scholarly journals Alternative splicing takes charge of interleukin-22 and interferon lambda 4 signaling

2018 ◽  
Author(s):  
Chrissie Lim
Keyword(s):  
Alternative Splicing ◽  
Intron Retention ◽  
Protein Isoforms ◽  
Functional Domain ◽  
Type I ◽  
Protein Coding ◽  
Interleukin 22 ◽  
Interferon Lambda ◽  
Type Iii Ifn ◽  
Overexpression System

Immune responses require the tight control of dose, location, strength and duration through genetic, epigenetic or biochemical regulation. Of these, the generation of alternatively-spliced constructs increases transcriptional and proteomic diversity in post-transcriptional modification, localization and functional domain integrity. Specifically, this thesis explores how splice variation engenders profound differences in the biological functions of interleukin-22 (IL-22) binding protein (IL-22BP) and interferon lambda 4 (IFNλ4), which are both central components of distinct cytokine pathways in mucosal immunity and inflammation. IL-22BP is a soluble receptor for IL-22 that is expressed as three isoforms in humans, though the physiological relevance of the three human isoforms has remained a mystery due to the absence of this variation in mice. We present novel findings that IL-22BPi1 is inactive due to intracellular retention by its unique exon, while IL-22BPi3 is also an antagonist but with differential activity from IL-22BPi2. Importantly, while IL-22BPi3 has widespread expression in steady-state homeostatic conditions, IL-22BPi2 is the only isoform induced by inflammatory TLR2/retinoic acid stimulation, highlighting important spatiotemporal control of the two isoforms that exploit their differential activities. IFNλ4 presents a different mystery in which the protein-coding variant is genetically associated with poorer clearance, but the mechanism for this association remains unclear. We investigated several non-canonical functions proposed by the field, including intrinsic differences in activity of the three protein isoforms and their interference with antiviral activites of other type I or III interferons. Establishing an overexpression system and purifying recombinant proteins, we found that only the full-length isoform is active and exhibits similar effects to canonical type III IFN IFNλ3, without any blockade of other IFN signaling. Simultaneously, functional IFNλ4 expression is suppressed in hepatocytes and dendritic cells through preferential splicing to increase intron retention and expression of inactive isoforms. Therefore, alternative splicing in IFNλ4 is an important mechanism to control IFNλ4 bioactivity. The divergent manners in which alternative splice forms impact the activity of both IL-22BP and IFNλ4 highlight the important contributions of this process to cytokine biology and bigger implications that escape detection by genomic analyses.

Pre-mRNA Splicing Mechanisms, Misregulation in Disease, and Therapeutic Strategies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-13-SCI-13
Author(s):  
Adrian Krainer
Keyword(s):  
Alternative Splicing ◽  
Research Funding ◽  
Therapeutic Strategies ◽  
Mrna Splicing ◽  
Protein Isoforms ◽  
Current Status ◽  
Targeted Therapeutics ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Normal Gene

Abstract Abstract SCI-13 Most eukaryotic protein-coding genes have one or more introns, and their transcripts can undergo alternative splicing, giving rise to multiple isoforms. Accurate splicing is essential for normal gene expression, and alternative splicing is a key mechanism for expanding the proteome and regulating the expression of diverse protein isoforms. This session will review the general mechanisms of pre-mRNA splicing and the regulation of alternative splicing. In addition, the process of how abnormal splicing arises as a result of intronic or exonic mutations in particular genes, or more globally as a result of splicing-factor misregulation, as well as the contribution of splicing misregulation to cancer, will be described. Lastly the current status of targeted therapeutics development, focusing on antisense approaches to correct abnormal splicing of specific genes or to modulate alternative splicing, will be discussed. Disclosures: Krainer: ISIS Pharmaceuticals: Consultancy, Patents & Royalties, Research Funding.

