scholarly journals Deep Splicing Code: Classifying Alternative Splicing Events Using Deep Learning

Genes ◽  
2019 ◽  
Vol 10 (8) ◽  
pp. 587 ◽  
Author(s):  
Zakaria Louadi ◽  
Mhaned Oubounyt ◽  
Hilal Tayara ◽  
Kil To Chong
Keyword(s):  
Deep Learning ◽  
Alternative Splicing ◽  
Computational Models ◽  
Genomic Sequence ◽  
Single Gene ◽  
Splicing Factors ◽  
Local Characteristics ◽  
Alternatively Spliced ◽  
Exon Junctions ◽  
Alternatively Spliced Exons

Alternative splicing (AS) is the process of combining different parts of the pre-mRNA to produce diverse transcripts and eventually different protein products from a single gene. In computational biology field, researchers try to understand AS behavior and regulation using computational models known as “Splicing Codes”. The final goal of these algorithms is to make an in-silico prediction of AS outcome from genomic sequence. Here, we develop a deep learning approach, called Deep Splicing Code (DSC), for categorizing the well-studied classes of AS namely alternatively skipped exons, alternative 5’ss, alternative 3’ss, and constitutively spliced exons based only on the sequence of the exon junctions. The proposed approach significantly improves the prediction and the obtained results reveal that constitutive exons have distinguishable local characteristics from alternatively spliced exons. Using the motif visualization technique, we show that the trained models learned to search for competitive alternative splice sites as well as motifs of important splicing factors with high precision. Thus, the proposed approach greatly expands the opportunities to improve alternative splicing modeling. In addition, a web-server for AS events prediction has been developed based on the proposed method and made available at https://home.jbnu.ac.kr/NSCL/dsc.htm.

scholarly journals Influence of Intron Length on Alternative Splicing of CD44

1998 ◽  
Vol 18 (10) ◽  
pp. 5930-5941 ◽  
Author(s):  
Martyn V. Bell ◽  
Alison E. Cowper ◽  
Marie-Paule Lefranc ◽  
John I. Bell ◽  
Gavin R. Screaton
Keyword(s):  
Alternative Splicing ◽  
Genomic Structure ◽  
Single Gene ◽  
Intron Length ◽  
Protein Isoforms ◽  
Major Influence ◽  
Eukaryotic Genes ◽  
Alternatively Spliced ◽  
Alternatively Spliced Exons

ABSTRACT Although the splicing of transcripts from most eukaryotic genes occurs in a constitutive fashion, some genes can undergo a process of alternative splicing. This is a genetically economical process which allows a single gene to give rise to several protein isoforms by the inclusion or exclusion of sequences into or from the mature mRNA. CD44 provides a unique example; more than 1,000 possible isoforms can be produced by the inclusion or exclusion of a central tandem array of 10 alternatively spliced exons. Certain alternatively spliced exons have been ascribed specific functions; however, independent regulation of the inclusion or skipping of each of these exons would clearly demand an extremely complex regulatory network. Such a network would involve the interaction of many exon-specific trans-acting factors with the pre-mRNA. Therefore, to assess whether the exons are indeed independently regulated, we have examined the alternative exon content of a large number of individual CD44 cDNA isoforms. This analysis shows that the downstream alternatively spliced exons are favored over those lying upstream and that alternative exons are often included in blocks rather than singly. Using a novel in vivo alternative splicing assay, we show that intron length has a major influence upon the alternative splicing of CD44. We propose a kinetic model in which short introns may overcome the poor recognition of alternatively spliced exons. These observations suggest that for CD44, intron length has been exploited in the evolution of the genomic structure to enable tissue-specific patterns of splicing to be maintained.

scholarly journals Trans-acting Factors Required for Inclusion of Regulated Exons in the Ultrabithorax mRNAs of Drosophila melanogaster

Genetics ◽  
1999 ◽  
Vol 151 (4) ◽  
pp. 1517-1529 ◽  
Author(s):  
James M Burnette ◽  
Allyson R Hatton ◽  
A Javier Lopez
Keyword(s):  
Drosophila Melanogaster ◽  
Alternative Splicing ◽  
P Element ◽  
Splicing Factors ◽  
Loss Of Function ◽  
Large Collection ◽  
Splicing Pattern ◽  
Alternatively Spliced ◽  
Hypomorphic Alleles

