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Pre-mRNA Splicing 2018
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Pre-mRNA Splicing 2018

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

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 31740

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
  • pre-mRNA processing in development and diseases

Prof. Akila Mayeda
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Related Special Issue

Published Papers (6 papers)

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Research

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12 pages, 2835 KiB  
Article
An RNA Switch of a Large Exon of Ninein Is Regulated by the Neural Stem Cell Specific-RNA Binding Protein, Qki5
by Yoshika Hayakawa-Yano and Masato Yano
Int. J. Mol. Sci. 2019, 20(5), 1010; https://doi.org/10.3390/ijms20051010 - 26 Feb 2019
Cited by 10 | Viewed by 3989
Abstract
A set of tissue-specific splicing factors are thought to govern alternative splicing events during neural progenitor cell (NPC)-to-neuron transition by regulating neuron-specific exons. Here, we propose one such factor, RNA-binding protein Quaking 5 (Qki5), which is specifically expressed in the early embryonic neural [...] Read more.
A set of tissue-specific splicing factors are thought to govern alternative splicing events during neural progenitor cell (NPC)-to-neuron transition by regulating neuron-specific exons. Here, we propose one such factor, RNA-binding protein Quaking 5 (Qki5), which is specifically expressed in the early embryonic neural stem cells. We performed mRNA-SEQ (Sequence) analysis using mRNAs obtained by developing cerebral cortices in Qk (Quaking) conditional knockout (cKO) mice. As expected, we found a large number of alternative splicing changes between control and conditional knockouts relative to changes in transcript levels. DAVID (The Database for Annotation, Visualization and Integrated Discovery) and Metascape analyses suggested that the affected spliced genes are involved in axon development and microtubule-based processes. Among these, the mRNA coding for the Ninein protein is listed as one of Qki protein-dependent alternative splicing targets. Interestingly, this exon encodes a very long polypeptide (2121 nt), and has been previously defined as a dynamic RNA switch during the NPC-to-neuron transition. Additionally, we validated that the regulation of this large exon is consistent with the Qki5-dependent alternative exon inclusion mode suggested by our previous Qki5 HITS-CLIP (high throughput sequencing-cross linking immunoprecipitation) analysis. Taken together, these data suggest that Qki5 is an important factor for alternative splicing in the NPC-to-neuron transition. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2018)
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12 pages, 2132 KiB  
Article
Cancer-Specifically Re-Spliced TSG101 mRNA Promotes Invasion and Metastasis of Nasopharyngeal Carcinoma
by Huey-Huey Chua, Toshiki Kameyama, Akila Mayeda and Te-Huei Yeh
Int. J. Mol. Sci. 2019, 20(3), 773; https://doi.org/10.3390/ijms20030773 - 12 Feb 2019
Cited by 10 | Viewed by 3948
Abstract
TSG101 (Tumor susceptibility 101) gene and its aberrantly spliced isoform, termed TSG101∆154-1054, are tightly linked to tumorigenesis in various cancers. The aberrant TSG101∆154-1054 mRNA is generated from cancer-specific re-splicing of mature TSG101 mRNA. The TSG101∆154-1054 protein protects the full-length TSG101 protein from ubiquitin-mediated [...] Read more.
TSG101 (Tumor susceptibility 101) gene and its aberrantly spliced isoform, termed TSG101∆154-1054, are tightly linked to tumorigenesis in various cancers. The aberrant TSG101∆154-1054 mRNA is generated from cancer-specific re-splicing of mature TSG101 mRNA. The TSG101∆154-1054 protein protects the full-length TSG101 protein from ubiquitin-mediated degradation, implicating TSG101∆154-1054 protein in the progression of cancer. Here, we confirmed that the presence of TSG101∆154-1054 mRNA indeed caused an accumulation of the TSG101 protein in biopsies of human nasopharyngeal carcinoma (NPC), which was recapitulated by the overexpression of TSG101∆154-1054 in the NPC cell line TW01. We demonstrate the potential function of the TSG101∆154-1054 protein in the malignancy of human NPC with scratch-wound healing and transwell invasion assays. By increasing the stability of the TSG101 protein, TSG101∆154-1054 specifically enhanced TSG101-mediated TW01 cell migration and invasion, suggesting the involvement in NPC metastasis in vivo. This finding sheds light on the functional significance of TSG101∆154-1054 generation via re-splicing of TSG101 mRNA in NPC metastasis and hints at its potential importance as a therapeutic target. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2018)
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9 pages, 1076 KiB  
