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International Journal of Molecular... Jun 2021Pre-mRNA splicing is an essential step in gene expression and is catalyzed by two machineries in eukaryotes: the major (U2 type) and minor (U12 type) spliceosomes. While... (Review)
Review
Pre-mRNA splicing is an essential step in gene expression and is catalyzed by two machineries in eukaryotes: the major (U2 type) and minor (U12 type) spliceosomes. While the majority of introns in humans are U2 type, less than 0.4% are U12 type, also known as minor introns (mi-INTs), and require a specialized spliceosome composed of U11, U12, U4atac, U5, and U6atac snRNPs. The high evolutionary conservation and apparent splicing inefficiency of U12 introns have set them apart from their major counterparts and led to speculations on the purpose for their existence. However, recent studies challenged the simple concept of mi-INTs splicing inefficiency due to low abundance of their spliceosome and confirmed their regulatory role in alternative splicing, significantly impacting the expression of their host genes. Additionally, a growing list of minor spliceosome-associated diseases with tissue-specific pathologies affirmed the importance of minor splicing as a key regulatory pathway, which when deregulated could lead to tissue-specific pathologies due to specific alterations in the expression of some minor-intron-containing genes. Consequently, uncovering how mi-INTs splicing is regulated in a tissue-specific manner would allow for better understanding of disease pathogenesis and pave the way for novel therapies, which we highlight in this review.
Topics: Animals; Disease; Evolution, Molecular; Humans; Introns; Organ Specificity; RNA Splicing; Spliceosomes
PubMed: 34199764
DOI: 10.3390/ijms22116062 -
FEBS Letters Apr 1987Exon insertions and exon duplications, two major mechanisms of exon shuffling, are shown to involve modules that have introns of the same phase class at both their 5'-... (Review)
Review
Exon insertions and exon duplications, two major mechanisms of exon shuffling, are shown to involve modules that have introns of the same phase class at both their 5'- and 3'-ends. At the sites of intronic recombinations exon insertions and duplications create new introns which belong to the same phase class as the recipient introns. As a consequence of repeated exon insertions and exon duplications introns of a single phase class predominate in the resulting genes, i.e. gene assembly by exon shuffling is reflected both by this nonrandom intron phase usage and by the correlation between the domain organization of the proteins and exon-intron organization of their genes. Genes that appeared before the eukaryote-prokaryote split do not show these diagnostic signs of exon shuffling. Since ancestral introns (e.g. self-splicing introns) did not favour intronic recombination, exon shuffling may not have been significant in the early part of protein evolution.
Topics: Animals; Biological Evolution; Exons; Introns; Peptide Hydrolases; RNA Splicing; Recombination, Genetic
PubMed: 3552723
DOI: 10.1016/0014-5793(87)80002-9 -
The Journal of Biological Chemistry Jan 2008Pre-mRNA splicing is a fundamental process required for the expression of most metazoan genes. It is carried out by the spliceosome, which catalyzes the removal of... (Review)
Review
Pre-mRNA splicing is a fundamental process required for the expression of most metazoan genes. It is carried out by the spliceosome, which catalyzes the removal of noncoding intronic sequences to assemble exons into mature mRNAs prior to export and translation. Given the complexity of higher eukaryotic genes and the relatively low level of splice site conservation, the precision of the splicing machinery in recognizing and pairing splice sites is impressive. Introns ranging in size from <100 up to 100,000 bases are removed efficiently. At the same time, a large number of alternative splicing events are observed between different cell types, during development, or during other biological processes. This extensive alternative splicing implies a significant flexibility of the spliceosome to identify and process exons within a given pre-mRNA. To reach this flexibility, splice site selection in higher eukaryotes has evolved to depend on multiple parameters such as splice site strength, the presence or absence of splicing regulators, RNA secondary structures, the exon/intron architecture, and the process of pre-mRNA synthesis itself. The relative contributions of each of these parameters control how efficiently splice sites are recognized and flanking introns are removed.
Topics: Alternative Splicing; Animals; Exons; Gene Expression Regulation; Humans; Introns; RNA Splice Sites
PubMed: 18024426
DOI: 10.1074/jbc.R700035200 -
BMC Genomics May 2020The evolutionary radiation of animals was accompanied by extensive expansion of gene and genome sizes, increased isoform diversity, and complexity of regulation.
BACKGROUND
The evolutionary radiation of animals was accompanied by extensive expansion of gene and genome sizes, increased isoform diversity, and complexity of regulation.
RESULTS
Here we show that the longest genes are enriched for expression in neuronal tissues of diverse vertebrates and of invertebrates. Additionally, we show that neuronal gene size expansion occurred predominantly through net gains in intron size, with a positional bias toward the 5' end of each gene.