Abstract Alternatively spliced Ultrabithorax mRNAs differ by the presence of internal exons mI and mII. Two approaches were used to identify trans-acting factors required for inclusion of these cassette exons. First, mutations in a set of genes implicated in the control of other alternative splicing decisions were tested for dominant effects on the Ubx alternative splicing pattern. To identify additional genes involved in regulation of Ubx splicing, a large collection of deficiencies was tested first for dominant enhancement of the haploinsufficient Ubx haltere phenotype and second for effects on the splicing pattern. Inclusion of the cassette exons in Ubx mRNAs was reduced strongly in heterozygotes for hypomorphic alleles of hrp48, which encodes a member of the hnRNP A/B family and is implicated in control of P-element splicing. Significant reductions of mI and mII inclusion were also observed in heterozygotes for loss-of-function alleles of virilizer, fl(2)d, and crooked neck. The products of virilizer and fl(2)d are also required for Sxl autoregulation at the level of splicing; crooked neck encodes a protein with structural similarities to yeast-splicing factors Prp39p and Prp42p. Deletion of at least five other loci caused significant reductions in the inclusion of mI and/or mII. Possible roles of identified factors are discussed in the context of the resplicing strategy for generation of alternative Ubx mRNAs.

scholarly journals Expression of Alternatively Spliced Sodium Channel α-Subunit Genes

2004 ◽  
Vol 279 (44) ◽  
pp. 46234-46241 ◽  
Author(s):  
Christopher K. Raymond ◽  
John Castle ◽  
Philip Garrett-Engele ◽  
Christopher D. Armour ◽  
Zhengyan Kan ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Sodium Channel ◽  
Dorsal Root Ganglia ◽  
Dorsal Root ◽  
Genomic Sequence ◽  
Molecular Medicine ◽  
Primate Model ◽  
Α Subunit ◽  
Alternatively Spliced ◽  
Splicing Patterns

Molecular medicine requires the precise definition of drug targets, and tools are now in place to provide genome-wide information on the expression and alternative splicing patterns of any known gene. DNA microarrays were used to monitor transcript levels of the nine well-characterized α-subunit sodium channel genes across a broad range of tissues from cynomolgus monkey, a non-human primate model. Alternative splicing of human transcripts for a subset of the genes that are expressed in dorsal root ganglia, SCN8A (Nav1.6), SCN9A (Nav1.7), and SCN11A (Nav1.9) was characterized in detail. Genomic sequence analysis among gene family paralogs and between cross-species orthologs suggested specific alternative splicing events within transcripts of these genes, all of which were experimentally confirmed in human tissues. Quantitative PCR revealed that certain alternative splice events are uniquely expressed in dorsal root ganglia. In addition to characterization of human transcripts, alternatively spliced sodium channel transcripts were monitored in a rat model for neuropathic pain. Consistent down-regulation of all transcripts was observed, as well as significant changes in the splicing patterns of SCN8A and SCN9A.

scholarly journals The gene structure and hypervariability of the complete Penaeus monodon Dscam gene

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kantamas Apitanyasai ◽  
Shiao-Wei Huang ◽  
Tze Hann Ng ◽  
Shu-Ting He ◽  
Yu-Hsun Huang ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Gene Structure ◽  
Transmembrane Domain ◽  
Stop Codon ◽  
Penaeus Monodon ◽  
Cytoplasmic Tail ◽  
Extracellular Region ◽  
Alternatively Spliced ◽  
Alternatively Spliced Exons ◽  
Selection Of

Abstract Using two advanced sequencing approaches, Illumina and PacBio, we derive the entire Dscam gene from an M2 assembly of the complete Penaeus monodon genome. The P. monodon Dscam (PmDscam) gene is ~266 kbp, with a total of 44 exons, 5 of which are subject to alternative splicing. PmDscam has a conserved architectural structure consisting of an extracellular region with hypervariable Ig domains, a transmembrane domain, and a cytoplasmic tail. We show that, contrary to a previous report, there are in fact 26, 81 and 26 alternative exons in N-terminal Ig2, N-terminal Ig3 and the entirety of Ig7, respectively. We also identified two alternatively spliced exons in the cytoplasmic tail, with transmembrane domains in exon variants 32.1 and 32.2, and stop codons in exon variants 44.1 and 44.2. This means that alternative splicing is involved in the selection of the stop codon. There are also 7 non-constitutive cytoplasmic tail exons that can either be included or skipped. Alternative splicing and the non-constitutive exons together produce more than 21 million isoform combinations from one PmDscam locus in the P. monodon gene. A public-facing database that allows BLAST searches of all 175 exons in the PmDscam gene has been established at http://pmdscam.dbbs.ncku.edu.tw/.