Multiple Scenarios of Transition to Chaos in the Alternative Splicing Model

2017 ◽  
Vol 27 (02) ◽  
pp. 1730006 ◽  
Author(s):  
Vladislav V. Kogai ◽  
Vitaly A. Likhoshvai ◽  
Stanislav I. Fadeev ◽  
Tamara M. Khlebodarova
Keyword(s):  
Alternative Splicing ◽  
Period Doubling ◽  
Genetic System ◽  
Protein Isoforms ◽  
Type I ◽  
Transition To Chaos ◽  
Delayed Arguments ◽  
The Mathematical Model ◽  
Period Doubling Bifurcations ◽  
Type Of Transition

We have investigated the scenarios of transition to chaos in the mathematical model of a genetic system constituted by a single transcription factor-encoding gene, the expression of which is self-regulated by a feedback loop that involves protein isoforms. Alternative splicing results in the synthesis of protein isoforms providing opposite regulatory outcomes — activation or repression. The model is represented by a differential equation with two delayed arguments. The possibility of transition to chaos dynamics via all classical scenarios: a cascade of period-doubling bifurcations, quasiperiodicity and type-I, type-II and type-III intermittencies, has been numerically demonstrated. The parametric features of each type of transition to chaos have been described.

scholarly journals Widespread separation of the polypyrimidine tract from 3’ AG by G tracts in association with alternative exons in metazoa and plants

2018 ◽  
Author(s):  
Hai Nguyen ◽  
Jiuyong Xie
Keyword(s):  
Alternative Splicing ◽  
Branch Point ◽  
Intron Retention ◽  
Regulatory Elements ◽  
Protein Isoforms ◽  
Model Organisms ◽  
Branch Points ◽  
Splice Sites ◽  
Polypyrimidine Tract ◽  
Whole Genome Analysis

SummaryAt the end of introns, the polypyrimidine tract (Py) is often close to the 3’ AG in a consensus (Y)20NCAGgt in humans. Interestingly, we have found that they could also be separated by purine-rich elements including G tracts in thousands of human genes. These regulatory elements between the Py and 3’AG (REPA) mainly regulate alternative 3’ splice sites (3’SS) and intron retention. Here we show their widespread distribution and special properties across kingdoms. The purine-rich 3’SS are found in up to about 60% of the introns among more than 1000 species/lineages by whole genome analysis, and up to 18% of these introns contain the REPA G tracts in about 2.4 millions of 3’SS in total. In particular, they are significantly enriched over their 3’SS and genome backgrounds in metazoa and plants, and highly associated with alternative splicing of genes in diverse functional clusters. They are also highly enriched (3-6 folds) in the canonical as well as aberrantly used 3’ splice sites in cancer patients carrying mutations of the branch point factor SF3B1 or the 3’AG binding factor U2AF35. Moreover, the REPA G tract-harbouring 3’SS have significantly reduced occurrences of branch point (BP) motifs between the −24 and −4 positions, in particular absent from the −7 - −5 positions in several model organisms examined. The more distant branch points are associated with increased occurrences of alternative splicing in human and zebrafish. The branch points, REPA G tracts and associated 3’SS motifs appear to have emerged differentially in a phylum- or species-specific way during evolution. Thus, there is widespread separation of the Py and 3’AG by REPA G tracts, likely evolved among different species or branches of life. This special 3’SS arrangement contributes to the generation of diverse transcript or protein isoforms in biological functions or diseases through alternative or aberrant splicing.

scholarly journals Genetics of alternative splicing evolution during sunflower domestication

2018 ◽  
Vol 115 (26) ◽  
pp. 6768-6773 ◽  
Author(s):  
Chris C. R. Smith ◽  
Silas Tittes ◽  
J. Paul Mendieta ◽  
Erin Collier-zans ◽  
Heather C. Rowe ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Intron Retention ◽  
Population Divergence ◽  
Evolutionary Transition ◽  
Differential Splicing ◽  
Evolutionary Transitions ◽  
Protein Coding ◽  
Standing Variation ◽  
Splice Forms ◽  
Splicing Patterns

