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Alternative Splicing: Recent Insights into Mechanisms and Functional Roles

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A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (15 November 2019) | Viewed by 56856

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Dr. Maria Paola Paronetto

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Department of Movement, Human and Health Sciences, University of Rome “Foro Italico”, Rome, Italy
Interests: alternative splicing; RNA metabolism; cancer genomics; RNA binding proteins; ewing sarcoma
Special Issues, Collections and Topics in MDPI journals

Dr. Claudia Ghigna

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Institute of Molecular Genetics Luigi Luca Cavalli-Sforza National Research Council (IGM-CNR), Via Abbiategrasso, 207, 27100 Pavia, Italy
Interests: alternative splicing; mRNA processing; RNA binding proteins; angiogeneis; vanscular biology; cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Alternative splicing is a post-transcriptional mechanism of gene expression generating multiple mature mRNA isoforms from the precursor mRNA, thus representing a fundamental step to expand the transcriptomic and proteomic diversity in multicellular organisms. A number of alternative splicing events are evolutionarily conserved among species, whereas others generate protein variants that selectively regulate cell-, tissue-, or development-specific programs in vertebrates. Moreover, several alternatively spliced exons encode for domains mediating protein–protein interactions or association with different ligands, thus supporting an important function in modulating highly connected protein networks or signaling pathways, with relevance in human diseases. In this regard, alternative splicing has recently emerged as a druggable mechanism, exploitable to ameliorate, or even cure, many human pathologies, including cancer.

Despite our recent progress in many computational and experimental approaches, our knowledge of the mechanisms or factors that generate specific alternative splicing variants as well as their roles in physiologically (or pathologically) relevant processes is still limited. The main goal of this Special Issue is to collect recent insights into the mechanisms and functional roles of alternative splicing regulation, how it operates to control or cooperate with other gene expression regulatory processes, its contribution to cell- and tissue-specific programs, and its alteration in human diseases.

Prof. Dr. Maria Paola Paronetto
Dr. Claudia Ghigna
Guest Editors

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Keywords

alternative splicing
gene expression
tissue-specific programs
splicing dysregulation in human diseases
RNA therapeutics

Published Papers (13 papers)

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Editorial

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3 pages, 174 KiB

Open AccessEditorial

Alternative Splicing: Recent Insights into Mechanisms and Functional Roles

by Claudia Ghigna and Maria Paola Paronetto

Cells 2020, 9(10), 2327; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9102327 - 20 Oct 2020

Cited by 2 | Viewed by 2018

Abstract

Alternative splicing generates multiple protein isoforms from one primary transcript and represents one of the major drivers of proteomic diversity in human cells [...] Full article

(This article belongs to the Special Issue Alternative Splicing: Recent Insights into Mechanisms and Functional Roles)

Research

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16 pages, 3734 KiB

Open AccessArticle

Poison-Exon Inclusion in DHX9 Reduces Its Expression and Sensitizes Ewing Sarcoma Cells to Chemotherapeutic Treatment

by Ramona Palombo, Veronica Verdile and Maria Paola Paronetto

Cells 2020, 9(2), 328; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020328 - 31 Jan 2020

Cited by 19 | Viewed by 3612

Abstract

Alternative splicing is a combinatorial mechanism by which exons are joined to produce multiple mRNA variants, thus expanding the coding potential and plasticity of eukaryotic genomes. Defects in alternative splicing regulation are associated with several human diseases, including cancer. Ewing sarcoma is an aggressive tumor of bone and soft tissue, mainly affecting adolescents and young adults. DHX9 is a key player in Ewing sarcoma malignancy, and its expression correlates with worse prognosis in patients. In this study, by screening a library of siRNAs, we have identified splicing factors that regulate the alternative inclusion of a poison exon in DHX9 mRNA, leading to its downregulation. In particular, we found that hnRNPM and SRSF3 bind in vivo to this poison exon and suppress its inclusion. Notably, DHX9 expression correlates with that of SRSF3 and hnRNPM in Ewing sarcoma patients. Furthermore, downregulation of SRSF3 or hnRNPM inhibited DHX9 expression and Ewing sarcoma cell proliferation, while sensitizing cells to chemotherapeutic treatment. Hence, our study suggests that inhibition of hnRNPM and SRSF3 expression or activity could be exploited as a therapeutic tool to enhance the efficacy of chemotherapy in Ewing sarcoma. Full article

