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Identification of a comprehensive alternative splicing function during epithelial-mesenchymal transition

ABSTRACT: Summary Epithelial-to-mesenchymal transition (EMT) is the underlying mechanism for tumor metastasis and shows the metastatic potential of tumor cells. Although the transcriptional regulation of EMT has been well studied, the role of alternative splicing (AS) regulation in EMT remains largely uncharacterized. The rapid accumulation of RNA-seq datasets has provided the opportunities for developing computational methods to associate mRNA isoform variations with EMT. In this study, we propose regularization models to identify significant AS events during EMT. Our experimental results confirm that the predicted AS events are closely related to apoptosis, focal adhesion-invadopodium shift and tight junction formation that are essential during EMT. Therefore, our study highlights the broad role of posttranscriptional regulation during EMT and identifies key subsets of AS events serving as distinct regulatory nodes. Graphical abstract Highlights • EMT-related AS events regulate the main characteristics of tumor cells• ESRP2 and LARP6 have opposite effects to TGF-β1 in regulating EMT-related AS events• HABP4 and WIBG have similar effects to TGF-β1 in regulating EMT-related AS events Molecular biology; Cell biology; Cancer

SUBMITTER: Qiu Y

PROVIDER: S-EPMC10140001 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Determination of a Comprehensive Alternative Splicing Regulatory Network and Combinatorial Regulation by Key Factors during the Epithelial-to-Mesenchymal Transition.

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Comprehensive Analysis of Alternative Splicing in Gastric Cancer Identifies Epithelial-Mesenchymal Transition Subtypes Associated with Survival.

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Commentary: HNRNPLL, a newly identified colorectal cancer metastasis suppressor, modulates alternative splicing of CD44 during epithelial-mesenchymal transition.

Project description: Not available

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Determination of a comprehensive alternative splicing regulatory network and the combinatorial regulation by key factors during Epithelial-to-Mesenchymal Transition

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-04-05 | E-GEOD-75492 | biostudies-arrayexpress

An ESRP-regulated splicing programme is abrogated during the epithelial-mesenchymal transition.

Project description:Alternative splicing achieves coordinated changes in post-transcriptional gene expression programmes through the activities of diverse RNA-binding proteins. Epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) are cell-type-specific regulators of transcripts that switch splicing during the epithelial-mesenchymal transition (EMT). To define a comprehensive programme of alternative splicing that is regulated during the EMT, we identified an extensive ESRP-regulated splicing network of hundreds of alternative splicing events within numerous genes with functions in cell-cell adhesion, polarity, and migration. Loss of this global ESRP-regulated epithelial splicing programme induces the phenotypic changes in cell morphology that are observed during the EMT. Components of this splicing signature provide novel molecular markers that can be used to characterize the EMT. Bioinformatics and experimental approaches revealed a high-affinity ESRP-binding motif and a predictive RNA map that governs their activity. This work establishes the ESRPs as coordinators of a complex alternative splicing network that adds an important post-transcriptional layer to the changes in gene expression that underlie epithelial-mesenchymal transitions during development and disease.

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PRKCSH Alternative Splicing Involves in Silica-Induced Expression of Epithelial-Mesenchymal Transition Markers and Cell Proliferation.

Project description:BackgroundMounting evidence suggests that alternative splicing is one of the ways for cells to adapt to environmental stress insults. The aim of this study was firstly to examine the effect of silica on the alternative splicing of lung fibrosis-associated genes.MethodsMicroarray analysis was used to construct the alternative splicing profile. Functional experiments were conducted using Cell Counting Kit-8, cell cycle, apoptosis, and epithelial-mesenchymal transition (EMT) analyses. Alternative splicing variants were verified by quantitative real-time polymerase chain reaction (qRT-PCR) polymerase chain reaction method.ResultsA total of 1850 genes that have alternative splices in response to silica insult were identified. PCDHB11, MALAT1, MT2A, RP11-126D17.1, and RP11-415I12.2 are the top 5 upregulated genes with occurrence of alternative splice, whereas NDE1, RNPEPL1, TREML2, CSF2RB, and PRKCSH are the top 5 downregulated genes with occurrence of alternative splice. Bioinformatic analysis showed these genes with the occurrence of alternative splice mainly are associated with EMT pathway, N-Glycan biosynthesis, and leukocyte transendothelial migration. Further study indicated that PRKCSH-2 knockdown promotes A549 cell proliferation potential by partially promoting EMT signals.ConclusionsSignificant changes in alternative splicing of silicosis-associated genes occur in patients with silicosis in silica conditions. Our study provides basic founding for further investigation into the detail molecular mechanisms underlying silica-induced silicosis.

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Determination of a comprehensive alternative splicing regulatory network and the combinatorial regulation by key factors during Epithelial-to-Mesenchymal Transition

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-04-05 | GSE75492 | GEO

Determination of a comprehensive alternative splicing regulatory network and the combinatorial regulation by key factors during Epithelial-to-Mesenchymal Transition [EMT.time course]

Project description:The epithelial to mesenchymal transition (EMT) is an essential biological process during embryonic development and has also been implicated in cancer metastasis. Previous studies have characterized transcriptional regulation and key transcription factors that impact EMT. However, the role of alternative splicing (AS) regulation in EMT has only recently emerged and remains relatively uncharacterized. Here we used a robust in vitro EMT model to dynamically and comprehensively characterize splicing switches during EMT in a temporal manner. We generated a H358 clone stably expressing a doxycycline (Dox)-inducible cDNA encoding a Zeb1-mCherry fusion protein. Over a 7-day time course following Dox treatment, cells have undergone EMT. We harvested total RNA and protein at each day of the EMT time course and a no Dox-treated control in biological triplicates. We made cDNA libraries for each replicate and subjected them to RNA-seq.

2016-04-05 | E-GEOD-75487 | biostudies-arrayexpress

Determination of a comprehensive alternative splicing regulatory network and the combinatorial regulation by key factors during Epithelial-to-Mesenchymal Transition [ESRP KD]

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2016-04-05 | E-GEOD-75489 | biostudies-arrayexpress

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