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Special Issue "Splicing Modulators Which Affect Gene Expression"

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

Deadline for manuscript submissions: 30 June 2022 | Viewed by 9789

Special Issue Editor

Prof. Dr. Daisuke Kaida
E-Mail Website
Guest Editor
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Interests: pre-mRNA splicing; transcription; cell cycle; chemical biology

Special Issue Information

Dear Colleagues,

Pre-mRNA splicing is one of the most important mechanisms for accurate gene expression in eukaryotic cells. More than 90% of human genes consist of exons and introns. Consequently, aberrations in splicing machineries cause not only a decrease of spliced mRNA which is the template for translation, but also accumulation of pre-mRNA which might be translated into truncated, aberrant proteins. Such a perturbation of gene expression results in several diseases in some cases. In recent years, splicing modulators including small chemical compounds and antisense oligos attract attention because of their usefulness for investigation of gene expression mechanism and their therapeutic potential. For instance, recent studies revealed that U1 snRNP protects pre-mRNA from premature cleavage and polyadenylation and that antisense oligo against the SMN2 gene corrects the splicing pattern and increases the amount of functional SMN proteins. Some splicing inhibitors have been investigated in phase 1/2 clinical studies. However, there are not many such splicing modulators with therapeutic activity. To cure a broad range of splicing-related diseases, more novel modulators and a deeper understanding of such modulators will be required. Papers related to the screening of novel splicing modulators, identification of molecular targets of modulators, as well as investigating mode of action of modulators, will be considered for this Special Issue.

Prof. Dr. Daisuke Kaida
Guest Editor

Manuscript Submission Information

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Keywords

  • pre-mRNA splicing
  • small chemical compound
  • antisense oligo
  • transcription
  • polyadenylation
  • translation
  • nuclear export
  • therapeutics

Published Papers (9 papers)