CONCLUSIONS
We find that intron and gene size expansion is a feature of many genes whose expression is enriched in nervous systems. We speculate that unique attributes of neurons may subject neuronal genes to evolutionary forces favoring net size expansion. This process could be associated with tissue-specific constraints on gene function and/or the evolution of increasingly complex gene regulation in nervous systems.
Topics: Animals; Evolution, Molecular; Gene Expression Regulation; Genes; Genome; Introns; Mutation; Nervous System; Organ Specificity; Phylogeny
PubMed: 32410625
DOI: 10.1186/s12864-020-6760-4 -
The Plant Cell May 2023This review is an attempt to establish concepts of splicing and alternative splicing giving proper relevance to introns, the key actors in this mechanism. It might also... (Review)
Review
This review is an attempt to establish concepts of splicing and alternative splicing giving proper relevance to introns, the key actors in this mechanism. It might also work as a guide for those who found their favorite gene undergoes alternative splicing and could benefit from gaining a theoretical framework to understand the possible impacts of this process. This is not a thorough review of all the work in the field, but rather a critical review of some of the most relevant work done to understand the underlying mechanisms of splicing and the key questions that remain unanswered such as: What is the physiological relevance of alternative splicing? What are the functions of the different outcomes? To what extent do different alternative splicing types contribute to the proteome? Intron retention is the most frequent alternative splicing event in plants and, although scientifically neglected, it is also common in animals. This is a heterogeneous type of alternative splicing that includes different sub-types with features that have distinctive consequences in the resulting transcripts. Remarkably, intron retention can be a dead end for a transcript, but it could also be a stable intermediate whose processing is resumed upon a particular signal or change in the cell status. New sequencing technologies combined with the study of intron lariats in different conditions might help to answer key questions and could help us to understand the actual relevance of introns in gene expression regulation.
Topics: Animals; Introns; Alternative Splicing; RNA Splicing
PubMed: 36648241
DOI: 10.1093/plcell/koad009 -
Cell Reports Sep 2022Since formation of the first proto-eukaryotes, gene repertoire and genome complexity have significantly increased. Among genetic elements responsible for this increase...
Since formation of the first proto-eukaryotes, gene repertoire and genome complexity have significantly increased. Among genetic elements responsible for this increase are tandem repeats. Here we describe a genome-wide analysis of large tandem repeats, called megasatellites, in 58 vertebrate genomes. Two bursts occurred, one after the radiation between Agnatha and Gnathostomata fishes and the second one in therian mammals. Megasatellites are enriched in subtelomeric regions and frequently encoded in genes involved in transcription regulation, intracellular trafficking, and cell membrane metabolism, reminiscent of what is observed in fungus genomes. The presence of many introns within young megasatellites suggests that an exon-intron DNA segment is first duplicated and amplified before accumulation of mutations in intronic parts partially erases the megasatellite in such a way that it becomes detectable only in exons. Our results suggest that megasatellite formation and evolution is a dynamic and still ongoing process in vertebrate genomes.
Topics: Animals; Evolution, Molecular; Exons; Genome, Fungal; Introns; Mammals; Vertebrates
PubMed: 36103826
DOI: 10.1016/j.celrep.2022.111347 -
Protein & Cell May 2023Emerging evidence suggests that intron-detaining transcripts (IDTs) are a nucleus-detained and polyadenylated mRNA pool for cell to quickly and effectively respond to...
Emerging evidence suggests that intron-detaining transcripts (IDTs) are a nucleus-detained and polyadenylated mRNA pool for cell to quickly and effectively respond to environmental stimuli and stress. However, the underlying mechanisms of detained intron (DI) splicing are still largely unknown. Here, we suggest that post-transcriptional DI splicing is paused at the Bact state, an active spliceosome but not catalytically primed, which depends on Smad Nuclear Interacting Protein 1 (SNIP1) and RNPS1 (a serine-rich RNA binding protein) interaction. RNPS1 and Bact components preferentially dock at DIs and the RNPS1 docking is sufficient to trigger spliceosome pausing. Haploinsufficiency of Snip1 attenuates neurodegeneration and globally rescues IDT accumulation caused by a previously reported mutant U2 snRNA, a basal spliceosomal component. Snip1 conditional knockout in the cerebellum decreases DI splicing efficiency and causes neurodegeneration. Therefore, we suggest that SNIP1 and RNPS1 form a molecular brake to promote spliceosome pausing, and that its misregulation contributes to neurodegeneration.