Alternative splicing can lead to chaos

2015 ◽  
Vol 13 (01) ◽  
pp. 1540003 ◽  
Author(s):  
Vitaly A. Likhoshvai ◽  
Vladislav V. Kogai ◽  
Stanislav I. Fadeev ◽  
Tamara M. Khlebodarova
Keyword(s):  
Alternative Splicing ◽  
Chaotic Dynamics ◽  
Single Gene ◽  
Regulatory Protein ◽  
Genetic System ◽  
Feedback Mechanism ◽  
Regulatory Proteins ◽  
Gene Encoding ◽  
Regulation Type ◽  
Alternatively Spliced

Alternative splicing is a widespread phenomenon in higher eukaryotes, where it serves as a mechanism to increase the functional diversity of proteins. This phenomenon has been described for different classes of proteins, including transcription regulatory proteins. We demonstrated that in the simplest genetic system model the formation of the alternatively spliced isoforms with opposite functions (activators and repressors) could be a cause of transition to chaotic dynamics. Under the simplest genetic system we understand a system consisting of a single gene encoding the structure of a transcription regulatory protein whose expression is regulated by a feedback mechanism. As demonstrated by numerical analysis of the models, if the synthesized isoforms regulate the expression of their own gene acting through different sites and independently of each other, for the generation of chaotic dynamics it is sufficient that the regulatory proteins have a dimeric structure. If regulatory proteins act through one site, the chaotic dynamics is generated in the system only when the repressor protein is either a tetrameric or a higher-dimensional multimer. In this case the activator can be a dimer. It was also demonstrated that if the transcription factor isoforms exhibit either activating or inhibiting activity and are lower-dimensional multimers (< 4), independently of the regulation type the model demonstrates either cyclic or stationary trajectories.

scholarly journals Aurora-A phosphorylates splicing factors and regulates alternative splicing

2020 ◽  
Author(s):  
Arun Prasath Damodaran ◽  
Olivia Gavard ◽  
Jean-Philippe Gagné ◽  
Malgorzata Ewa Rogalska ◽  
Estefania Mancini ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Direct Interaction ◽  
Splicing Factors ◽  
Sequencing Analysis ◽  
Aurora A Kinase ◽  
Aurora A ◽  
Nuclear Speckles ◽  
Rrm Domain ◽  
Alternatively Spliced

ABSTRACTAurora-A kinase is well known to regulate progression through mitosis. However, the kinase also performs additional functions that could explain the failure of its inhibitors to be effective in cancer treatments. To identify these functions, we applied a proteomics approach to search for interactors of Aurora-A. We found a large number of proteins involved in pre-mRNA splicing, strongly suggesting an important role for Aurora-A in this biological process. Consistently, we first report the subcellular localization of Aurora-A in nuclear speckles, the storehouse of splicing proteins. We also demonstrate direct interaction of Aurora-A with RRM domain-containing splicing factors such as hnRNP and SR proteins and their phosphorylation in vitro. Further, RNA-sequencing analysis following pharmacological inhibition of Aurora-A resulted in alternative splicing changes corresponding to 505 genes, including genes with functions regulated by Aurora-A kinase. Finally, we report enrichment of RNA motifs within the alternatively spliced regions affected by Aurora-A kinase inhibition which are bound by Aurora-A interacting splicing factors, suggesting that Aurora-A regulates alternative splicing by modulating the activity of these interacting splicing factors. Overall our work identified Aurora-A as a novel splicing kinase and for the first time, describes a broad role of Aurora-A in regulating alternative splicing.

scholarly journals An alternatively spliced zebrafish jnk1a transcript has an essential and non-redundant role in development of the first heart field derived proximal ventricular chamber

2019 ◽  
Author(s):  
A Santos-Ledo ◽  
S Washer ◽  
T Dhanaseelan ◽  
P Chrystal ◽  
T Papoutsi ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Heart Development ◽  
Planar Cell Polarity ◽  
Cardiac Development ◽  
Single Gene ◽  
Jun Kinase ◽  
Downstream Effectors ◽  
Heart Malformation ◽  
Alternatively Spliced ◽  
First Heart Field

