Mechanism of alternative splicing and its regulation

Wang, Yan; Liu, Jing; Huang, Bo; Xu, Ye; Li, Jing; Huang, Linfeng; Lin, Jen‐Kou; Zhang, Jing; Min, Qing‐Hua; Yang, Weiming; Wang, Xiaozhong

doi:10.3892/br.2014.407

Cited by 330 publications

(292 citation statements)

References 80 publications

(69 reference statements)

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“…AS regulation is complex and involves both cis -acting elements (exonic or intronic splicing enhancers and silencers) and trans -acting factors (serine-arginine (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs)), as well as RNA and chromatin structures [15]. Among mechanisms responsible for AS regulation, the production of circular RNAs (circRNAs) has been recently hypothesized.…”

Section: Introductionmentioning

confidence: 99%

The Characterization of GSDMB Splicing and Backsplicing Profiles Identifies Novel Isoforms and a Circular RNA That Are Dysregulated in Multiple Sclerosis

Cardamone

Paraboschi

Rimoldi

et al. 2017

IJMS

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Abnormalities in alternative splicing (AS) are emerging as recurrent features in autoimmune diseases (AIDs). In particular, a growing body of evidence suggests the existence of a pathogenic association between a generalized defect in splicing regulatory genes and multiple sclerosis (MS). Moreover, several studies have documented an unbalance in alternatively-spliced isoforms in MS patients possibly contributing to the disease etiology. In this work, using a combination of PCR-based techniques (reverse-transcription (RT)-PCR, fluorescent-competitive, real-time, and digital RT-PCR assays), we investigated the alternatively-spliced gene encoding Gasdermin B, GSDMB, which was repeatedly associated with susceptibility to asthma and AIDs. The in-depth characterization of GSDMB AS and backsplicing profiles led us to the identification of an exonic circular RNA (ecircRNA) as well as of novel GSDMB in-frame and out-of-frame isoforms. The non-productive splicing variants were shown to be downregulated by the nonsense-mediated mRNA decay (NMD) in human cell lines, suggesting that GSDMB levels are significantly modulated by NMD. Importantly, both AS isoforms and the identified ecircRNA were significantly dysregulated in peripheral blood mononuclear cells of relapsing-remitting MS patients compared to controls, further supporting the notion that aberrant RNA metabolism is a characteristic feature of the disease.

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Section: Introductionmentioning

confidence: 99%

The Characterization of GSDMB Splicing and Backsplicing Profiles Identifies Novel Isoforms and a Circular RNA That Are Dysregulated in Multiple Sclerosis

Cardamone

Paraboschi

Rimoldi

et al. 2017

IJMS

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“…This splicing mechanism has gained a great deal of interest as it has been shown to generate a variety of proteins from a single pre-mature transcript (Wang et al , 2015). Significant amounts of mammalian genes undergo alternative splicing, which ultimately generates a huge array of proteins that outnumbers the total number of genes that are present in the body (International Human Genome Sequencing, 2004; Mazin et al , 2013; McLean et al , 2012; Wang et al , 2015; Xu et al , 2002). α-SYN gene is no exception, as it also undergoes alternative splicing (Beyer and Ariza, 2013; McLean et al , 2012).…”

Section: Regulation Of α-Synuclein Expression and Parkinson’s Diseasementioning

confidence: 99%

Deregulation of α-synuclein in Parkinson’s disease: Insight from epigenetic structure and transcriptional regulation of SNCA

Guhathakurta

Bok

Evangelista

et al. 2017

Progress in Neurobiology

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Understanding regulation of α-synuclein has long been a central focus for Parkinson’s disease (PD) researchers. Accumulation of this protein in the Lewy body or neurites, mutations in the coding region of the gene and strong association of α-synuclein encoding gene multiplication (duplication/triplication) with familial form of PD have indicated the importance of this molecule in pathogenesis of the disease. Several years of research identified many potential faulty pathways associated with accumulation of α-synuclein inside dopaminergic neurons and its transmission to neighboring ones. Concurrently, an appreciable body of research is growing to understand the epigenetic and genetic deregulation of α-synuclein that might contribute to the disease pathology. Completion of the ENCODE (Encyclopedia of DNA Elements) project and recent advancement made in the epigenetic and trans factor mediated regulation of each gene, has tremendously accelerated the need to carefully understand the epigenetic structure of the gene (SNCA) encoding α-synuclein protein in order to decipher the regulation and contribution of α-synuclein to the pathogenesis of PD. We have also analyzed the detailed epigenetic structure of this gene with knowledge from ENCODE database, which may open new avenues in α-synuclein research. Interestingly, we have found that the gene contains several transcriptionally activate histone modifications and associated potential transcription factor binding sites in the non-coding areas that strongly suggest alternative regulatory pathways. Altogether this review will provide interesting insight of α-synuclein gene regulation from epigenetic, genetic and post-transcriptional perspectives and their potential implication in the PD pathogenesis.