Article
Quantifying BRCA1 and BRCA2 mRNA Isoform Expression Levels in Single Cells
by Vanessa L. Lattimore, John F. Pearson, Arthur E. Morley-Bunker, kConFab Investigators, Amanda B. Spurdle, Bridget A. Robinson, Margaret J. Currie and Logan C. Walker
Int. J. Mol. Sci. 2019, 20(3), 693; https://doi.org/10.3390/ijms20030693 - 06 Feb 2019
Cited by 1 | Viewed by 3308
Abstract
BRCA1 and BRCA2 spliceogenic variants are often associated with an elevated risk of breast and ovarian cancers. Analyses of BRCA1 and BRCA2 splicing patterns have traditionally used technologies that sample a population of cells but do not account for the variation that may [...] Read more.
BRCA1 and BRCA2 spliceogenic variants are often associated with an elevated risk of breast and ovarian cancers. Analyses of BRCA1 and BRCA2 splicing patterns have traditionally used technologies that sample a population of cells but do not account for the variation that may be present between individual cells. This novel proof of concept study utilises RNA in situ hybridisation to measure the absolute expression of BRCA1 and BRCA2 mRNA splicing events in single lymphoblastoid cells containing known spliceogenic variants (BRCA1c.671-2 A>G or BRCA2c.7988 A>T). We observed a large proportion of cells (>42%) in each sample that did not express mRNA for the targeted gene. Increased levels (average mRNA molecules per cell) of BRCA2 ∆17_18 were observed in the cells containing the known spliceogenic variant BRCA2c.7988 A>T, but cells containing BRCA1c.671-2 A>G were not found to express significantly increased levels of BRCA1 ∆11, as had been shown previously. Instead, we show for each variant carrier sample that a higher proportion of cells expressed the targeted splicing event compared to control cells. These results indicate that BRCA1/2 mRNA is expressed stochastically, suggesting that previously reported results using RT-PCR may have been influenced by the number of cells with BRCA1/2 mRNA expression and may not represent an elevation of constitutive mRNA expression. Detection of mRNA expression in single cells allows for a more comprehensive understanding of how spliceogenic variants influence the expression of mRNA isoforms. However, further research is required to assess the utility of this technology to measure the expression of predicted spliceogenic BRCA1 and BRCA2 variants in a diagnostic setting. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2018)
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11 pages, 1779 KiB  
Article
STE20/PAKA Protein Kinase Gene Releases an Autoinhibitory Domain through Pre-mRNA Alternative Splicing in the Dermatophyte Trichophyton rubrum
by Eriston V. Gomes, Julio C. Bortolossi, Pablo R. Sanches, Niege S. Mendes, Nilce M. Martinez-Rossi and Antonio Rossi
Int. J. Mol. Sci. 2018, 19(11), 3654; https://doi.org/10.3390/ijms19113654 - 20 Nov 2018
Cited by 10 | Viewed by 3249
Abstract
Signaling pathways are highly diverse in filamentous fungi, allowing the cells to receive and process ambient information. Interaction of components from different pathways results in signaling networks. The mitogen-activated protein kinase (MAPK) pathway is dependent on phosphorylation that is accomplished by kinase proteins. [...] Read more.
Signaling pathways are highly diverse in filamentous fungi, allowing the cells to receive and process ambient information. Interaction of components from different pathways results in signaling networks. The mitogen-activated protein kinase (MAPK) pathway is dependent on phosphorylation that is accomplished by kinase proteins. Thus, the STE/PAK protein kinase family plays essential roles in MAPK signal transduction, regulating several cellular functions. The STE/PAK protein displays an autoinhibitory (Cdc42/Rac interactive binding—CRIB) domain on its N-terminal portion, which interacts with the C-terminal catalytic kinase domain. Based on current knowledge, for the STE/PAK kinase to be activated, molecular signals (e.g., interaction with the activated form of Rac1 and Cdc42 proteins) or proteolytic cleavage by caspase 3 is necessary. Both mechanisms release the kinase domain from the CRIB interaction. Here, we hypothesize a novel molecular mechanism for the activation of STE20/PAKA kinase in Trichophyton rubrum based on an alternative pre-mRNA splicing process. Our data suggest that, because of the retention of intron 1 of this gene, it is theoretically possible that the translation of STE20/PAKA kinase will be free of its autoinhibitory CRIB domain. These findings indicate a rapid response system to environmental changes. Furthermore, STE20/PAKA may be a potential T. rubrum virulence factor and an interesting target for new drugs against dermatophytes. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2018)
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Review