AbstractAlternative splicing is a ubiquitous mechanism for producing different mRNA species from a single gene, resulting in proteomic diversity. Despite potential for regulating embryogenesis, its developmental role remains under-investigated. The Jun kinase (Jnk) genes, considered downstream effectors of the non-canonical Wnt planar cell polarity pathway, utilise extensive and evolutionarily-conserved alternative splicing. Although many PCP members are associated with heart malformation, the role of Jnk genes in cardiac development, and specifically which alternatively spliced transcripts orchestrate these processes, remain unknown. In this study we exploit the jnk1 duplication and subspecialisation found in zebrafish to reveal an essential and non-redundant requirement for jnk1a in cardiac development. We characterise alternatively spliced jnk1a/jnk1b transcripts and demonstrate that hypoplasia of the proximal ventricular component, which corresponds to human hypoplastic left ventricle, can only be rescued by the jnk1a Ex7 Lg transcript. These studies highlight the importance of Jnk signalling and alternative splicing in heart development

scholarly journals Sequence and Evolutionary Features for the Alternatively Spliced Exons of Eukaryotic Genes

2019 ◽  
Vol 20 (15) ◽  
pp. 3834 ◽  
Author(s):  
Shi-Yi Chen ◽  
Cao Li ◽  
Xianbo Jia ◽  
Song-Jia Lai
Keyword(s):  
Alternative Splicing ◽  
High Throughput Sequencing ◽  
Point Of View ◽  
Sequencing Technologies ◽  
Eukaryotic Genes ◽  
Splicing Pattern ◽  
Evolutionary Features ◽  
Alternatively Spliced ◽  
Alternative Splicing Events ◽  
Alternatively Spliced Exons

Alternative splicing of pre-mRNAs is a crucial mechanism for maintaining protein diversity in eukaryotes without requiring a considerable increase of genes in the number. Due to rapid advances in high-throughput sequencing technologies and computational algorithms, it is anticipated that alternative splicing events will be more intensively studied to address different kinds of biological questions. The occurrences of alternative splicing mean that all exons could be classified to be either constitutively or alternatively spliced depending on whether they are virtually included into all mature mRNAs. From an evolutionary point of view, therefore, the alternatively spliced exons would have been associated with distinctive biological characteristics in comparison with constitutively spliced exons. In this paper, we first outline the representative types of alternative splicing events and exon classification, and then review sequence and evolutionary features for the alternatively spliced exons. The main purpose is to facilitate understanding of the biological implications of alternative splicing in eukaryotes. This knowledge is also helpful to establish computational approaches for predicting the splicing pattern of exons.

scholarly journals Alternative splicing links histone modifications to stem cell fate decision

2017 ◽  
Author(s):  
Yungang Xu ◽  
Weiling Zhao ◽  
Scott D. Olson ◽  
Karthik S. Prabhakara ◽  
Xiaobo Zhou
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Alternative Splicing ◽  
Cell Fate ◽  
Histone Modifications ◽  
Cell Fate Decision ◽  
Stem Cell Fate ◽  
Alternatively Spliced ◽  
Fate Decision ◽  
Alternatively Spliced Exons

AbstractBackgroundUnderstanding the embryonic stem cell (ESC) fate decision between self-renewal and proper differentiation is important for developmental biology and regenerative medicine. Attention has focused on mechanisms involving histone modifications, alternative pre-mRNA splicing, and cell-cycle progression. However, their intricate interrelations and joint contributions to ESC fate decision remain unclear.ResultsWe analyze the transcriptomes and epigenomes of human ESC and five types of differentiated cells. We identify thousands of alternatively spliced exons and reveal their development and lineage-dependent characterizations. Several histone modifications show dynamic changes in alternatively spliced exons and three are strongly associated with 52.8% of alternative splicing events upon hESC differentiation. The histone modification-associated alternatively spliced genes predominantly function in G2/M phases and ATM/ATR-mediated DNA damage response pathway for cell differentiation, whereas other alternatively spliced genes are enriched in the G1 phase and pathways for self-renewal. These results imply a potential epigenetic mechanism by which some histone modifications contribute to ESC fate decision through the regulation of alternative splicing in specific pathways and cell-cycle genes. Supported by experimental validations and extended dataset from Roadmap/ENCODE projects, we exemplify this mechanism by a cell cycle-related transcription factor, PBX1, which regulates the pluripotency regulatory network by binding to NANOG. We suggest that the isoform switch from PBX1a to PBX1b links H3K36me3 to hESC fate determination through the PSIP1/SRSF1 adaptor, which results in the exon skipping of PBX1.ConclusionWe reveal the mechanism by which alternative splicing links histone modifications to stem cell fate decision.

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