components are linked to diseases such as Roifman syndrome, Lowry-Wood syndrome, and early-onset cerebellar ataxia (EOCA). Here we report that besides increased minor intron retention, Roifman syndrome and EOCA can also be characterized by elevated alternative splicing (AS) around minor introns. Consistent with the idea that the assembly/activity of the minor spliceosome informs AS in minor intron-containing genes (MIGs), inhibition of all minor spliceosome snRNAs led to upregulated AS. Notably, alternatively spliced MIG isoforms were bound to polysomes in the U11-null dorsal telencephalon, which suggested that aberrant MIG protein expression could contribute to disease pathogenesis. In agreement, expression of an aberrant isoform of the MIG Dctn3 by in utero electroporation, affected radial glial cell divisions. Finally, we show that AS around minor introns is executed by the major spliceosome and is regulated by U11-59K of the minor spliceosome, which forms exon-bridging interactions with proteins of the major spliceosome. Overall, we extend the exon-definition model to MIGs and postulate that disruptions of exon-bridging interactions might contribute to disease severity and pathogenesis.

scholarly journals Alternative Splicing in the Obligate Biotrophic Oomycete Pathogen Pseudoperonospora cubensis

2015 ◽  
Vol 28 (3) ◽  
pp. 298-309 ◽  
Author(s):  
Alyssa Burkhardt ◽  
Alex Buchanan ◽  
Jason S. Cumbie ◽  
Elizabeth A. Savory ◽  
Jeff H. Chang ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Intron Retention ◽  
Draft Genome ◽  
Pseudoperonospora Cubensis ◽  
Rna Seq ◽  
Transcriptome Regulation ◽  
Oomycete Pathogen ◽  
Alternatively Spliced ◽  
Genome Annotations ◽  
Obligate Pathogen

Pseudoperonospora cubensis is an obligate pathogen and causative agent of cucurbit downy mildew. To help advance our understanding of the pathogenicity of P. cubensis, we used RNA-Seq to improve the quality of its reference genome sequence. We also characterized the RNA-Seq dataset to inventory transcript isoforms and infer alternative splicing during different stages of its development. Almost half of the original gene annotations were improved and nearly 4,000 previously unannotated genes were identified. We also demonstrated that approximately 24% of the expressed genome and nearly 55% of the intron-containing genes from P. cubensis had evidence for alternative splicing. Our analyses revealed that intron retention is the predominant alternative splicing type in P. cubensis, with alternative 5′- and alternative 3′-splice sites occurring at lower frequencies. Representatives of the newly identified genes and predicted alternatively spliced transcripts were experimentally validated. The results presented herein highlight the utility of RNA-Seq for improving draft genome annotations and, through this approach, we demonstrate that alternative splicing occurs more frequently than previously predicted. In total, the current study provides evidence that alternative splicing plays a key role in transcriptome regulation and proteome diversification in plant-pathogenic oomycetes.

scholarly journals The Emergence of the Metabolic Signaling of the Nucleoredoxin-like Genes during Evolution

2022 ◽  
Author(s):  
Najate Ait-Ali ◽  
Frederic Blond ◽  
Emmanuelle Clerin ◽  
Ala Morshedian ◽  
Quenol Cesar ◽  
...  
Keyword(s):  
Biological Activity ◽  
Alternative Splicing ◽  
Intron Retention ◽  
Hydra Vulgaris ◽  
Metabolic Signaling ◽  
Retinal Degenerations ◽  
Animal Phyla ◽  
Alternatively Spliced ◽  
Early Vertebrates ◽  
Rod And Cone Photoreceptors

The nucleoredoxin-like genes NXNL1 and NXNL2 were identified through the biological activity of rod-derived cone viability factors (RdCVF and RdCVF2), the alternatively spliced variants produced by intron retention, that mediate signaling between rod and cone photoreceptors by stimulating glucose uptake. These therapeutic genes for inherited retinal degenerations also produce by splicing thioredoxin-like proteins that reduce oxidized cysteines in photoreceptor proteins. The first NXNL genes date from the first animal phyla. Intron retention produces an active RdCVF protein in the tentacles of Hydra vulgaris, a species without eyes. A Scallop RdCVF protein is produced by ciliated photoreceptors of the retina and binds its receptor, BSG1. In the lamprey, a descendent of early vertebrates, RdCVF metabolic signaling between rod and cones is fully established. In the mouse, the production of BSG1 by photoreceptors is regulated by cell-specific splicing inhibition. RdCVF signaling predates photoreceptors and evolved through two alternative splicing events.