(This article belongs to the Special Issue Alternative Splicing: Recent Insights into Mechanisms and Functional Roles)

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20 pages, 3945 KiB

Open AccessArticle

Splicing Players Are Differently Expressed in Sporadic Amyotrophic Lateral Sclerosis Molecular Clusters and Brain Regions

by Valentina La Cognata, Giulia Gentile, Eleonora Aronica and Sebastiano Cavallaro

Cells 2020, 9(1), 159; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010159 - 08 Jan 2020

Cited by 17 | Viewed by 3948

Abstract

Splicing is a tightly orchestrated process by which the brain produces protein diversity over time and space. While this process specializes and diversifies neurons, its deregulation may be responsible for their selective degeneration. In amyotrophic lateral sclerosis (ALS), splicing defects have been investigated at the singular gene level without considering the higher-order level, involving the entire splicing machinery. In this study, we analyzed the complete spectrum (396) of genes encoding splicing factors in the motor cortex (41) and spinal cord (40) samples from control and sporadic ALS (SALS) patients. A substantial number of genes (184) displayed significant expression changes in tissue types or disease states, were implicated in distinct splicing complexes and showed different topological hierarchical roles based on protein–protein interactions. The deregulation of one of these splicing factors has a central topological role, i.e., the transcription factor YBX1, which might also have an impact on stress granule formation, a pathological marker associated with ALS. Full article

(This article belongs to the Special Issue Alternative Splicing: Recent Insights into Mechanisms and Functional Roles)

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20 pages, 3323 KiB

Open AccessFeature PaperArticle

Gene Expression Profiles Controlled by the Alternative Splicing Factor Nova2 in Endothelial Cells

by Elisa Belloni, Anna Di Matteo, Davide Pradella, Margherita Vacca, Christopher D. R. Wyatt, Roberta Alfieri, Antonio Maffia, Simone Sabbioneda and Claudia Ghigna

Cells 2019, 8(12), 1498; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8121498 - 23 Nov 2019

Cited by 9 | Viewed by 3979

Abstract

Alternative splicing (AS) plays an important role in expanding the complexity of the human genome through the production of specialized proteins regulating organ development and physiological functions, as well as contributing to several pathological conditions. How AS programs impact on the signaling pathways controlling endothelial cell (EC) functions and vascular development is largely unknown. Here we identified, through RNA-seq, changes in mRNA steady-state levels in ECs caused by the neuro-oncological ventral antigen 2 (Nova2), a key AS regulator of the vascular morphogenesis. Bioinformatics analyses identified significant enrichment for genes regulated by peroxisome proliferator-activated receptor-gamma (Ppar-γ) and E2F1 transcription factors. We also showed that Nova2 in ECs controlled the AS profiles of Ppar-γ and E2F dimerization partner 2 (Tfdp2), thus generating different protein isoforms with distinct function (Ppar-γ) or subcellular localization (Tfdp2). Collectively, our results supported a mechanism whereby Nova2 integrated splicing decisions in order to regulate Ppar-γ and E2F1 activities. Our data added a layer to the sequential series of events controlled by Nova2 in ECs to orchestrate vascular biology. Full article

(This article belongs to the Special Issue Alternative Splicing: Recent Insights into Mechanisms and Functional Roles)

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Graphical abstract

17 pages, 2041 KiB

Open AccessArticle

Alternative Splicing of RAD6B and Not RAD6A Is Selectively Increased in Melanoma: Identification and Functional Characterization

by Ambikai Gajan, Carly E. Martin, Seongho Kim, Milap Joshi, Sharon K. Michelhaugh, Ido Sloma, Sandeep Mittal, Steven Firestine and Malathy P. V. Shekhar

