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Pre-mRNA Splicing 2015
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Pre-mRNA Splicing 2015

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 November 2015) | Viewed by 56084

Special Issue Editor

Prof. Dr. Akila Mayeda

E-Mail Website
Guest Editor
Division of Gene Expression Mechanism, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake 470-1192, Aichi, Japan
Interests: pre-mRNA splicing; mechanism of splicing; regulation of splicing; aberrant splicing in diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In eukaryotes, most gene transcripts (pre-mRNAs) are interrupted by intervening sequences termed “introns”, which are precisely removed by a process called splicing.  This process is essential since spliced mRNAs serve as the templates of proteins.  The higher eukaryotes have been evolved to gain more and more introns of increasing size; this evolution enables complexity and flexibility in the splicing process, and produces alternative splicing.  In humans, alternative splicing is a successful, major strategy for expressing a full proteome of at least 120,000 proteins from an unexpectedly small genome of, at most, 20,500 genes.  Recent studies have revealed that over 90% of human genes undergo alternative splicing; over 60% of such splicing processes are tissue-specifically regulated.  Regulations in the splicing process are definitely crucial for a wide variety of biological and physiological phenomena.  The process is therefore highly discriminatory and faithful, and mis-regulation in this process causes disorders in cell functions, which often leads to severe clinical consequences.

This special issue of the International Journal of Molecular Sciences (IJMS), “Pre-mRNA Splicing,” will cover a broad range of basic and applied studies of pre-mRNA splicing. Topics include, but are not limited to: the mechanism and regulation of constitutive and alternative splicing, pre-mRNA–protein interactions, hnRNP/mRNP assembly and functions, global analyses and evolutional studies of pre-mRNAs and splicing factors, and pre-mRNA processing in development and diseases.

Prof. Akila Mayeda
Guest Editor

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Keywords

  • constitutive splicing
  • alternative splicing
  • aberrant splicing
  • splicing mechanism
  • splicing regulation
  • splicing factors
  • splicing enhancers
  • splicing silencers
  • snRNPs
  • hnRNPs
  • mRNPs
  • SR proteins

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Published Papers (7 papers)