scholarly journals Alternative Spliced Transcripts as Cancer Markers

2001 ◽  
Vol 17 (2) ◽  
pp. 67-75 ◽  
Author(s):  
Otavia L. Caballero ◽  
Sandro J. de Souza ◽  
Ricardo R. Brentani ◽  
Andrew J. G. Simpson
Keyword(s):  
Alternative Splicing ◽  
Tumor Tissue ◽  
Intron Retention ◽  
Apparent Discrepancy ◽  
Cancer Markers ◽  
Variable Position ◽  
Eukaryotic Mrnas ◽  
Alternatively Spliced ◽  
Higher Eukaryotes ◽  
Mature Mrnas

Eukaryotic mRNAs are transcribed as precursors containing their intronic sequences. These are subsequently excised and the exons are spliced together to form mature mRNAs. This process can lead to transcript diversification through the phenomenon of alternative splicing. Alternative splicing can take the form of one or more skipped exons, variable position of intron splicing or intron retention. The effect of alternative splicing in expanding protein repertoire might partially underlie the apparent discrepancy between gene number and the complexity of higher eukaryotes. It is likely that more than 50% form. Many cancer-associated genes, such as CD44 and WT1 are alternatively spliced. Variation of the splicing process occurs during tumor progression and may play a major role in tumorigenesis. Furthermore, alternatively spliced transcripts may be extremely useful as cancer markers, since it appears likely that there may be striking contrasts in usage of alternatively spliced transcript variants between normal and tumor tissue than in alterations in the general levels of gene expression.

scholarly journals Exon definition facilitates reliable control of alternative splicing in the RON proto-oncogene

2019 ◽  
Author(s):  
M. Enculescu ◽  
S. Braun ◽  
S. T. Setty ◽  
K. Zarnack ◽  
J. König ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Epithelial To Mesenchymal Transition ◽  
Intron Retention ◽  
Regulatory Elements ◽  
Protein Isoforms ◽  
Splicing Regulation ◽  
Exon Definition ◽  
Mesenchymal Transition ◽  
Mrna Maturation ◽  
Exon 11

ABSTRACTAlternative splicing is a key step in eukaryotic gene expression that allows the production of multiple protein isoforms from the same gene. Even though splicing is perturbed in many diseases, we currently lack insights into regulatory mechanisms promoting its precision and efficiency. We analyse high-throughput mutagenesis data obtained for an alternatively spliced exon in the proto-oncogene RON and determine the functional units that control this splicing event. Using mathematical modeling of distinct splicing mechanisms, we show that alternative splicing is based in RON on a so-called ‘exon definition’ mechanism. Here, the recognition of the adjacent exons by the spliceosome is required for removal of an intron. We use our model to analyze the differences between the exon and intron definition scenarios and find that exon definition is crucial to prevent the accumulation of deleterious, partially spliced retention products during alternative splicing regulation. Furthermore, it modularizes splicing control, as multiple regulatory inputs are integrated into a common net input, irrespective of the location and nature of the corresponding cis-regulatory elements in the pre-mRNA. Our analysis suggests that exon definition promotes robust and reliable splicing outcomes in RON splicing.SIGNIFICANCEDuring mRNA maturation, pieces of the pre-mRNA (introns) are removed during splicing, and remaining parts (exons) are joined together. In alternative splicing, certain exons are either included or excluded, resulting in different splice products. Inclusion of RON alternative exon 11 leads to a functional receptor tyrosine kinase, while skipping results in a constitutively active receptor that promotes epithelial-to-mesenchymal transition and contributes to tumour invasiveness. Intron retention results in to deleterious isoforms that cannot be translated properly. Using kinetic modeling, we investigate the combinatorial regulation of this important splicing decision, and find that the experimental data supports a so-called exon definition mechanism. We show that this mechanism enhances the precision of alternative splicing regulation and prevents the retention of introns in the mature mRNA.

Large-scale analysis of the cassava transcriptome reveals the impact of cold stress on alternative splicing

2019 ◽  
Author(s):  
Shuxia Li ◽  
Xiang Yu ◽  
Zhihao Cheng ◽  
Changying Zeng ◽  
Wenbin Li ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Drought Stress ◽  
Cold Stress ◽  
Large Scale ◽  
Intron Retention ◽  
Global Analysis ◽  
Premature Termination Codon ◽  
Alternatively Spliced ◽  
Alternative Splicing Events ◽  
The Impact