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Research

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Article
Roles of Physicochemical and Structural Properties of RNA-Binding Proteins in Predicting the Activities of Trans-Acting Splicing Factors with Machine Learning
Int. J. Mol. Sci. 2022, 23(8), 4426; https://doi.org/10.3390/ijms23084426 - 17 Apr 2022
Viewed by 413
Abstract
Trans-acting splicing factors play a pivotal role in modulating alternative splicing by specifically binding to cis-elements in pre-mRNAs. There are approximately 1500 RNA-binding proteins (RBPs) in the human genome, but the activities of these RBPs in alternative splicing are unknown. Since determining RBP [...] Read more.
Trans-acting splicing factors play a pivotal role in modulating alternative splicing by specifically binding to cis-elements in pre-mRNAs. There are approximately 1500 RNA-binding proteins (RBPs) in the human genome, but the activities of these RBPs in alternative splicing are unknown. Since determining RBP activities through experimental methods is expensive and time consuming, the development of an efficient computational method for predicting the activities of RBPs in alternative splicing from their sequences is of great practical importance. Recently, a machine learning model for predicting the activities of splicing factors was built based on features of single and dual amino acid compositions. Here, we explored the role of physicochemical and structural properties in predicting their activities in alternative splicing using machine learning approaches and found that the prediction performance is significantly improved by including these properties. By combining the minimum redundancy–maximum relevance (mRMR) method and forward feature searching strategy, a promising feature subset with 24 features was obtained to predict the activities of RBPs. The feature subset consists of 16 dual amino acid compositions, 5 physicochemical features, and 3 structural features. The physicochemical and structural properties were as important as the sequence composition features for an accurate prediction of the activities of splicing factors. The hydrophobicity and distribution of coil are suggested to be the key physicochemical and structural features, respectively. Full article
(This article belongs to the Special Issue Splicing Modulators Which Affect Gene Expression)
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Article
CCNE1 and E2F1 Partially Suppress G1 Phase Arrest Caused by Spliceostatin A Treatment
Int. J. Mol. Sci. 2021, 22(21), 11623; https://doi.org/10.3390/ijms222111623 - 27 Oct 2021
Cited by 1 | Viewed by 609
Abstract
The potent splicing inhibitor spliceostatin A (SSA) inhibits cell cycle progression at the G1 and G2/M phases. We previously reported that upregulation of the p27 cyclin-dependent kinase inhibitor encoded by CDKN1B and its C-terminal truncated form, namely p27*, which is translated from CDKN1B [...] Read more.
The potent splicing inhibitor spliceostatin A (SSA) inhibits cell cycle progression at the G1 and G2/M phases. We previously reported that upregulation of the p27 cyclin-dependent kinase inhibitor encoded by CDKN1B and its C-terminal truncated form, namely p27*, which is translated from CDKN1B pre-mRNA, is one of the causes of G1 phase arrest caused by SSA treatment. However, the detailed molecular mechanism underlying G1 phase arrest caused by SSA treatment remains to be elucidated. In this study, we found that SSA treatment caused the downregulation of cell cycle regulators, including CCNE1, CCNE2, and E2F1, at both the mRNA and protein levels. We also found that transcription elongation of the genes was deficient in SSA-treated cells. The overexpression of CCNE1 and E2F1 in combination with CDKN1B knockout partially suppressed G1 phase arrest caused by SSA treatment. These results suggest that the downregulation of CCNE1 and E2F1 contribute to the G1 phase arrest induced by SSA treatment, although they do not exclude the involvement of other factors in SSA-induced G1 phase arrest. Full article
(This article belongs to the Special Issue Splicing Modulators Which Affect Gene Expression)
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Article
Computational Methods to Study Human Transcript Variants in COVID-19 Infected Lung Cancer Cells
Int. J. Mol. Sci. 2021, 22(18), 9684; https://doi.org/10.3390/ijms22189684 - 07 Sep 2021
Cited by 1 | Viewed by 925
Abstract