Cells 2019, 8(11), 1375; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8111375 - 01 Nov 2019

Cited by 7 | Viewed by 2379

Abstract

Rad6B, a principal component of the translesion synthesis pathway, and activator of canonical Wnt signaling, plays an essential role in cutaneous melanoma development and progression. As Rad6 is encoded by two genes, namely, UBE2A (RAD6A) and UBE2B (RAD6B), in humans, we compared their expressions in melanomas and normal melanocytes. While both genes are weakly expressed in normal melanocytes, Rad6B is more robustly expressed in melanoma lines and patient-derived metastatic melanomas than RAD6A. The characterization of RAD6B transcripts revealed coexpression of various splice variants representing truncated or modified functional versions of wild-type RAD6B in melanomas, but not in normal melanocytes. Notably, two RAD6B isoforms with intact catalytic domains, RAD6BΔexon4 and RAD6Bintron5ins, were identified. We confirmed that RAD6BΔexon4 and RAD6Bintron5ins variants are expressed as 14 and 15 kDa proteins, respectively, with functional in vivo ubiquitin conjugating activity. Whole exome sequence analysis of 30 patient-derived melanomas showed RAD6B variants coexpressed with wild-type RAD6B in all samples analyzed, and RAD6Bintron5ins variants were found in half the cases. These variants constitute the majority of the RAD6B transcriptome in contrast to RAD6A, which was predominantly wild-type. The expression of functional RAD6B variants only in melanomas reveals RAD6B’s molecular heterogeneity and its association with melanoma pathogenesis. Full article

(This article belongs to the Special Issue Alternative Splicing: Recent Insights into Mechanisms and Functional Roles)

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14 pages, 2749 KiB

Open AccessArticle

Alternative Splicing in Heat Shock Protein Transcripts as a Mechanism of Cell Adaptation in Trichophyton rubrum

by João Neves-da-Rocha, Tamires A. Bitencourt, Vanderci M. de Oliveira, Pablo R. Sanches, Antonio Rossi and Nilce M. Martinez-Rossi

Cells 2019, 8(10), 1206; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8101206 - 05 Oct 2019

Cited by 20 | Viewed by 4473

Abstract

Heat shock proteins (HSPs) are involved in critical processes like host tissue invasion, resistance, and pathogenicity in dermatophytes. RNA-Seq analysis of Trichophyton rubrum exposed to undecanoic acid (UDA) revealed intron retention events in HSP transcripts. Because HSPs are modulated in response to various stimuli and as alternative splicing (AS) can result in a broad diversity in the proteome of eukaryotic cells, our objective was to confirm the aforementioned retention events, investigating their consequences and extent. Furthermore, we aimed to determine: (1) the expression profile of HSP genes in an infection-like scenario and (2) the importance of Hsp90 for the keratinolytic potential of T. rubrum. RT and qPCR analyses comparing the exposure to UDA and terbinafine (TRB) confirmed the presence of two mRNA isoforms of the hsp7-like gene, with distinct expression patterns in response to UDA and TRB. The HSP expression profile revealed two upregulated, three downregulated, and four unmodulated transcripts; Hsp90 inhibition by 17-AAG resulted in a significant decrease in keratinolytic potential at 37 °C. Altogether, these results broaden the current knowledge on the importance of HSP-mediated pathways for cell adaptation and other aspects of dermatophyte biology, indicating that HSP network proteins can be potential targets for antifungal therapy. Full article

(This article belongs to the Special Issue Alternative Splicing: Recent Insights into Mechanisms and Functional Roles)

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19 pages, 4392 KiB

Open AccessArticle

Exposure to Ionizing Radiation Triggers Prolonged Changes in Circular RNA Abundance in the Embryonic Mouse Brain and Primary Neurons

by André Claude Mbouombouo Mfossa, Helene Thekkekara Puthenparampil, Auchi Inalegwu, Amelie Coolkens, Sarah Baatout, Mohammed A. Benotmane, Danny Huylebroeck and Roel Quintens

