scholarly journals Genome-wide Analysis of Alternative Pre-mRNA Splicing

2007 ◽  
Vol 283 (3) ◽  
pp. 1229-1233 ◽  
Author(s):  
Claudia Ben-Dov ◽  
Britta Hartmann ◽  
Josefin Lundgren ◽  
Juan Valcárcel
Keyword(s):  
Alternative Splicing ◽  
Large Scale ◽  
Mrna Splicing ◽  
Diagnostic Tools ◽  
Primary Transcript ◽  
Genome Wide ◽  
Human Genes ◽  
Multicellular Organisms ◽  
Eukaryotic Genomes ◽  
Key Questions

Alternative splicing of mRNA precursors allows the synthesis of multiple mRNAs from a single primary transcript, significantly expanding the information content and regulatory possibilities of higher eukaryotic genomes. High-throughput enabling technologies, particularly large-scale sequencing and splicing-sensitive microarrays, are providing unprecedented opportunities to address key questions in this field. The picture emerging from these pioneering studies is that alternative splicing affects most human genes and a significant fraction of the genes in other multicellular organisms, with the potential to greatly influence the evolution of complex genomes. A combinatorial code of regulatory signals and factors can deploy physiologically coherent programs of alternative splicing that are distinct from those regulated at other steps of gene expression. Pre-mRNA splicing and its regulation play important roles in human pathologies, and genome-wide analyses in this area are paving the way for improved diagnostic tools and for the identification of novel and more specific pharmaceutical targets.

Evidence of the modulation of mRNA splicing fidelity in humans by oxidative stress and p53

Genome ◽  
2007 ◽  
Vol 50 (10) ◽  
pp. 946-953 ◽  
Author(s):  
Kim Disher ◽  
Adonis Skandalis
Keyword(s):  
Oxidative Stress ◽  
Alternative Splicing ◽  
Molecular Mechanisms ◽  
Splice Variants ◽  
Dna Lesions ◽  
Mrna Splicing ◽  
Aberrant Splice ◽  
Biological Phenomenon ◽  
Mrna Splice ◽  
Human Genes

The majority of human genes generate mRNA splice variants and while there is little doubt that alternative splicing is an important biological phenomenon, it has also become apparent that some splice variants are associated with disease. To elucidate the molecular mechanisms responsible for generating aberrant splice variants, we have investigated alternative splicing of the human genes HPRT and POLB following oxidative stress in different genetic backgrounds. Our study revealed that splicing fidelity is sensitive to oxidative stress. Following treatment of cells with H2O2, the overall frequency of aberrant, unproductive splice variants increased in both loci. At least in POLB, splicing fidelity is p53 dependent. In the absence of p53, the frequency of POLB splice variants is elevated but oxidative stress does not further increase the frequency of splice variants. Our data indicate that mis-splicing following oxidative stress represents a novel and significant genotoxic outcome and that it is not simply DNA lesions induced by oxidative stress that lead to mis-splicing but changes in the alternative splicing machinery itself.

scholarly journals A new view of transcriptome complexity and regulation through the lens of local splicing variations

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Jorge Vaquero-Garcia ◽  
Alejandro Barrera ◽  
Matthew R Gazzara ◽  
Juan González-Vallinas ◽  
Nicholas F Lahens ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Alternative Splicing ◽  
Gene Function ◽  
Specific Protein ◽  
Mrna Splicing ◽  
New Approach ◽  
Genome Wide ◽  
Mouse Tissues ◽  
Splice Variation ◽  
Novel Isoforms

Alternative splicing (AS) can critically affect gene function and disease, yet mapping splicing variations remains a challenge. Here, we propose a new approach to define and quantify mRNA splicing in units of local splicing variations (LSVs). LSVs capture previously defined types of alternative splicing as well as more complex transcript variations. Building the first genome wide map of LSVs from twelve mouse tissues, we find complex LSVs constitute over 30% of tissue dependent transcript variations and affect specific protein families. We show the prevalence of complex LSVs is conserved in humans and identify hundreds of LSVs that are specific to brain subregions or altered in Alzheimer's patients. Amongst those are novel isoforms in the Camk2 family and a novel poison exon in Ptbp1, a key splice factor in neurogenesis. We anticipate the approach presented here will advance the ability to relate tissue-specific splice variation to genetic variation, phenotype, and disease.

scholarly journals Nascent RNA Sequencing Reveals Widespread Pausing and Divergent Initiation at Human Promoters