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Research

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6977 KiB  
Article
Alternative Splicing in Adhesion- and Motility-Related Genes in Breast Cancer
by Rosanna Aversa, Anna Sorrentino, Roberta Esposito, Maria Rosaria Ambrosio, Angela Amato, Alberto Zambelli, Alfredo Ciccodicola, Luciana D’Apice and Valerio Costa
Int. J. Mol. Sci. 2016, 17(1), 121; https://doi.org/10.3390/ijms17010121 - 16 Jan 2016
Cited by 16 | Viewed by 6619
Abstract
Breast cancer is the most common tumor and the second leading cause of cancer death among woman, mainly caused by the metastatic spread. Tumor invasiveness is due to an altered expression of adhesion molecules. Among them, semaphorins are of peculiar interest. Cancer cells [...] Read more.
Breast cancer is the most common tumor and the second leading cause of cancer death among woman, mainly caused by the metastatic spread. Tumor invasiveness is due to an altered expression of adhesion molecules. Among them, semaphorins are of peculiar interest. Cancer cells can manipulate alternative splicing patterns to modulate the expression of adhesion- and motility-related molecules, also at the isoform level. In this study, combining RNA-Sequencing on MCF-7 to targeted experimental validations—in human breast cell lines and breast tumor biopsies—we identified 12 new alternative splicing transcripts in genes encoding adhesion- and motility-related molecules, including semaphorins, their receptors and co-receptors. Among them, a new SEMA3F transcript is expressed in all breast cell lines and breast cancer biopsies, and is translated into a new semaphorin 3F isoform. In silico analysis predicted that most of the new putative proteins lack functional domains, potentially missing some functions and acquiring new ones. Our findings better describe the extent of alternative splicing in breast cancer and highlight the need to further investigate adhesion- and motility-related molecules to gain insights into breast cancer progression. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2015)
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2124 KiB  
Article
Altered Pre-mRNA Splicing Caused by a Novel Intronic Mutation c.1443+5G>A in the Dihydropyrimidinase (DPYS) Gene
by Yoko Nakajima, Judith Meijer, Chunhua Zhang, Xu Wang, Tomomi Kondo, Tetsuya Ito, Doreen Dobritzsch and André B. P. Van Kuilenburg
Int. J. Mol. Sci. 2016, 17(1), 86; https://doi.org/10.3390/ijms17010086 - 12 Jan 2016
Cited by 12 | Viewed by 6086
Abstract
Dihydropyrimidinase (DHP) deficiency is an autosomal recessive disease caused by mutations in the DPYS gene. Patients present with highly elevated levels of dihydrouracil and dihydrothymine in their urine, blood and cerebrospinal fluid. The analysis of the effect of mutations in DPYS on pre-mRNA [...] Read more.
Dihydropyrimidinase (DHP) deficiency is an autosomal recessive disease caused by mutations in the DPYS gene. Patients present with highly elevated levels of dihydrouracil and dihydrothymine in their urine, blood and cerebrospinal fluid. The analysis of the effect of mutations in DPYS on pre-mRNA splicing is hampered by the fact that DHP is primarily expressed in liver and kidney cells. The minigene approach can detect mRNA splicing aberrations using cells that do not express the endogenous mRNA. We have used a minigene-based approach to analyze the effects of a presumptive pre-mRNA splicing mutation in two newly identified Chinese pediatric patients with DHP deficiency. Mutation analysis of DPYS showed that both patients were compound heterozygous for a novel intronic mutation c.1443+5G>A in intron 8 and a previously described missense mutation c.1001A>G (p.Q334R) in exon 6. Wild-type and the mutated minigene constructs, containing exons 7, 8 and 9 of DPYS, yielded different splicing products after expression in HEK293 cells. The c.1443+5G>A mutation resulted in altered pre-mRNA splicing of the DPYS minigene construct with full skipping of exon 8. Analysis of the DHP crystal structure showed that the deletion of exon 8 severely affects folding, stability and homooligomerization of the enzyme as well as disruption of the catalytic site. Thus, the analysis suggests that the c.1443+5G>A mutation results in aberrant splicing of the pre-mRNA encoding DHP, underlying the DHP deficiency in two unrelated Chinese patients. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2015)
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1055 KiB  
Article
Meta-Analysis of Multiple Sclerosis Microarray Data Reveals Dysregulation in RNA Splicing Regulatory Genes
by Elvezia Maria Paraboschi, Giulia Cardamone, Valeria Rimoldi, Donato Gemmati, Marta Spreafico, Stefano Duga, Giulia Soldà and Rosanna Asselta
Int. J. Mol. Sci. 2015, 16(10), 23463-23481; https://doi.org/10.3390/ijms161023463 - 30 Sep 2015
Cited by 19 | Viewed by 6701
Abstract
Abnormalities in RNA metabolism and alternative splicing (AS) are emerging as important players in complex disease phenotypes. In particular, accumulating evidence suggests the existence of pathogenic links between multiple sclerosis (MS) and altered AS, including functional studies showing that an imbalance in alternatively-spliced [...] Read more.
Abnormalities in RNA metabolism and alternative splicing (AS) are emerging as important players in complex disease phenotypes. In particular, accumulating evidence suggests the existence of pathogenic links between multiple sclerosis (MS) and altered AS, including functional studies showing that an imbalance in alternatively-spliced isoforms may contribute to disease etiology. Here, we tested whether the altered expression of AS-related genes represents a MS-specific signature. A comprehensive comparative analysis of gene expression profiles of publicly-available microarray datasets (190 MS cases, 182 controls), followed by gene-ontology enrichment analysis, highlighted a significant enrichment for differentially-expressed genes involved in RNA metabolism/AS. In detail, a total of 17 genes were found to be differentially expressed in MS in multiple datasets, with CELF1 being dysregulated in five out of seven studies. We confirmed CELF1 downregulation in MS (p = 0.0015) by real-time RT-PCRs on RNA extracted from blood cells of 30 cases and 30 controls. As a proof of concept, we experimentally verified the unbalance in alternatively-spliced isoforms in MS of the NFAT5 gene, a putative CELF1 target. In conclusion, for the first time we provide evidence of a consistent dysregulation of splicing-related genes in MS and we discuss its possible implications in modulating specific AS events in MS susceptibility genes. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2015)
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1761 KiB  
Article
Identification and Validation of Evolutionarily Conserved Unusually Short Pre-mRNA Introns in the Human Genome
by Makoto K. Shimada, Noriko Sasaki-Haraguchi and Akila Mayeda
Int. J. Mol. Sci. 2015, 16(5), 10376-10388; https://doi.org/10.3390/ijms160510376 - 7 May 2015
Cited by 11 | Viewed by 6799
Abstract
According to the length distribution of human introns, there is a large population of short introns with a threshold of 65 nucleotides (nt) and a peak at 85 nt. Using human genome and transcriptome databases, we investigated the introns shorter than 66 nt, [...] Read more.
According to the length distribution of human introns, there is a large population of short introns with a threshold of 65 nucleotides (nt) and a peak at 85 nt. Using human genome and transcriptome databases, we investigated the introns shorter than 66 nt, termed ultra-short introns, the identities of which are scarcely known. Here, we provide for the first time a list of bona fide human ultra-short introns, which have never been characterized elsewhere. By conducting BLAST searches of the databases, we screened 22 introns (37–65 nt) with conserved lengths and sequences among closely related species. We then provide experimental and bioinformatic evidence for the splicing of 15 introns, of which 12 introns were remarkably G-rich and 9 introns contained completely inefficient splice sites and/or branch sites. These unorthodox characteristics of ultra-short introns suggest that there are unknown splicing mechanisms that differ from the well-established mechanism. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2015)
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2945 KiB  
Article
Long Noncoding RNA MALAT-1 Enhances Stem Cell-Like Phenotypes in Pancreatic Cancer Cells
by Feng Jiao, Hai Hu, Ting Han, Cuncun Yuan, Lei Wang, Ziliang Jin, Zhen Guo and Liwei Wang
Int. J. Mol. Sci. 2015, 16(4), 6677-6693; https://doi.org/10.3390/ijms16046677 - 24 Mar 2015
Cited by 146 | Viewed by 9490
Abstract
Cancer stem cells (CSCs) play a vital role in tumor initiation, progression, metastasis, chemoresistance, and recurrence. The mechanisms that maintain the stemness of these cells remain largely unknown. Our previous study indicated that MALAT-1 may serve as an oncogenic long noncoding RNA in [...] Read more.
Cancer stem cells (CSCs) play a vital role in tumor initiation, progression, metastasis, chemoresistance, and recurrence. The mechanisms that maintain the stemness of these cells remain largely unknown. Our previous study indicated that MALAT-1 may serve as an oncogenic long noncoding RNA in pancreatic cancer by promoting epithelial-mesenchymal transition (EMT) and regulating CSCs markers expression. More significantly, there is emerging evidence that the EMT process may give rise to CSCs, or at least cells with stem cell-like properties. Therefore, we hypothesized that MALAT-1 might enhance stem cell-like phenotypes in pancreatic cancer cells. In this study, our data showed that MALAT-1 could increase the proportion of pancreatic CSCs, maintain self-renewing capacity, decrease the chemosensitivity to anticancer drugs, and accelerate tumor angiogenesis in vitro. In addition, subcutaneous nude mouse xenografts revealed that MALAT-1 could promote tumorigenicity of pancreatic cancer cells in vivo. The underlying mechanisms may involve in increased expression of self-renewal related factors Sox2. Collectively, we for the first time found the potential effects of MALAT-1 on the stem cell-like phenotypes in pancreatic cancer cells, suggesting a novel role of MALAT-1 in tumor stemness, which remains to be fully elucidated. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2015)
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2286 KiB  
Article
Species-Dependent Splice Recognition of a Cryptic Exon Resulting from a Recurrent Intronic CEP290 Mutation that Causes Congenital Blindness
by Alejandro Garanto, Lonneke Duijkers and Rob W. J. Collin
Int. J. Mol. Sci. 2015, 16(3), 5285-5298; https://doi.org/10.3390/ijms16035285 - 9 Mar 2015
Cited by 26 | Viewed by 5790
Abstract
A mutation in intron 26 of CEP290 (c.2991+1655A>G) is the most common genetic cause of Leber congenital amaurosis (LCA), a severe type of inherited retinal degeneration. This mutation creates a cryptic splice donor site, resulting in the insertion of an aberrant exon (exon [...] Read more.
A mutation in intron 26 of CEP290 (c.2991+1655A>G) is the most common genetic cause of Leber congenital amaurosis (LCA), a severe type of inherited retinal degeneration. This mutation creates a cryptic splice donor site, resulting in the insertion of an aberrant exon (exon X) into ~50% of all CEP290 transcripts. A humanized mouse model with this mutation did not recapitulate the aberrant CEP290 splicing observed in LCA patients, suggesting differential recognition of cryptic splice sites between species. To further assess this phenomenon, we generated two CEP290 minigene constructs, with and without the intronic mutation, and transfected these in cell lines of various species. RT-PCR analysis revealed that exon X is well recognized by the splicing machinery in human and non-human primate cell lines. Intriguingly, this recognition decreases in cell lines derived from species such as dog and rodents, and it is completely absent in Drosophila. In addition, other cryptic splicing events corresponding to sequences in intron 26 of CEP290 were observed to varying degrees in the different cell lines. Together, these results highlight the complexity of splice site recognition among different species, and show that care is warranted when generating animal models to mimic splice site mutations in vivo. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2015)
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Review