Cells 2019, 8(8), 778; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8080778 - 26 Jul 2019

Cited by 16 | Viewed by 4842

Abstract

The exposure of mouse embryos in utero and primary cortical neurons to ionizing radiation results in the P53-dependent activation of a subset of genes that is highly induced during brain development and neuronal maturation, a feature that these genes reportedly share with circular RNAs (circRNAs). Interestingly, some of these genes are predicted to express circular transcripts. In this study, we validated the abundance of the circular transcript variants of four P53 target genes (Pvt1, Ano3, Sec14l5, and Rnf169). These circular variants were overall more stable than their linear counterparts. They were furthermore highly enriched in the brain and their transcript levels continuously increase during subsequent developmental stages (from embryonic day 12 until adulthood), while no further increase could be observed for linear mRNAs beyond post-natal day 30. Finally, whereas radiation-induced expression of P53 target mRNAs peaks early after exposure, several of the circRNAs showed prolonged induction in irradiated embryonic mouse brain, primary mouse cortical neurons, and mouse blood. Together, our results indicate that the circRNAs from these P53 target genes are induced in response to radiation and they corroborate the findings that circRNAs may represent biomarkers of brain age. We also propose that they may be superior to mRNA as long-term biomarkers for radiation exposure. Full article

(This article belongs to the Special Issue Alternative Splicing: Recent Insights into Mechanisms and Functional Roles)

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17 pages, 3456 KiB

Open AccessArticle

Large Scale Profiling of Protein Isoforms Using Label-Free Quantitative Proteomics Revealed the Regulation of Nonsense-Mediated Decay in Moso Bamboo (Phyllostachys edulis)

by Xiaolan Yu, Yongsheng Wang, Markus V. Kohnen, Mingxin Piao, Min Tu, Yubang Gao, Chentao Lin, Zecheng Zuo and Lianfeng Gu

Cells 2019, 8(7), 744; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8070744 - 19 Jul 2019

Cited by 11 | Viewed by 5277

Abstract

Moso bamboo is an important forest species with a variety of ecological, economic, and cultural values. However, the gene annotation information of moso bamboo is only based on the transcriptome sequencing, lacking the evidence of proteome. The lignification and fiber in moso bamboo leads to a difficulty in the extraction of protein using conventional methods, which seriously hinders research on the proteomics of moso bamboo. The purpose of this study is to establish efficient methods for extracting the total proteins from moso bamboo for following mass spectrometry-based quantitative proteome identification. Here, we have successfully established a set of efficient methods for extracting total proteins of moso bamboo followed by mass spectrometry-based label-free quantitative proteome identification, which further improved the protein annotation of moso bamboo genes. In this study, 10,376 predicted coding genes were confirmed by quantitative proteomics, accounting for 35.8% of all annotated protein-coding genes. Proteome analysis also revealed the protein-coding potential of 1015 predicted long noncoding RNA (lncRNA), accounting for 51.03% of annotated lncRNAs. Thus, mass spectrometry-based proteomics provides a reliable method for gene annotation. Especially, quantitative proteomics revealed the translation patterns of proteins in moso bamboo. In addition, the 3284 transcript isoforms from 2663 genes identified by Pacific BioSciences (PacBio) single-molecule real-time long-read isoform sequencing (Iso-Seq) was confirmed on the protein level by mass spectrometry. Furthermore, domain analysis of mass spectrometry-identified proteins encoded in the same genomic locus revealed variations in domain composition pointing towards a functional diversification of protein isoform. Finally, we found that part transcripts targeted by nonsense-mediated mRNA decay (NMD) could also be translated into proteins. In summary, proteomic analysis in this study improves the proteomics-assisted genome annotation of moso bamboo and is valuable to the large-scale research of functional genomics in moso bamboo. In summary, this study provided a theoretical basis and technical support for directional gene function analysis at the proteomics level in moso bamboo. Full article

