Transcriptomic profile of cystic fibrosis patients identifies type I interferon response and ribosomal stalk proteins as potential modifiers of disease severity

Kormann, Michael; Dewerth, Alexander; Eichner, Felizitas A.; Baskaran, Praveen; Hector, Andreas; Regamey, Nicolas; Hartl, Dominik; Handgretinger, Rupert; Antony, Justin S.

doi:10.1371/journal.pone.0183526

Cited by 24 publications

(28 citation statements)

References 45 publications

(54 reference statements)

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“…Several previous studies have studied the role of host gene regulation in CF patients [5,68]. While results from previous studies are based on either phenotypic observations, examining candidate genes such as CFTR, or an exploration of gene expression data from respiratory or blood samples [5,69], our work is the first, as far as we know, that focused on a comprehensive transcriptomic analysis of colon biopsies.…”

Section: Discussionmentioning

confidence: 99%

Interactions between the gut microbiome and host gene regulation in cystic fibrosis

et al. 2020

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Background: Cystic fibrosis is the most common autosomal recessive genetic disease in Caucasians. It is caused by mutations in the CFTR gene, leading to poor hydration of mucus and impairment of the respiratory, digestive, and reproductive organ functions. Advancements in medical care have led to markedly increased longevity of patients with cystic fibrosis, but new complications have emerged, such as early onset of colorectal cancer. Although the pathogenesis of colorectal cancer in cystic fibrosis remains unclear, altered host-microbe interactions might play a critical role. To investigate this, we characterized changes in the microbiome and host gene expression in the colonic mucosa of cystic fibrosis patients relative to healthy controls, and identified host gene-microbiome interactions in the colon of cystic fibrosis patients. Methods: We performed RNA-seq on colonic mucosa samples from cystic fibrosis patients and healthy controls to determine differentially expressed host genes. We also performed 16S rRNA sequencing to characterize the colonic mucosal microbiome and identify gut microbes that are differentially abundant between patients and healthy controls. Lastly, we modeled associations between relative abundances of specific bacterial taxa in the gut mucosa and host gene expression. Results: We find that 1543 genes, including CFTR, show differential expression in the colon of cystic fibrosis patients compared to healthy controls. These genes are enriched with functions related to gastrointestinal and colorectal cancer, such as metastasis of colorectal cancer, tumor suppression, p53, and mTOR signaling pathways. In addition, patients with cystic fibrosis show decreased gut microbial diversity, decreased abundance of butyrate producing bacteria, such as Ruminococcaceae and Butyricimonas, and increased abundance of other taxa, such as Actinobacteria and Clostridium. An integrative analysis identified colorectal cancer-related genes, including LCN2 and DUOX2, for which gene expression is correlated with the abundance of colorectal cancer-associated bacteria, such as Ruminococcaceae and Veillonella. Conclusions: In addition to characterizing host gene expression and mucosal microbiome in cystic fibrosis patients, our study explored the potential role of host-microbe interactions in the etiology of colorectal cancer in cystic fibrosis. Our results provide biomarkers that may potentially serve as targets for stratifying risk of colorectal cancer in patients with cystic fibrosis.

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Section: Discussionmentioning

confidence: 99%

Interactions between the gut microbiome and host gene regulation in cystic fibrosis

et al. 2020

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“…An additional transcriptomic study comparing the peripheral blood leukocytes of CF subjects with mild and severe lung disease was performed by Kormann et al [64] Enrichment analyses identified genes of the type I interferon response, as well as ribosomal stalk proteins, as upregulated in mild disease. Such modifiers of CF lung disease may have implications as new biomarkers or targets for intervention.…”

Section: Mrna Profilingmentioning

confidence: 99%

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Strub

McCray

2020

Genes

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Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The diversity of mutations and the multiple ways by which the protein is affected present challenges for therapeutic development. The observation that the Phe508del-CFTR mutant protein is temperature sensitive provided proof of principle that mutant CFTR could escape proteosomal degradation and retain partial function. Several specific protein interactors and quality control checkpoints encountered by CFTR during its proteostasis have been investigated for therapeutic purposes, but remain incompletely understood. Furthermore, pharmacological manipulation of many CFTR interactors has not been thoroughly investigated for the rescue of Phe508del-CFTR. However, high-throughput screening technologies helped identify several small molecule modulators that rescue CFTR from proteosomal degradation and restore partial function to the protein. Here, we discuss the current state of CFTR transcriptomic and biogenesis research and small molecule therapy development. We also review recent progress in CFTR proteostasis modulators and discuss how such treatments could complement current FDA-approved small molecules.

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“…Transcriptomic analyses in airway cell lines and nasal epithelial cell samples showed expression changes in genes involved in cell proliferation, inflammation and immune responses, protein metabolism, and calcium and membrane pathways [22][23][24]. More recently, blood samples from CF patients presenting either severe or mild lung disease were analyzed: genes of the type I interferon response and ribosomal stalk proteins were differentially expressed [25]. However, no healthy subjects were compared with CF patients in that study.…”

Section: Discussionmentioning

confidence: 97%

Blood co-expression modules identify potential modifier genes of diabetes and lung function in cystic fibrosis

et al. 2020

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Cystic fibrosis (CF) is a rare genetic disease that affects the respiratory and digestive systems. Lung disease is variable among CF patients and associated with the development of comorbidities and chronic infections. The rate of lung function deterioration depends not only on the type of mutations in CFTR, the disease-causing gene, but also on modifier genes. In the present study, we aimed to identify genes and pathways that (i) contribute to the pathogenesis of cystic fibrosis and (ii) modulate the associated comorbidities. We profiled blood samples in CF patients and healthy controls and analyzed RNA-seq data with Weighted Gene Correlation Network Analysis (WGCNA). Interestingly, lung function, body mass index, the presence of diabetes, and chronic P. aeruginosa infections correlated with four modules of co-expressed genes. Detailed inspection of networks and hub genes pointed to cell adhesion, leukocyte trafficking and production of reactive oxygen species as central mechanisms in lung function decline and cystic fibrosis-related diabetes. Of note, we showed that blood is an informative surrogate tissue to study the contribution of inflammation to lung disease and diabetes in CF patients. Finally, we provided evidence that WGCNA is useful to analyze-omic datasets in rare genetic diseases as patient cohorts are inevitably small.

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Transcriptomic profile of cystic fibrosis patients identifies type I interferon response and ribosomal stalk proteins as potential modifiers of disease severity

Cited by 24 publications

References 45 publications

Interactions between the gut microbiome and host gene regulation in cystic fibrosis

Interactions between the gut microbiome and host gene regulation in cystic fibrosis

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Blood co-expression modules identify potential modifier genes of diabetes and lung function in cystic fibrosis

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