Transcriptome meta-analysis reveals common differential and global gene expression profiles in cystic fibrosis and other respiratory disorders and identifies CFTR regulators

Clarke, Luka A.; Botelho, Hugo M.; Sousa, Lisete; Falcão, André O.; Amaral, Margarida D.

doi:10.1016/j.ygeno.2015.07.005

Cited by 32 publications

(33 citation statements)

References 64 publications

(102 reference statements)

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“…23 our own meta-analysis of data of gene expression profile revealed that CF nasal cells' have a significant overlap with genes related to undifferentiated epithelial phenotype 62 .…”

Section: Accepted Manuscriptmentioning

confidence: 92%

Human Epididymis Protein 4: A Novel Serum Inflammatory Biomarker in Cystic Fibrosis

Nagy

Fila

Clarke

et al. 2016

Chest

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“…23 our own meta-analysis of data of gene expression profile revealed that CF nasal cells' have a significant overlap with genes related to undifferentiated epithelial phenotype 62 .…”

Section: Accepted Manuscriptmentioning

confidence: 92%

Human Epididymis Protein 4: A Novel Serum Inflammatory Biomarker in Cystic Fibrosis

Nagy

Fila

Clarke

et al. 2016

Chest

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“…Many studies have reported that CFTR functions as a tumour suppressor 14 – 16 , and some suggested a link between CFTR downregulation in tumour cells and induction of epithelial–mesenchymal transition (EMT) 17 – 19 . Recent transcriptional profiling analysis revealed impaired epithelial differentiation and an EMT signature in CF airways 20 . However, it is unknown whether EMT is indeed active in CF and if so, what is the trigger, dysfunctional CFTR or a secondary disease event (e.g., chronic inflammation).…”

Section: Introductionmentioning

confidence: 99%

Mutant CFTR Drives TWIST1 mediated epithelial–mesenchymal transition

et al. 2020

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Cystic fibrosis (CF) is a monogenetic disease resulting from mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene encoding an anion channel. Recent evidence indicates that CFTR plays a role in other cellular processes, namely in development, cellular differentiation and wound healing. Accordingly, CFTR has been proposed to function as a tumour suppressor in a wide range of cancers. Along these lines, CF was recently suggested to be associated with epithelial–mesenchymal transition (EMT), a latent developmental process, which can be re-activated in fibrosis and cancer. However, it is unknown whether EMT is indeed active in CF and if EMT is triggered by dysfunctional CFTR itself or a consequence of secondary complications of CF. In this study, we investigated the occurrence of EMT in airways native tissue, primary cells and cell lines expressing mutant CFTR through the expression of epithelial and mesenchymal markers as well as EMT-associated transcription factors. Transepithelial electrical resistance, proliferation and regeneration rates, and cell resistance to TGF-β1induced EMT were also measured. CF tissues/cells expressing mutant CFTR displayed several signs of active EMT, namely: destructured epithelial proteins, defective cell junctions, increased levels of mesenchymal markers and EMT-associated transcription factors, hyper-proliferation and impaired wound healing. Importantly, we found evidence that the mutant CFTR triggered EMT was mediated by EMT-associated transcription factor TWIST1. Further, our data show that CF cells are over-sensitive to EMT but the CF EMT phenotype can be reversed by CFTR modulator drugs. Altogether, these results identify for the first time that EMT is intrinsically triggered by the absence of functional CFTR through a TWIST1 dependent mechanism and indicate that CFTR plays a direct role in EMT protection. This mechanistic link is a plausible explanation for the high incidence of fibrosis and cancer in CF, as well as for the role of CFTR as tumour suppressor protein.

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“…Transcriptome analysis documented 873 differentially expressed genes (DEGs) in IPF, and reported significant alternative splicing of 440 genes (Nance et al, ). Comparative transcriptome analyses on IPF, airway epithelial injury and cystic fibrosis demonstrated a strong association of genes in dedifferentiation and epithelial injury, and implied that transcriptional modulations might be commonly observed in the processes including epithelial–mesenchymal transition and inflammation for respiratory fibrogenic diseases (Clarke, Botelho, Sousa, Falcao, & Amaral, ). Nevertheless, the pathogenesis and molecular mechanistic details of IPF may not appropriately represent those of silicosis, and transcriptional evaluations specifically focused on airborne silica toxicity are in demand.…”

Section: Introductionmentioning

confidence: 99%

Comparative RNA‐Seq transcriptome analysis on silica induced pulmonary inflammation and fibrosis in mice silicosis model

Chen

Yao

et al. 2018

J of Applied Toxicology

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Silicosis is a long-established public health issue in developing countries due to increasingly serious air pollution and poorly implemented occupational safety regulation. Inhalation of silica triggers cytotoxicity, oxidative stress, pulmonary inflammation and eventually silicosis. Current understanding in the pathogenesis and mechanism of silicosis is limited, and no effective cure is clinically available once silicosis is developed. A number of studies were conducted to investigate silica-induced alternate gene expressions in pulmonary cells. However, transcriptome analysis in a silicosis animal model is needed. This study was performed to evaluate the transcriptional alternations in silicotic mice using comparative RNA-Seq. A silicosis mice model was established by intratracheal instillation of silica suspensions, and validated by histological examinations. High-throughput sequencing and differential gene expression analysis revealed 749 upregulated genes and 70 downregulated genes in the silicosis model. Genes related to immune cell interactions, immune cell responses and inflammation were significantly enriched. Cytokine-cytokine receptor interaction and downstream JAK-STAT signaling pathways were the most significantly enriched KEGG pathways. Reverse transcription-polymerase chain reaction analysis and immunohistochemistry were performed to validate further the differential expression patterns of representative genes. The reported results in this study provide the basis for elucidating the molecular mechanisms for silica-induced pulmonary inflammation and fibrosis, and support the prevention and treatment of silicosis.

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Transcriptome meta-analysis reveals common differential and global gene expression profiles in cystic fibrosis and other respiratory disorders and identifies CFTR regulators

Cited by 32 publications

References 64 publications

Human Epididymis Protein 4: A Novel Serum Inflammatory Biomarker in Cystic Fibrosis

Human Epididymis Protein 4: A Novel Serum Inflammatory Biomarker in Cystic Fibrosis

Mutant CFTR Drives TWIST1 mediated epithelial–mesenchymal transition

Comparative RNA‐Seq transcriptome analysis on silica induced pulmonary inflammation and fibrosis in mice silicosis model

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