Topics: Spliceosomes; Introns; RNA Splicing; RNA, Messenger; Cell Nucleus
PubMed: 37027487
DOI: 10.1093/procel/pwac008 -
Scientific Reports Sep 2020RNA-Seq expression analysis currently relies primarily upon exon expression data. The recognized role of introns during translation, and the presence of substantial...
RNA-Seq expression analysis currently relies primarily upon exon expression data. The recognized role of introns during translation, and the presence of substantial RNA-Seq counts attributable to introns, provide the rationale for the simultaneous consideration of both exon and intron data. We describe here a method for the coordinated analysis of exon and intron data by investigating their relationship within individual genes and across samples, while taking into account changes in both variability and expression level. This coordinated analysis of exon and intron data offers strong evidence for significant differences that distinguish the profiles of the exon-only expression data from the combined exon and intron data. One advantage of our proposed method, called matched change characterization for exons and introns (MEI), is its straightforward applicability to existing archived data using small modifications to standard RNA-Seq pipelines. Using MEI, we demonstrate that when data are examined for changes in variability across control and case conditions, novel differential changes can be detected. Notably, when MEI criteria were employed in the analysis of an archived data set involving polyarthritic subjects, the number of differentially expressed genes was expanded by sevenfold. More importantly, the observed changes in exon and intron variability with statistically significant false discovery rates could be traced to specific immune pathway gene networks. The application of MEI analysis provides a strategy for incorporating the significance of exon and intron variability and further developing the role of using both exons and intron sequencing counts in studies of gene regulatory processes.
Topics: Aged; Aged, 80 and over; Computational Biology; Exons; Female; Gene Expression Regulation; Humans; Introns; Male; Middle Aged; Workflow
PubMed: 32973253
DOI: 10.1038/s41598-020-72482-w -
International Journal of Molecular... Feb 2015Introns represent almost half of the human genome, yet their vast majority is eliminated from eukaryotic transcripts through RNA splicing. Nevertheless, they feature key... (Review)
Review
Introns represent almost half of the human genome, yet their vast majority is eliminated from eukaryotic transcripts through RNA splicing. Nevertheless, they feature key elements and functions that deserve further interest. At the level of DNA, introns are genomic segments that can shelter independent transcription units for coding and non-coding RNAs which transcription may interfere with that of the host gene, and regulatory elements that can influence gene expression and splicing itself. From the RNA perspective, some introns can be subjected to alternative splicing. Intron retention appear to provide some plasticity to the nature of the protein produced, its distribution in a given cell type and timing of its translation. Intron retention may also serve as a switch to produce coding or non-coding RNAs from the same transcription unit. Conversely, splicing of introns has been directly implicated in the production of small regulatory RNAs. Hence, splicing of introns also appears to provide plasticity to the type of RNA produced from a genetic locus (coding, non-coding, short or long). We addressed these aspects to add to our understanding of mechanisms that control the fate of introns and could be instrumental in regulating genomic output and hence cell fate.
Topics: Alternative Splicing; Animals; Exons; Gene Expression Regulation; Genetic Variation; Genome; Humans; Introns; Models, Genetic; RNA, Messenger
PubMed: 25710723
DOI: 10.3390/ijms16034429 -
The Journal of International Medical... Nov 2021We conducted meta-analysis of relevant case-control trials to determine the association between endothelial nitric oxide synthase (eNOS) intron 4a/b gene polymorphisms... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
We conducted meta-analysis of relevant case-control trials to determine the association between endothelial nitric oxide synthase (eNOS) intron 4a/b gene polymorphisms and hypertension susceptibility.
METHODS
We searched the PubMed, Cochrane, and Embase databases using relevant keywords and reviewed pertinent literature sources. All articles published up to July 2019 were considered for inclusion. Based on the qualified studies, we performed a meta-analysis of the associations between eNOS intron 4a/b polymorphisms and the risk of hypertension.
RESULTS
Fourteen studies were included in this meta-analysis, including 3344 cases and 3377 controls. The eNOS intron 4a/b locus was significantly associated with increased susceptibility to hypertension (including essential hypertension) in the overall population, according to dominant, allelic, homozygote, heterozygote, and regressive models, in the mixed population according to the regressive model, and in Caucasians according to the dominant, allelic, heterozygote, and regressive models. The eNOS intron 4a/b locus was also significantly associated with increased susceptibility to essential hypertension in the mixed population according to the heterozygote model.
CONCLUSION
eNOS intron 4a/b gene polymorphisms increase susceptibility to hypertension, including essential hypertension.
Topics: Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Introns; Nitric Oxide Synthase Type III; Polymorphism, Genetic
PubMed: 34851752
DOI: 10.1177/0300060520979230