(This article belongs to the Special Issue Alternative Splicing: Recent Insights into Mechanisms and Functional Roles)

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11 pages, 4133 KiB

Open AccessFeature PaperArticle

Activation of Cryptic 3′ Splice-Sites by SRSF2 Contributes to Cassette Exon Skipping

by Heegyum Moon, Ha Na Jang, Yongchao Liu, Namjeong Choi, Jagyeong Oh, Jiyeon Ha, Xuexiu Zheng and Haihong Shen

Cells 2019, 8(7), 696; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8070696 - 10 Jul 2019

Cited by 9 | Viewed by 3481

Abstract

Here we show that the serine/arginine rich splicing factor 2 (SRSF2) promotes cryptic 3′ splice-site (3′AG′) usage during cassette exon exclusion in survival of motor neuron (SMN2) minigenes. Deletion of the 3′AG′ (3′AG′1), its associated branch point (BP′) and polypyrimidine tract (PPT′) sequences directs SRSF2 to promote a second 3′AG′ (3′AG′2) with less conserved associated region for intron splicing. Furthermore, deletion of both 3′AG′1 and 3′AG′2 and their associated sequences triggered usage of a third 3′AG′3 that has very weak associated sequences. Interestingly, when intron splicing was directed to the 3′AG′ cryptic splice-sites, intron splicing from the canonical 3′AG splice-site was reduced along with a decrease in cassette exon inclusion. Moreover, multiple SRSF2 binding sites within the intron are responsible for 3′AG′ activation. We conclude that SRSF2 facilitates exon exclusion by activating a cryptic 3′AG′ and inhibiting downstream intron splicing. Full article

(This article belongs to the Special Issue Alternative Splicing: Recent Insights into Mechanisms and Functional Roles)

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Review

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18 pages, 949 KiB

Open AccessReview

An Intricate Connection between Alternative Splicing and Phenotypic Plasticity in Development and Cancer

by Giuseppe Biamonti, Lucia Infantino, Daniela Gaglio and Angela Amato

Cells 2020, 9(1), 34; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010034 - 21 Dec 2019

Cited by 19 | Viewed by 4826

Abstract

During tumor progression, hypoxia, nutrient deprivation or changes in the extracellular environment (i.e., induced by anti-cancer drugs) elicit adaptive responses in cancer cells. Cellular plasticity increases the chance that tumor cells may survive in a challenging microenvironment, acquire new mechanisms of resistance to conventional drugs, and spread to distant sites. Re-activation of stem pathways appears as a significant cause of cellular plasticity because it promotes the acquisition of stem-like properties through a profound phenotypic reprogramming of cancer cells. In addition, it is a major contributor to tumor heterogeneity, depending on the coexistence of phenotypically distinct subpopulations in the same tumor bulk. Several cellular mechanisms may drive this fundamental change, in particular, high-throughput sequencing technologies revealed a key role for alternative splicing (AS). Effectively, AS is one of the most important pre-mRNA processes that increases the diversity of transcriptome and proteome in a tissue- and development-dependent manner. Moreover, defective AS has been associated with several human diseases. However, its role in cancer cell plasticity and tumor heterogeneity remains unclear. Therefore, unravelling the intricate relationship between AS and the maintenance of a stem-like phenotype may explain molecular mechanisms underlying cancer cell plasticity and improve cancer diagnosis and treatment. Full article

(This article belongs to the Special Issue Alternative Splicing: Recent Insights into Mechanisms and Functional Roles)

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19 pages, 2422 KiB

Open AccessReview

Serine-Arginine Protein Kinase 1 (SRPK1) as a Prognostic Factor and Potential Therapeutic Target in Cancer: Current Evidence and Future Perspectives

by Ilias P. Nikas, Sophie C. Themistocleous, Stavroula A. Paschou, Konstantinos I. Tsamis and Han Suk Ryu

Cells 2020, 9(1), 19; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010019 - 19 Dec 2019