Microbes and viruses are known to alter host transcriptomes by means of infection. In light of recent challenges posed by the COVID-19 pandemic, a deeper understanding of the disease at the transcriptome level is needed. However, research about transcriptome reprogramming by post-transcriptional regulation [...] Read more.
Microbes and viruses are known to alter host transcriptomes by means of infection. In light of recent challenges posed by the COVID-19 pandemic, a deeper understanding of the disease at the transcriptome level is needed. However, research about transcriptome reprogramming by post-transcriptional regulation is very limited. In this study, computational methods developed by our lab were applied to RNA-seq data to detect transcript variants (i.e., alternative splicing (AS) and alternative polyadenylation (APA) events). The RNA-seq data were obtained from a publicly available source, and they consist of mock-treated and SARS-CoV-2 infected (COVID-19) lung alveolar (A549) cells. Data analysis results show that more AS events are found in SARS-CoV-2 infected cells than in mock-treated cells, whereas fewer APA events are detected in SARS-CoV-2 infected cells. A combination of conventional differential gene expression analysis and transcript variants analysis revealed that most of the genes with transcript variants are not differentially expressed. This indicates that no strong correlation exists between differential gene expression and the AS/APA events in the mock-treated or SARS-CoV-2 infected samples. These genes with transcript variants can be applied as another layer of molecular signatures for COVID-19 studies. In addition, the transcript variants are enriched in important biological pathways that were not detected in the studies that only focused on differential gene expression analysis. Therefore, the pathways may lead to new molecular mechanisms of SARS-CoV-2 pathogenesis. Full article
(This article belongs to the Special Issue Splicing Modulators Which Affect Gene Expression)
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Article
AS-Quant: Detection and Visualization of Alternative Splicing Events with RNA-seq Data
Int. J. Mol. Sci. 2021, 22(9), 4468; https://doi.org/10.3390/ijms22094468 - 25 Apr 2021
Cited by 1 | Viewed by 1446
Abstract
(1) Background: A simplistic understanding of the central dogma falls short in correlating the number of genes in the genome to the number of proteins in the proteome. Post-transcriptional alternative splicing contributes to the complexity of the proteome and is critical in understanding [...] Read more.
(1) Background: A simplistic understanding of the central dogma falls short in correlating the number of genes in the genome to the number of proteins in the proteome. Post-transcriptional alternative splicing contributes to the complexity of the proteome and is critical in understanding gene expression. mRNA-sequencing (RNA-seq) has been widely used to study the transcriptome and provides opportunity to detect alternative splicing events among different biological conditions. Despite the popularity of studying transcriptome variants with RNA-seq, few efficient and user-friendly bioinformatics tools have been developed for the genome-wide detection and visualization of alternative splicing events. (2) Results: We propose AS-Quant, (Alternative Splicing Quantitation), a robust program to identify alternative splicing events from RNA-seq data. We then extended AS-Quant to visualize the splicing events with short-read coverage plots along with complete gene annotation. The tool works in three major steps: (i) calculate the read coverage of the potential spliced exons and the corresponding gene; (ii) categorize the events into five different categories according to the annotation, and assess the significance of the events between two biological conditions; (iii) generate the short reads coverage plot for user specified splicing events. Our extensive experiments on simulated and real datasets demonstrate that AS-Quant outperforms the other three widely used baselines, SUPPA2, rMATS, and diffSplice for detecting alternative splicing events. Moreover, the significant alternative splicing events identified by AS-Quant between two biological contexts were validated by RT-PCR experiment. (3) Availability: AS-Quant is implemented in Python 3.0. Source code and a comprehensive user’s manual are freely available online. Full article
(This article belongs to the Special Issue Splicing Modulators Which Affect Gene Expression)
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Review

