scholarly journals The fitness cost of mis-splicing is the main determinant of alternative splicing patterns

2017 ◽  
Author(s):  
Baptiste Saudemont ◽  
Alexandra Popa ◽  
Joanna L. Parmley ◽  
Vincent Rocher ◽  
Corinne Blugeon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Splice Variants ◽  
Intron Retention ◽  
Relative Proportion ◽  
Regulation Of Gene Expression ◽  
Fitness Cost ◽  
Expression Level ◽  
Unicellular Eukaryote ◽  
Eukaryotic Genes

ABSTRACTMost eukaryotic genes are subject to alternative splicing (AS), which may contribute to the production of functional protein variants or to the regulation of gene expression, notably via nonsense-mediated mRNA decay (NMD). However, a fraction of splice variants might correspond to spurious transcripts, and the question of the relative proportion of splicing errors vs. functional splice variants remains highly debated. We propose here a test to quantify the fraction of AS events corresponding to errors. This test is based on the fact that the fitness cost of splicing errors increases with the number of introns in a gene and with expression level. We first analyzed the transcriptome of the intron-rich unicellular eukaryote Paramecium tetraurelia. We show that both in normal and in NMD-deficient cells, AS rates (intron retention, alternative splice site usage or cryptic intron splicing) strongly decrease with increasing expression level and with increasing number of introns. This relationship is observed both for AS events that are detectable by NMD or not, which invalidates the hypothesis of a possible link with the regulation of gene expression. Our results indicate that in genes with a median expression level, 92%-98% of observed splice variants correspond to errors. Interestingly, we observed the same patterns in human transcriptomes. These results are consistent with the mutation-selection-drift theory, which predicts that genes under weaker selective pressure should accumulate more maladaptive substitutions, and therefore should be more prone to errors of gene expression.

scholarly journals Phosphorylation-Mediated Regulation of Alternative Splicing in Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Chiara Naro ◽  
Claudio Sette
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Posttranslational Modifications ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Splice Variants ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Eukaryotic Cells ◽  
Macromolecular Complex

Alternative splicing (AS) is one of the key processes involved in the regulation of gene expression in eukaryotic cells. AS catalyzes the removal of intronic sequences and the joining of selected exons, thus ensuring the correct processing of the primary transcript into the mature mRNA. The combinatorial nature of AS allows a great expansion of the genome coding potential, as multiple splice-variants encoding for different proteins may arise from a single gene. Splicing is mediated by a large macromolecular complex, the spliceosome, whose activity needs a fine regulation exerted bycis-acting RNA sequence elements andtrans-acting RNA binding proteins (RBP). The activity of both core spliceosomal components and accessory splicing factors is modulated by their reversible phosphorylation. The kinases and phosphatases involved in these posttranslational modifications significantly contribute to AS regulation and to its integration in the complex regulative network that controls gene expression in eukaryotic cells. Herein, we will review the major canonical and noncanonical splicing factor kinases and phosphatases, focusing on those whose activity has been implicated in the aberrant splicing events that characterize neoplastic transformation.

scholarly journals The circadian clock shapes the Arabidopsis transcriptome by regulating alternative splicing and alternative polyadenylation

2020 ◽  
Vol 295 (22) ◽  
pp. 7608-7619 ◽  
Author(s):  
Yuchen Yang ◽  
Yun Li ◽  
Aziz Sancar ◽  
Onur Oztas
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Circadian Clock ◽  
Posttranscriptional Regulation ◽  
Environmental Changes ◽  
Intron Retention ◽  
Regulation Of Gene Expression ◽  
Alternative Polyadenylation ◽  
Genome Wide ◽  
Plant Genes

The circadian clock in plants temporally coordinates biological processes throughout the day, synchronizing gene expression with diurnal environmental changes. Circadian oscillator proteins are known to regulate the expression of clock-controlled plant genes by controlling their transcription. Here, using a high-throughput RNA-Seq approach, we examined genome-wide circadian and diurnal control of the Arabidopsis transcriptome, finding that the oscillation patterns of different transcripts of multitranscript genes can exhibit substantial differences and demonstrating that the circadian clock affects posttranscriptional regulation. In parallel, we found that two major posttranscriptional mechanisms, alternative splicing (AS; especially intron retention) and alternative polyadenylation (APA), display circadian rhythmicity resulting from oscillation in the genes involved in AS and APA. Moreover, AS-related genes exhibited rhythmic AS and APA regulation, adding another layer of complexity to circadian regulation of gene expression. We conclude that the Arabidopsis circadian clock not only controls transcription of genes but also affects their posttranscriptional regulation by influencing alternative splicing and alternative polyadenylation.