Abstract Alternative splicing is an essential post-transcriptional regulatory mechanism that can impact mRNA stability and protein diversity of eukaryotic genomes. Although numerous forms of stress-responsive alternative splicing have been identified in model plants, a large-scale study of alternative splicing dynamics under abiotic stress conditions in cassava has not been conducted. Here, we report the parallel employment of isoform-Seq, ssRNA-Seq, and Degradome-Seq to investigate the diversity, abundance, and fate of alternatively spliced isoforms in response to cold and drought stress. We identified 38 164 alternative splicing events, among which 3292 and 1025 events were significantly regulated by cold and drought stress, respectively. Intron retention was the most abundant subtype of alternative splicing. Global analysis of splicing regulators revealed that the number of their alternatively spliced isoforms and the corresponding abundance were specifically modulated by cold stress. We found that 58.5% of cold-regulated alternative splicing events introduced a premature termination codon into the transcripts, and 77.6% of differential alternative splicing events were detected by Degradome-Seq. Our data reveal that cold intensely affects both quantitative and qualitative aspects of gene expression via alternative splicing pathways, and advances our understanding of the high complexity and specificity of gene regulation in response to abiotic stresses. Alternative splicing is responsible for reprogramming of the transcriptome and the sensitivity of cassava plants to cold.

scholarly journals Minor spliceosome inactivation in the developing mouse cortex causes self-amplifying radial glial cell death and microcephaly

2017 ◽  
Author(s):  
Marybeth Baumgartner ◽  
Anouk M. Olthof ◽  
Katery C. Hyatt ◽  
Christopher Lemoine ◽  
Kyle Drake ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Glial Cell ◽  
Progenitor Cell ◽  
Intron Retention ◽  
Cortical Development ◽  
Conditional Knockout ◽  
Small Nuclear Rna ◽  
Radial Glial Cell ◽  
Nuclear Rna ◽  
Radial Glial

AbstractInactivation of the minor spliceosome has been linked to microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1). To interrogate how minor intron splicing regulates cortical development, we employed Emx1-Cre to ablate Rnu11, which encodes the minor spliceosome-specific U11 small nuclear RNA (snRNA), in the developing cortex (pallium). Rnu11 cKO mice were born with microcephaly, caused by death of self-amplifying radial glial cells (RGCs). However, both intermediate progenitor cells (IPCs) and neurons were produced in the U11-null pallium. RNAseq of the pallium revealed elevated minor intron retention in the mutant, particularly in genes regulating cell cycle. Moreover, the only downregulated minor intron-containing gene (MIG) was Spc24, which regulates kinetochore assembly. These findings were consistent with the observation of fewer RGCs entering cytokinesis prior to RGC loss, underscoring the requirement of minor splicing for cell cycle progression in RGCs. Overall, we provide a potential explanation of how disruption of minor splicing might cause microcephaly in MOPD1.Summary StatementHere we report the first mammalian model to investigate the role of the minor spliceosome in cortical development and microcephaly.List of abbreviations usedMOPD1=microcephalic osteodysplastic primordial dwarfism type 1; snRNA=small nuclear RNA; cKO=conditional knockout; NPC=neural progenitor cell; RGC=radial glial cell; IPC=intermediate progenitor cell; MIG=minor intron-containing gene

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.

scholarly journals Alternative splicing landscapes in Arabidopsis thaliana across tissues and stress conditions highlight major functional differences with animals

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Guiomar Martín ◽  
Yamile Márquez ◽  
Federica Mantica ◽  
Paula Duque ◽  
Manuel Irimia
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Alternative Splicing ◽  
Stress Responses ◽  
Target Genes ◽  
Intron Retention ◽  
Single Gene ◽  
Exon Skipping ◽  
Environmental Response ◽  
Biotic Stresses

Abstract Background Alternative splicing (AS) is a widespread regulatory mechanism in multicellular organisms. Numerous transcriptomic and single-gene studies in plants have investigated AS in response to specific conditions, especially environmental stress, unveiling substantial amounts of intron retention that modulate gene expression. However, a comprehensive study contrasting stress-response and tissue-specific AS patterns and directly comparing them with those of animal models is still missing. Results We generate a massive resource for Arabidopsis thaliana, PastDB, comprising AS and gene expression quantifications across tissues, development and environmental conditions, including abiotic and biotic stresses. Harmonized analysis of these datasets reveals that A. thaliana shows high levels of AS, similar to fruitflies, and that, compared to animals, disproportionately uses AS for stress responses. We identify core sets of genes regulated specifically by either AS or transcription upon stresses or among tissues, a regulatory specialization that is tightly mirrored by the genomic features of these genes. Unexpectedly, non-intron retention events, including exon skipping, are overrepresented across regulated AS sets in A. thaliana, being also largely involved in modulating gene expression through NMD and uORF inclusion. Conclusions Non-intron retention events have likely been functionally underrated in plants. AS constitutes a distinct regulatory layer controlling gene expression upon internal and external stimuli whose target genes and master regulators are hardwired at the genomic level to specifically undergo post-transcriptional regulation. Given the higher relevance of AS in the response to different stresses when compared to animals, this molecular hardwiring is likely required for a proper environmental response in A. thaliana.

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