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1689 KiB  
Review
Coupling and Coordination in Gene Expression Processes with Pre-mRNA Splicing
by Kewu Pan, Jimmy Tsz Hang Lee, Zhe Huang and Chi-Ming Wong
Int. J. Mol. Sci. 2015, 16(3), 5682-5696; https://doi.org/10.3390/ijms16035682 - 11 Mar 2015
Cited by 6 | Viewed by 13960
Abstract
A processing is a tightly regulated and highly complex pathway which includes transcription, splicing, editing, transportation, translation and degradation. It has been well-documented that splicing of RNA polymerase II medicated nascent transcripts occurs co-transcriptionally and is functionally coupled to other RNA processing. Recently, [...] Read more.
A processing is a tightly regulated and highly complex pathway which includes transcription, splicing, editing, transportation, translation and degradation. It has been well-documented that splicing of RNA polymerase II medicated nascent transcripts occurs co-transcriptionally and is functionally coupled to other RNA processing. Recently, increasing experimental evidence indicated that pre-mRNA splicing influences RNA degradation and vice versa. In this review, we summarized the recent findings demonstrating the coupling of these two processes. In addition, we highlighted the importance of splicing in the production of intronic miRNA and circular RNAs, and hence the discovery of the novel mechanisms in the regulation of gene expression. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2015)
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