Linking transcription, RNA polymerase II elongation and alternative splicing

2020 ◽  
Vol 477 (16) ◽  
pp. 3091-3104 ◽  
Author(s):  
Luciana E. Giono ◽  
Alberto R. Kornblihtt
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Rna Polymerase Ii ◽  
Environmental Changes ◽  
Transcription Elongation ◽  
Single Gene ◽  
Regulation Of Gene Expression ◽  
Regulation Of Transcription ◽  
Stepping Stones ◽  
Eukaryotic Transcription

Gene expression is an intricately regulated process that is at the basis of cell differentiation, the maintenance of cell identity and the cellular responses to environmental changes. Alternative splicing, the process by which multiple functionally distinct transcripts are generated from a single gene, is one of the main mechanisms that contribute to expand the coding capacity of genomes and help explain the level of complexity achieved by higher organisms. Eukaryotic transcription is subject to multiple layers of regulation both intrinsic — such as promoter structure — and dynamic, allowing the cell to respond to internal and external signals. Similarly, alternative splicing choices are affected by all of these aspects, mainly through the regulation of transcription elongation, making it a regulatory knob on a par with the regulation of gene expression levels. This review aims to recapitulate some of the history and stepping-stones that led to the paradigms held today about transcription and splicing regulation, with major focus on transcription elongation and its effect on alternative splicing.

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.

scholarly journals Regulation of Multiple Core Spliceosomal Proteins by Alternative Splicing-Coupled Nonsense-Mediated mRNA Decay

2008 ◽  
Vol 28 (13) ◽  
pp. 4320-4330 ◽  
Author(s):  
Arneet L. Saltzman ◽  
Yoon Ki Kim ◽  
Qun Pan ◽  
Matthew M. Fagnani ◽  
Lynne E. Maquat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Mrna Decay ◽  
Splice Variants ◽  
Cellular Functions ◽  
Regulate Gene Expression ◽  
Premature Termination Codons ◽  
Microarray Profiling ◽  
Nonsense Mediated Mrna Decay ◽  
Regulate Gene

ABSTRACT Alternative splicing (AS) can regulate gene expression by introducing premature termination codons (PTCs) into spliced mRNA that subsequently elicit transcript degradation by the nonsense-mediated mRNA decay (NMD) pathway. However, the range of cellular functions controlled by this process and the factors required are poorly understood. By quantitative AS microarray profiling, we find that there are significant overlaps among the sets of PTC-introducing AS events affected by individual knockdown of the three core human NMD factors, Up-Frameshift 1 (UPF1), UPF2, and UPF3X/B. However, the levels of some PTC-containing splice variants are less or not detectably affected by the knockdown of UPF2 and/or UPF3X, compared with the knockdown of UPF1. The intron sequences flanking the affected alternative exons are often highly conserved, suggesting important regulatory roles for these AS events. The corresponding genes represent diverse cellular functions, and surprisingly, many encode core spliceosomal proteins and assembly factors. We further show that conserved, PTC-introducing AS events are enriched in genes that encode core spliceosomal proteins. Where tested, altering the expression levels of these core spliceosomal components affects the regulation of PTC-containing splice variants from the corresponding genes. Together, our results show that AS-coupled NMD can have different UPF factor requirements and is likely to regulate many general components of the spliceosome. The results further implicate general spliceosomal components in AS regulation.

scholarly journals Cellular stressors may alter islet hormone cell proportions by moderation of alternative splicing patterns

2019 ◽  
Vol 28 (16) ◽  
pp. 2763-2774 ◽  
Author(s):  
Nicola Jeffery ◽  
Sarah Richardson ◽  
David Chambers ◽  
Noel G Morgan ◽  
Lorna W Harries
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Regulation Of Gene Expression ◽  
Splicing Factor ◽  
Splicing Regulation ◽  
Messenger Ribonucleic Acid ◽  
Splicing Patterns ◽  
Cellular Stressors