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“…Additionally, alternative selection of 5' and 3' splice sites, coupled with variable adenylation of the transcript, results in further modification of protein products (Gueroussov et al, 2015;Tian & Manley, 2017). The splicing process consists of two major steps: assembly of the spliceosome and the actual splicing of pre-mRNA (Wang et al, 2015). In brief, the spliceosome is comprised of several small nuclear ribonucleoproteins that positionally establish the 5' splice site, the branch point sequence, and the 3' site.…”

Section: Introductionmentioning

confidence: 99%

“…In brief, the spliceosome is comprised of several small nuclear 110 ribonucleoproteins that positionally establish the 5' splice site, the branch point sequence, and the 3' site. An assembly of spliceosome complexes and eight evolutionarily-conserved RNA-dependent ATPases/helicases is then followed by the execution of numerous splicing steps, ultimately resulting in exon excision, exon ligation, or intron retention (Wang et al, 2015). The inclusion of an exon in the final mRNA product is entirely driven by cis-and trans-acting elements/factors.…”

Section: Introductionmentioning

confidence: 99%

Stress-mediated convergence of splicing landscapes in male and female Rock Doves

Lang

MacManes

Calisi

et al. 2019

Preprint

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Background: The process of alternative splicing provides a unique mechanism by which eukaryotes are able to produce numerous protein products from the same gene. Heightened variability in the proteome has been thought to potentiate increased behavioral complexity and response flexibility to environmental stimuli, thus contributing to more refined traits on which natural and sexual selection can act. While it has been long known that various forms of environmental stress can negatively affect sexual behavior and reproduction, we know little of how stress can affect the alternative splicing associated with these events, and less still about how splicing may differ between sexes. Using the model of the rock dove (Columba livia), our team previously uncovered sexual dimorphism in the basal and stress-responsive gene transcription of a biological system necessary for facilitating sexual behavior and reproduction, the hypothlamic-pituitary-gonadal (HPG) axis. In this study, we delve further into understanding the mechanistic underpinnings of how changes in the environment can affect reproduction by testing the alternative splicing response of the HPG axis to an external stressor in both sexes.Results: This study reveals dramatic baseline differences in HPG alternative splicing between males and females. However, post submitting subjects to a restraint stress paradigm, we found a significant reduction in these differences between the sexes. In both stress and control treatments, we identified a higher incidence of splicing activity in the pituitary in both sexes as compared to other tissues. Of these splicing events, the core exon event is the most abundant form of splicing and more frequently occurs in the coding regions of the gene. Overall, we observed less splicing activity in the 3'UTR end of transcripts than the 5'UTR or coding regions. Conclusions:Our results provide vital new insight into sex-specific aspects of the stress response on the HPG axis at an unprecedented proximate level. Males and females uniquely respond to stress, yet exhibit splicing patterns suggesting a convergent, optimal splicing landscape for stress response. This information has the potential to inform evolutionary theory as well as the development of highly-specific drug targets for stress-induced reproductive dysfunction.

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Mechanism of alternative splicing and its regulation

Cited by 330 publications

References 80 publications

The Characterization of GSDMB Splicing and Backsplicing Profiles Identifies Novel Isoforms and a Circular RNA That Are Dysregulated in Multiple Sclerosis

The Characterization of GSDMB Splicing and Backsplicing Profiles Identifies Novel Isoforms and a Circular RNA That Are Dysregulated in Multiple Sclerosis

Deregulation of α-synuclein in Parkinson’s disease: Insight from epigenetic structure and transcriptional regulation of SNCA

Stress-mediated convergence of splicing landscapes in male and female Rock Doves

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