Alternative splicing enables organisms to produce the diversity of proteins necessary for multicellular life by using relatively few protein-coding genes. Although differences in splicing have been identified among divergent taxa, the shorter-term evolution of splicing is understudied. The origins of novel splice forms, and the contributions of alternative splicing to major evolutionary transitions, are largely unknown. This study used transcriptomes of wild and domesticated sunflowers to examine splice differentiation and regulation during domestication. We identified substantial splicing divergence between wild and domesticated sunflowers, mainly in the form of intron retention. Transcripts with divergent splicing were enriched for seed-development functions, suggesting that artificial selection impacted splicing patterns. Mapping of quantitative trait loci (QTLs) associated with 144 differential splicing cases revealed primarilytrans-acting variation affecting splicing patterns. A large proportion of identified QTLs contain known spliceosome proteins and are associated with splicing variation in multiple genes. Examining a broader set of wild and domesticated sunflower genotypes revealed that most differential splicing patterns in domesticated sunflowers likely arose from standing variation in wildHelianthus annuusand gained frequency during the domestication process. However, several domesticate-associated splicing patterns appear to be introgressed from otherHelianthusspecies. These results suggest that sunflower domestication involved selection on pleiotropic regulatory alleles. More generally, our findings indicate that substantial differences in isoform abundances arose rapidly during a recent evolutionary transition and appear to contribute to adaptation and population divergence.

scholarly journals Interferon Lambda: A New Sword in Cancer Immunotherapy

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Ahmed Lasfar ◽  
Walid Abushahba ◽  
Murugabaskar Balan ◽  
Karine A. Cohen-Solal
Keyword(s):  
Viral Infections ◽  
Type I ◽  
Type Ii ◽  
Type Iii ◽  
Group Type ◽  
Interferon Lambda ◽  
New Type ◽  
Cell Type Specific ◽  
Type Iii Ifn

The discovery of the interferon-lambda (IFN-λ) family has considerably contributed to our understanding of the role of interferon not only in viral infections but also in cancer. IFN-λproteins belong to the new type III IFN group. Type III IFN is structurally similar to type II IFN (IFN-γ) but functionally identical to type I IFN (IFN-α/β). However, in contrast to type I or type II IFNs, the response to type III IFN is highly cell-type specific. Only epithelial-like cells and to a lesser extent some immune cells respond to IFN-λ. This particular pattern of response is controlled by the differential expression of the IFN-λreceptor, which, in contrast to IFN-α, should result in limited side effects in patients. Recently, we and other groups have shown in several animal models a potent antitumor role of IFN-λthat will open a new challenging era for the current IFN therapy.

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.

scholarly journals Interferon lambda signals in maternal tissues to exert protective and pathologic effects in a gestational-stage dependent manner

2022 ◽  
Author(s):  
Rebecca L. Casazza ◽  
Drake T Philip ◽  
Helen M. Lazear
Keyword(s):  
Congenital Infection ◽  
Antiviral Effect ◽  
Poly I:C ◽  
Type I ◽  
Dependent Manner ◽  
Transplacental Transmission ◽  
Interferon Lambda ◽  
Healthy Pregnancy ◽  
Gestational Stage ◽  
Type Iii Ifn

Interferon lambda (IFN-λ, type III IFN) is constitutively secreted from human placental cells in culture and reduces Zika virus (ZIKV) transplacental transmission in mice. However, the roles of IFN-λ during healthy pregnancy and in restricting congenital infection remain unclear. Here we used mice lacking the IFN-λ receptor (Ifnlr1-/-) to generate pregnancies lacking either maternal or fetal IFN-λ responsiveness and found that the antiviral effect of IFN-λ resulted from signaling exclusively in maternal tissues. This protective effect depended on gestational stage, as infection earlier in pregnancy (E7 rather than E9) resulted in enhanced transplacental transmission of ZIKV. In Ifnar1-/- dams, which sustain robust ZIKV infection, maternal IFN-λ signaling caused fetal resorption and intrauterine growth restriction. Pregnancy pathology elicited by poly(I:C) treatment also was mediated by maternal IFN-λ signaling, specifically in maternal leukocytes, and also occurred in a gestational stage-dependent manner. These findings identify an unexpected effect of IFN-λ signaling specifically in maternal (rather than placental or fetal) tissues, which is distinct from the pathogenic effects of IFN-αβ (type I IFN) during pregnancy. These results highlight the complexity of immune signaling at the maternal-fetal interface, where disparate outcomes can result from signaling at different gestational stages.