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27 pages, 2905 KiB  
Review
Alternative Splicing in Angiogenesis
by Elizabeth Bowler and Sebastian Oltean
Int. J. Mol. Sci. 2019, 20(9), 2067; https://doi.org/10.3390/ijms20092067 - 26 Apr 2019
Cited by 63 | Viewed by 12051
Abstract
Alternative splicing of pre-mRNA allows the generation of multiple splice isoforms from a given gene, which can have distinct functions. In fact, splice isoforms can have opposing functions and there are many instances whereby a splice isoform acts as an inhibitor of canonical [...] Read more.
Alternative splicing of pre-mRNA allows the generation of multiple splice isoforms from a given gene, which can have distinct functions. In fact, splice isoforms can have opposing functions and there are many instances whereby a splice isoform acts as an inhibitor of canonical isoform function, thereby adding an additional layer of regulation to important processes. Angiogenesis is an important process that is governed by alternative splicing mechanisms. This review focuses on the alternative spliced isoforms of key genes that are involved in the angiogenesis process; VEGF-A, VEGFR1, VEGFR2, NRP-1, FGFRs, Vasohibin-1, Vasohibin-2, HIF-1α, Angiopoietin-1 and Angiopoietin-2. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2018)
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666 KiB  
Review
Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?
by Lucie Grodecká, Emanuele Buratti and Tomáš Freiberger
Int. J. Mol. Sci. 2017, 18(8), 1668; https://doi.org/10.3390/ijms18081668 - 31 Jul 2017
Cited by 28 | Viewed by 4671
Abstract
For more than three decades, researchers have known that consensus splice sites alone are not sufficient regulatory elements to provide complex splicing regulation. Other regulators, so-called splicing regulatory elements (SREs) are needed. Most importantly, their sequence variants often underlie the development of various [...] Read more.
For more than three decades, researchers have known that consensus splice sites alone are not sufficient regulatory elements to provide complex splicing regulation. Other regulators, so-called splicing regulatory elements (SREs) are needed. Most importantly, their sequence variants often underlie the development of various human disorders. However, due to their variable location and high degeneracy, these regulatory sequences are also very difficult to recognize and predict. Many different approaches aiming to identify SREs have been tried, often leading to the development of in silico prediction tools. While these tools were initially expected to be helpful to identify splicing-affecting mutations in genetic diagnostics, we are still quite far from meeting this goal. In fact, most of these tools are not able to accurately discern the SRE-affecting pathological variants from those not affecting splicing. Nonetheless, several recent evaluations have given appealing results (namely for EX-SKIP, ESRseq and Hexplorer predictors). In this review, we aim to summarize the history of the different approaches to SRE prediction, and provide additional validation of these tools based on patients’ clinical data. Finally, we evaluate their usefulness for diagnostic settings and discuss the challenges that have yet to be met. Full article
(This article belongs to the Special Issue Pre-mRNA Splicing 2018)
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