Science ◽  
2008 ◽  
Vol 322 (5909) ◽  
pp. 1845-1848 ◽  
Author(s):  
Leighton J. Core ◽  
Joshua J. Waterfall ◽  
John T. Lis
Keyword(s):  
Messenger Rna ◽  
Large Scale ◽  
Molecular Machines ◽  
Antisense Transcription ◽  
Rna Polymerases ◽  
Promoter Regions ◽  
Rna Molecules ◽  
Genome Wide ◽  
Human Genes ◽  
Active Genes

RNA polymerases are highly regulated molecular machines. We present a method (global run-on sequencing, GRO-seq) that maps the position, amount, and orientation of transcriptionally engaged RNA polymerases genome-wide. In this method, nuclear run-on RNA molecules are subjected to large-scale parallel sequencing and mapped to the genome. We show that peaks of promoter-proximal polymerase reside on ∼30% of human genes, transcription extends beyond pre-messenger RNA 3′ cleavage, and antisense transcription is prevalent. Additionally, most promoters have an engaged polymerase upstream and in an orientation opposite to the annotated gene. This divergent polymerase is associated with active genes but does not elongate effectively beyond the promoter. These results imply that the interplay between polymerases and regulators over broad promoter regions dictates the orientation and efficiency of productive transcription.

scholarly journals Alternative Splicing: Expanding the Landscape of Cancer Biomarkers and Therapeutics

2020 ◽  
Vol 21 (23) ◽  
pp. 9032
Author(s):  
Cláudia Bessa ◽  
Paulo Matos ◽  
Peter Jordan ◽  
Vânia Gonçalves
Keyword(s):  
Alternative Splicing ◽  
Messenger Rna ◽  
Human Cancer ◽  
Genetic Alterations ◽  
Altered Expression ◽  
Genome Wide ◽  
Human Genes ◽  
Transcriptional Regulatory Mechanism ◽  
A Genome ◽  
Wide Scale

Alternative splicing (AS) is a critical post-transcriptional regulatory mechanism used by more than 95% of transcribed human genes and responsible for structural transcript variation and proteome diversity. In the past decade, genome-wide transcriptome sequencing has revealed that AS is tightly regulated in a tissue- and developmental stage-specific manner, and also frequently dysregulated in multiple human cancer types. It is currently recognized that splicing defects, including genetic alterations in the spliced gene, altered expression of both core components or regulators of the precursor messenger RNA (pre-mRNA) splicing machinery, or both, are major drivers of tumorigenesis. Hence, in this review we provide an overview of our current understanding of splicing alterations in cancer, and emphasize the need to further explore the cancer-specific splicing programs in order to obtain new insights in oncology. Furthermore, we also discuss the recent advances in the identification of dysregulated splicing signatures on a genome-wide scale and their potential use as biomarkers. Finally, we highlight the therapeutic opportunities arising from dysregulated splicing and summarize the current approaches to therapeutically target AS in cancer.

scholarly journals Splicing Programs and Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Sophie Germann ◽  
Lise Gratadou ◽  
Martin Dutertre ◽  
Didier Auboeuf
Keyword(s):  
Alternative Splicing ◽  
Gene Networks ◽  
Large Scale ◽  
Splicing Factors ◽  
Novel Technologies ◽  
Normal Tissues ◽  
Genome Wide ◽  
Splicing Variants ◽  
Cancer Initiation ◽  
Genetic Mechanisms

Numerous studies report splicing alterations in a multitude of cancers by using gene-by-gene analysis. However, understanding of the role of alternative splicing in cancer is now reaching a new level, thanks to the use of novel technologies allowing the analysis of splicing at a large-scale level. Genome-wide analyses of alternative splicing indicate that splicing alterations can affect the products of gene networks involved in key cellular programs. In addition, many splicing variants identified as being misregulated in cancer are expressed in normal tissues. These observations suggest that splicing programs contribute to specific cellular programs that are altered during cancer initiation and progression. Supporting this model, recent studies have identified splicing factors controlling cancer-associated splicing programs. The characterization of splicing programs and their regulation by splicing factors will allow a better understanding of the genetic mechanisms involved in cancer initiation and progression and the development of new therapeutic targets.

scholarly journals Annotation and differential analysis of alternative splicing using de novo assembly of RNAseq data