A Dynamic Intron Retention Program in the Mammalian Megakaryocyte and Erythrocyte Lineages

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2380-2380
Author(s):  
Christopher R Edwards ◽  
Rob Middleton ◽  
Xiuli An ◽  
Tejaswini Mishra ◽  
Narla Mohandas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Conflicts Of Interest ◽  
Intron Retention ◽  
Expression Patterns ◽  
Erythroid Differentiation ◽  
Cell Types ◽  
Mrna Levels ◽  
Protein Coding ◽  
Nonsense Mediated Decay

Abstract Intron retention (IR), the least studied form of alternative splicing, has recently been shown to have important biological roles in a variety of cell types. While it can alter a gene's protein-coding sequence, it is becoming particularly well-known for its potential to impact gene expression by destabilizing mRNAs through the nonsense-mediated decay pathway or by promoting their retention in the nucleus. A complex, dynamic, and biologically important IR program has been described in maturing mammalian granulocytes, but it is unknown whether IR occurs broadly in other hematopoietic lineages. We therefore globally assessed IR in the mammalian erythroid and megakaryocyte lineages. Intron Retention Finder, a bioinformatics tool that measures IR in RNA-seq datasets, was used to analyze IR in primary cells of the erythroid and megakaryocyte lineages as well as their common progenitor cells. Both lineages exhibit an extensive differential IR program involving hundreds of introns and genes. Complex IR patterns were seen in murine erythropoiesis from the megakaryocytic-erythroid branch point throughout the terminal maturation stages. Within the terminally differentiating proerythroblast to orthochromatic erythroblast stages, hundreds of introns saw their retention level increase as cells differentiate while a smaller set exhibited an opposing trend. Similarly complex patterns including a dramatic IR increase in orthochromatic erythroblasts were observed during human terminal erythroid differentiation, but not involving the murine orthologous introns or genes. Despite the common origin of erythroid cells and megakaryocytes and their overlapping gene expression patterns, the megakaryocytic IR program is entirely distinct from that of the erythroid lineage with regards to introns, genes, and affected gene ontologies. This suggests that the dynamic IR patterns are not simply the result of general maturational changes, but rather may arise via lineage-specific mechanisms. Importantly, we observed an inverse relationship between IR and gene expression changes, supporting the hypothesis that IR serves to regulate mRNA levels. Our findings add a new dimension to the megakaryocyte and erythroid transcription programs by expanding the mechanisms of gene control to include this understudied form of alternative splicing. Disclosures No relevant conflicts of interest to declare.

scholarly journals Alternative Splicing of the Aflatoxin-Associated Baeyer–Villiger Monooxygenase from Aspergillus flavus: Characterisation of MoxY Isoforms

Toxins ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 521 ◽  
Author(s):  
Carmien Tolmie ◽  
Martha Smit ◽  
Diederik Opperman
Keyword(s):  
Alternative Splicing ◽  
Aspergillus Flavus ◽  
Intron Retention ◽  
Start Codon ◽  
Type I ◽  
Aflatoxin Biosynthesis ◽  
Biosynthesis Gene Cluster ◽  
C Terminus ◽  
N Terminus

Aflatoxins are carcinogenic mycotoxins that are produced by the filamentous fungus Aspergillus flavus, a contaminant of numerous food crops. Aflatoxins are synthesised via the aflatoxin biosynthesis pathway, with the enzymes involved encoded by the aflatoxin biosynthesis gene cluster. MoxY is a type I Baeyer–Villiger monooxygenase (BVMO), responsible for the conversion of hydroxyversicolorone (HVN) and versicolorone (VN) to versiconal hemiacetal acetate (VHA) and versiconol acetate (VOAc), respectively. Using mRNA data, an intron near the C-terminus was identified that is alternatively spliced, creating two possible MoxY isoforms which exist in vivo, while analysis of the genomic DNA suggests an alternative start codon leading to possible elongation of the N-terminus. These four variants of the moxY gene were recombinantly expressed in Escherichia coli, and their activity evaluated with respect to their natural substrates HVN and VN, as well as surrogate ketone substrates. Activity of the enzyme is absolutely dependent on the additional 22 amino acid residues at the N-terminus. Two MoxY isoforms with alternative C-termini, MoxYAltN and MoxYAltNC, converted HVN and VN, in addition to a range of ketone substrates. Stability and flavin-binding data suggest that MoxYAltN is, most likely, the dominant isoform. MoxYAltNC is generated by intron splicing, in contrast to intron retention, which is the most prevalent type of alternative splicing in ascomycetes. The alternative C-termini did not alter the substrate acceptance profile, or regio- or enantioselectivity of the enzyme, but did significantly affect the solubility and stability.

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