Abstract Changes to islet cell identity in response to type 2 diabetes (T2D) have been reported in rodent models, but are less well characterized in humans. We assessed the effects of aspects of the diabetic microenvironment on hormone staining, total gene expression, splicing regulation and the alternative splicing patterns of key genes in EndoC-βH1 human beta cells. Genes encoding islet hormones [somatostatin (SST), insulin (INS), Glucagon (GCG)], differentiation markers [Forkhead box O1 (FOXO1), Paired box 6, SRY box 9, NK6 Homeobox 1, NK6 Homeobox 2] and cell stress markers (DNA damage inducible transcript 3, FOXO1) were dysregulated in stressed EndoC-βH1 cells, as were some serine arginine rich splicing factor splicing activator and heterogeneous ribonucleoprotein particle inhibitor genes. Whole transcriptome analysis of primary T2D islets and matched controls demonstrated dysregulated splicing for ~25% of splicing events, of which genes themselves involved in messenger ribonucleic acid processing and regulation of gene expression comprised the largest group. Approximately 5% of EndoC-βH1 cells exposed to these factors gained SST positivity in vitro. An increased area of SST staining was also observed ex vivo in pancreas sections recovered at autopsy from donors with type 1 diabetes (T1D) or T2D (9.3% for T1D and 3% for T2D, respectively compared with 1% in controls). Removal of the stressful stimulus or treatment with the AKT Serine/Threonine kinase inhibitor SH-6 restored splicing factor expression and reversed both hormone staining effects and patterns of gene expression. This suggests that reversible changes in hormone expression may occur during exposure to diabetomimetic cellular stressors, which may be mediated by changes in splicing regulation.

scholarly journals Alternative Splicing During the Chlamydomonasreinhardtii Cell Cycle

2020 ◽  
Vol 10 (10) ◽  
pp. 3797-3810
Author(s):  
Manishi Pandey ◽  
Gary D. Stormo ◽  
Susan K. Dutcher
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Alternative Splicing ◽  
Chlamydomonas Reinhardtii ◽  
Intron Retention ◽  
Exon Skipping ◽  
Dark Phase ◽  
Periodic Patterns ◽  
Genome Wide ◽  
Splicing Pattern

Genome-wide analysis of transcriptome data in Chlamydomonas reinhardtii shows periodic patterns in gene expression levels when cultures are grown under alternating light and dark cycles so that G1 of the cell cycle occurs in the light phase and S/M/G0 occurs during the dark phase. However, alternative splicing, a process that enables a greater protein diversity from a limited set of genes, remains largely unexplored by previous transcriptome based studies in C. reinhardtii. In this study, we used existing longitudinal RNA-seq data obtained during the light-dark cycle to investigate the changes in the alternative splicing pattern and found that 3277 genes (19.75% of 17,746 genes) undergo alternative splicing. These splicing events include Alternative 5′ (Alt 5′), Alternative 3′ (Alt 3′) and Exon skipping (ES) events that are referred as alternative site selection (ASS) events and Intron retention (IR) events. By clustering analysis, we identified a subset of events (26 ASS events and 10 IR events) that show periodic changes in the splicing pattern during the cell cycle. About two-thirds of these 36 genes either introduce a pre-termination codon (PTC) or introduce insertions or deletions into functional domains of the proteins, which implicate splicing in altering gene function. These findings suggest that alternative splicing is also regulated during the Chlamydomonas cell cycle, although not as extensively as changes in gene expression. The longitudinal changes in the alternative splicing pattern during the cell cycle captured by this study provides an important resource to investigate alternative splicing in genes of interest during the cell cycle in Chlamydomonas reinhardtii and other eukaryotes.

scholarly journals Sex-Specific Selection Drives the Evolution of Alternative Splicing in Birds

2020 ◽  
Author(s):  
Thea F Rogers ◽  
Daniela H Palmer ◽  
Alison E Wright
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Alternative Splicing ◽  
Bird Species ◽  
Gene Expression Level ◽  
Expression Level ◽  
Selection Pressures ◽  
Specific Adaptation ◽  
Beneficial Effects ◽  
Males And Females

Abstract Males and females of the same species share the majority of their genomes, yet they are frequently exposed to conflicting selection pressures. Gene regulation is widely assumed to resolve these conflicting sex-specific selection pressures, and although there has been considerable focus on elucidating the role of gene expression level in sex-specific adaptation, other regulatory mechanisms have been overlooked. Alternative splicing enables different transcripts to be generated from the same gene, meaning that exons which have sex-specific beneficial effects can in theory be retained in the gene product, whereas exons with detrimental effects can be skipped. However, at present, little is known about how sex-specific selection acts on broad patterns of alternative splicing. Here, we investigate alternative splicing across males and females of multiple bird species. We identify hundreds of genes that have sex-specific patterns of splicing and establish that sex differences in splicing are correlated with phenotypic sex differences. Additionally, we find that alternatively spliced genes have evolved rapidly as a result of sex-specific selection and suggest that sex differences in splicing offer another route to sex-specific adaptation when gene expression level changes are limited by functional constraints. Overall, our results shed light on how a diverse transcriptional framework can give rise to the evolution of phenotypic sexual dimorphism.

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