2016 ◽  
Author(s):  
Clara Benoit-Pilven ◽  
Camille Marchet ◽  
Emilie Chautard ◽  
Leandro Lima ◽  
Marie-Pierre Lambert ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
De Novo ◽  
Exon Skipping ◽  
Differential Analysis ◽  
Genome Wide ◽  
Human Genes ◽  
Rnaseq Data ◽  
Splicing Variants ◽  
Novel Variants ◽  
Event Based

AbstractGenome-wide analyses reveal that more than 90% of multi exonic human genes produce at least two transcripts through alternative splicing (AS). Various bioinformatics methods are available to analyze AS from RNAseq data. Most methods start by mapping the reads to an annotated reference genome, but some start by a de novo assembly of the reads. In this paper, we present a systematic comparison of a mapping-first approach (FaRLine) and an assembly-first approach (KisSplice). These two approaches are event-based, as they focus on the regions of the transcripts that vary in their exon content. We applied these methods to an RNAseq dataset from a neuroblastoma SK-N-SH cell line (ENCODE) differentiated or not using retinoic acid. We found that the predictions of the two pipelines overlapped (70% of exon skipping events were common), but with noticeable differences. The assembly-first approach allowed to find more novel variants, including novel unannotated exons and splice sites. It also predicted AS in families of paralog genes. The mapping-first approach allowed to find more lowly expressed splicing variants, and was better in predicting exons overlapping repeated elements. This work demonstrates that annotating AS with a single approach leads to missing a large number of candidates. We further show that these candidates cannot be neglected, since many of them are differentially regulated across conditions, and can be validated experimentally. We therefore advocate for the combine use of both mapping-first and assembly-first approaches for the annotation and differential analysis of AS from RNAseq data.

scholarly journals AVATAR: A database for genome-wide alternative splicing event detection through analysis of large scale ESTs and mRNAs

2005 ◽  
Vol 1 (1) ◽  
pp. 16-18 ◽  
Author(s):  
Fang Rong Hsu ◽  
Hwan-You Chang ◽  
Yaw-Lin Lin ◽  
Yin-Te Tsai ◽  
Hui-Ling Peng ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Event Detection ◽  
Large Scale ◽  
Genome Wide

scholarly journals Genome-wide analyses of the prognosis-related mRNA alternative splicing landscape and novel splicing factors based on large-scale low grade glioma cohort

Aging ◽  
2020 ◽  
Vol 12 (13) ◽  
pp. 13684-13700
Author(s):  
Wang-Rui Liu ◽  
Chuan-Yu Li ◽  
Wen-Hao Xu ◽  
Xiao-Juan Liu ◽  
Hai-Dan Tang ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Large Scale ◽  
Low Grade Glioma ◽  
Splicing Factors ◽  
Low Grade ◽  
Genome Wide

scholarly journals Pathway-guided analysis identifies Myc-dependent alternative pre-mRNA splicing in aggressive prostate cancers

2020 ◽  
Vol 117 (10) ◽  
pp. 5269-5279 ◽  
Author(s):  
John W. Phillips ◽  
Yang Pan ◽  
Brandon L. Tsai ◽  
Zhijie Xie ◽  
Levon Demirdjian ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Rna Splicing ◽  
Large Scale ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Splicing ◽  
Cancer Driver ◽  
Genes Encoding ◽  
Prostate Cancers

We sought to define the landscape of alternative pre-mRNA splicing in prostate cancers and the relationship of exon choice to known cancer driver alterations. To do so, we compiled a metadataset composed of 876 RNA-sequencing (RNA-Seq) samples from five publicly available sources representing a range of prostate phenotypes from normal tissue to drug-resistant metastases. We subjected these samples to exon-level analysis with rMATS-turbo, purpose-built software designed for large-scale analyses of splicing, and identified 13,149 high-confidence cassette exon events with variable incorporation across samples. We then developed a computational framework, pathway enrichment-guided activity study of alternative splicing (PEGASAS), to correlate transcriptional signatures of 50 different cancer driver pathways with these alternative splicing events. We discovered that Myc signaling was correlated with incorporation of a set of 1,039 cassette exons enriched in genes encoding RNA binding proteins. Using a human prostate epithelial transformation assay, we confirmed the Myc regulation of 147 of these exons, many of which introduced frameshifts or encoded premature stop codons. Our results connect changes in alternative pre-mRNA splicing to oncogenic alterations common in prostate and many other cancers. We also establish a role for Myc in regulating RNA splicing by controlling the incorporation of nonsense-mediated decay-determinant exons in genes encoding RNA binding proteins.

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