Cited by 23 | Viewed by 5326

Abstract

Cancer, a heterogeneous disease composed of tumor cells and microenvironment, is driven by deregulated processes such as increased proliferation, invasion, metastasis, angiogenesis, and evasion of apoptosis. Alternative splicing, a mechanism led by splicing factors, is implicated in carcinogenesis by affecting any of the processes above. Accumulating evidence suggests that serine-arginine protein kinase 1 (SRPK1), an enzyme that phosphorylates splicing factors rich in serine/arginine domains, has a prognostic and potential predictive role in various cancers. Its upregulation is correlated with higher tumor staging, grading, and shorter survival. SRPK1 is also highly expressed in the premalignant changes of some cancers, showing a potential role in the early steps of carcinogenesis. Of interest, its downregulation in preclinical models has mostly been tumor-suppressive and affected diverse processes heterogeneously, depending on the oncogenic context. In addition, targeting SRPK1 has enhanced sensitivity to platinum-based chemotherapy in some cancers. Lastly, its aberrant function has been noted not only in cancer cells but also in the endothelial cells of the microenvironment. Although the aforementioned evidence seems promising, more studies are needed to reinforce the use of SRPK1 inhibitors in clinical trials. Full article

(This article belongs to the Special Issue Alternative Splicing: Recent Insights into Mechanisms and Functional Roles)

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21 pages, 1538 KiB

Open AccessReview

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

by Pamela Bielli, Vittoria Pagliarini, Marco Pieraccioli, Cinzia Caggiano and Claudio Sette

Cells 2020, 9(1), 10; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9010010 - 18 Dec 2019

Cited by 14 | Viewed by 4229

Abstract

Brain tumors are a heterogeneous group of neoplasms ranging from almost benign to highly aggressive phenotypes. The malignancy of these tumors mostly relies on gene expression reprogramming, which is frequently accompanied by the aberrant regulation of RNA processing mechanisms. In brain tumors, defects in alternative splicing result either from the dysregulation of expression and activity of splicing factors, or from mutations in the genes encoding splicing machinery components. Aberrant splicing regulation can generate dysfunctional proteins that lead to modification of fundamental physiological cellular processes, thus contributing to the development or progression of brain tumors. Herein, we summarize the current knowledge on splicing abnormalities in brain tumors and how these alterations contribute to the disease by sustaining proliferative signaling, escaping growth suppressors, or establishing a tumor microenvironment that fosters angiogenesis and intercellular communications. Lastly, we review recent efforts aimed at developing novel splicing-targeted cancer therapies, which employ oligonucleotide-based approaches or chemical modulators of alternative splicing that elicit an impact on brain tumor biology. Full article

(This article belongs to the Special Issue Alternative Splicing: Recent Insights into Mechanisms and Functional Roles)

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22 pages, 890 KiB

Open AccessFeature PaperReview

Machine Learning Approaches for the Prioritization of Genomic Variants Impacting Pre-mRNA Splicing

by Charlie F Rowlands, Diana Baralle and Jamie M Ellingford

Cells 2019, 8(12), 1513; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8121513 - 26 Nov 2019

Cited by 34 | Viewed by 7151

Abstract

Defects in pre-mRNA splicing are frequently a cause of Mendelian disease. Despite the advent of next-generation sequencing, allowing a deeper insight into a patient’s variant landscape, the ability to characterize variants causing splicing defects has not progressed with the same speed. To address this, recent years have seen a sharp spike in the number of splice prediction tools leveraging machine learning approaches, leaving clinical geneticists with a plethora of choices for in silico analysis. In this review, some basic principles of machine learning are introduced in the context of genomics and splicing analysis. A critical comparative approach is then used to describe seven recent machine learning-based splice prediction tools, revealing highly diverse approaches and common caveats. We find that, although great progress has been made in producing specific and sensitive tools, there is still much scope for personalized approaches to prediction of variant impact on splicing. Such approaches may increase diagnostic yields and underpin improvements to patient care. Full article

(This article belongs to the Special Issue Alternative Splicing: Recent Insights into Mechanisms and Functional Roles)

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