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Review
Evolution of the Early Spliceosomal Complex—From Constitutive to Regulated Splicing
Int. J. Mol. Sci. 2021, 22(22), 12444; https://doi.org/10.3390/ijms222212444 - 18 Nov 2021
Cited by 1 | Viewed by 788
Abstract
Pre-mRNA splicing is a major process in the regulated expression of genes in eukaryotes, and alternative splicing is used to generate different proteins from the same coding gene. Splicing is a catalytic process that removes introns and ligates exons to create the RNA [...] Read more.
Pre-mRNA splicing is a major process in the regulated expression of genes in eukaryotes, and alternative splicing is used to generate different proteins from the same coding gene. Splicing is a catalytic process that removes introns and ligates exons to create the RNA sequence that codifies the final protein. While this is achieved in an autocatalytic process in ancestral group II introns in prokaryotes, the spliceosome has evolved during eukaryogenesis to assist in this process and to finally provide the opportunity for intron-specific splicing. In the early stage of splicing, the RNA 5′ and 3′ splice sites must be brought within proximity to correctly assemble the active spliceosome and perform the excision and ligation reactions. The assembly of this first complex, termed E-complex, is currently the least understood process. We focused in this review on the formation of the E-complex and compared its composition and function in three different organisms. We highlight the common ancestral mechanisms in S. cerevisiae, S. pombe, and mammals and conclude with a unifying model for intron definition in constitutive and regulated co-transcriptional splicing. Full article
(This article belongs to the Special Issue Splicing Modulators Which Affect Gene Expression)
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Review
miRNA-Based Regulation of Alternative RNA Splicing in Metazoans
Int. J. Mol. Sci. 2021, 22(21), 11618; https://doi.org/10.3390/ijms222111618 - 27 Oct 2021
Cited by 3 | Viewed by 1288
Abstract
Alternative RNA splicing is an important regulatory process used by genes to increase their diversity. This process is mainly executed by specific classes of RNA binding proteins that act in a dosage-dependent manner to include or exclude selected exons in the final transcripts. [...] Read more.
Alternative RNA splicing is an important regulatory process used by genes to increase their diversity. This process is mainly executed by specific classes of RNA binding proteins that act in a dosage-dependent manner to include or exclude selected exons in the final transcripts. While these processes are tightly regulated in cells and tissues, little is known on how the dosage of these factors is achieved and maintained. Several recent studies have suggested that alternative RNA splicing may be in part modulated by microRNAs (miRNAs), which are short, non-coding RNAs (~22 nt in length) that inhibit translation of specific mRNA transcripts. As evidenced in tissues and in diseases, such as cancer and neurological disorders, the dysregulation of miRNA pathways disrupts downstream alternative RNA splicing events by altering the dosage of splicing factors involved in RNA splicing. This attractive model suggests that miRNAs can not only influence the dosage of gene expression at the post-transcriptional level but also indirectly interfere in pre-mRNA splicing at the co-transcriptional level. The purpose of this review is to compile and analyze recent studies on miRNAs modulating alternative RNA splicing factors, and how these events contribute to transcript rearrangements in tissue development and disease. Full article
(This article belongs to the Special Issue Splicing Modulators Which Affect Gene Expression)
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Review
Nuclear mRNA Quality Control and Cytoplasmic NMD Are Linked by the Guard Proteins Gbp2 and Hrb1
Int. J. Mol. Sci. 2021, 22(20), 11275; https://doi.org/10.3390/ijms222011275 - 19 Oct 2021
Cited by 2 | Viewed by 761
Abstract
Pre-mRNA splicing is critical for cells, as defects in this process can lead to altered open reading frames and defective proteins, potentially causing neurodegenerative diseases and cancer. Introns are removed in the nucleus and splicing is documented by the addition of exon-junction-complexes (EJCs) [...] Read more.
Pre-mRNA splicing is critical for cells, as defects in this process can lead to altered open reading frames and defective proteins, potentially causing neurodegenerative diseases and cancer. Introns are removed in the nucleus and splicing is documented by the addition of exon-junction-complexes (EJCs) at exon-exon boundaries. This “memory” of splicing events is important for the ribosome, which translates the RNAs in the cytoplasm. In case a stop codon was detected before an EJC, translation is blocked and the RNA is eliminated by the nonsense-mediated decay (NMD). In the model organism Saccharomyces cerevisiae, two guard proteins, Gbp2 and Hrb1, have been identified as nuclear quality control factors for splicing. In their absence, intron-containing mRNAs leak into the cytoplasm. Their presence retains transcripts until the process is completed and they release the mRNAs by recruitment of the export factor Mex67. On transcripts that experience splicing problems, these guard proteins recruit the nuclear RNA degradation machinery. Interestingly, they continue their quality control function on exported transcripts. They support NMD by inhibiting translation and recruiting the cytoplasmic degradation factors. In this way, they link the nuclear and cytoplasmic quality control systems. These discoveries are also intriguing for humans, as homologues of these guard proteins are present also in multicellular organisms. Here, we provide an overview of the quality control mechanisms of pre-mRNA splicing, and present Gbp2 and Hrb1, as well as their human counterparts, as important players in these pathways. Full article
(This article belongs to the Special Issue Splicing Modulators Which Affect Gene Expression)
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Review
Minor Intron Splicing from Basic Science to Disease
Int. J. Mol. Sci. 2021, 22(11), 6062; https://doi.org/10.3390/ijms22116062 - 04 Jun 2021
Cited by 2 | Viewed by 1625
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Splicing Modulators Which Affect Gene Expression)
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Review
Rapidly Growing Protein-Centric Technologies to Extensively Identify Protein–RNA Interactions: Application to the Analysis of Co-Transcriptional RNA Processing
Int. J. Mol. Sci. 2021, 22(10), 5312; https://doi.org/10.3390/ijms22105312 - 18 May 2021
Cited by 4 | Viewed by 972
Abstract
During mRNA transcription, diverse RNA-binding proteins (RBPs) are recruited to RNA polymerase II (RNAP II) transcription machinery. These RBPs bind to distinct sites of nascent RNA to co-transcriptionally operate mRNA processing. Recent studies have revealed a close relationship between transcription and co-transcriptional RNA [...] Read more.
During mRNA transcription, diverse RNA-binding proteins (RBPs) are recruited to RNA polymerase II (RNAP II) transcription machinery. These RBPs bind to distinct sites of nascent RNA to co-transcriptionally operate mRNA processing. Recent studies have revealed a close relationship between transcription and co-transcriptional RNA processing, where one affects the other’s activity, indicating an essential role of protein–RNA interactions for the fine-tuning of mRNA production. Owing to their limited amount in cells, the detection of protein–RNA interactions specifically assembled on the transcribing RNAP II machinery still remains challenging. Currently, cross-linking and immunoprecipitation (CLIP) has become a standard method to detect in vivo protein–RNA interactions, although it requires a large amount of input materials. Several improved methods, such as infrared-CLIP (irCLIP), enhanced CLIP (eCLIP), and target RNA immunoprecipitation (tRIP), have shown remarkable enhancements in the detection efficiency. Furthermore, the utilization of an RNA editing mechanism or proximity labeling strategy has achieved the detection of faint protein–RNA interactions in cells without depending on crosslinking. This review aims to explore various methods being developed to detect endogenous protein–RNA interaction sites and discusses how they may be applied to the analysis of co-transcriptional RNA processing. Full article
(This article belongs to the Special Issue Splicing Modulators Which Affect Gene Expression)
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