Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue
Abstract Cystic fibrosis (CF), caused by mutations to CFTR, leads to severe and progressive lung disease. The most common mutant, ΔF508-CFTR, undergoes proteasomal degradation, extinguishing its anion channel function. Numerous in vitro interventions have been identified to partially rescue ΔF508-CF...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2020-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-020-76347-0 |
| _version_ | 1818681341116416000 |
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| author | Rachel A. Hodos Matthew D. Strub Shyam Ramachandran Li Li Paul B. McCray Joel T. Dudley |
| author_facet | Rachel A. Hodos Matthew D. Strub Shyam Ramachandran Li Li Paul B. McCray Joel T. Dudley |
| author_sort | Rachel A. Hodos |
| collection | DOAJ |
| description | Abstract Cystic fibrosis (CF), caused by mutations to CFTR, leads to severe and progressive lung disease. The most common mutant, ΔF508-CFTR, undergoes proteasomal degradation, extinguishing its anion channel function. Numerous in vitro interventions have been identified to partially rescue ΔF508-CFTR function yet remain poorly understood. Improved understanding of both the altered state of CF cells and the mechanisms of existing rescue strategies could reveal novel therapeutic strategies. Toward this aim, we measured transcriptional profiles of established temperature, genetic, and chemical interventions that rescue ΔF508-CFTR and also re-analyzed public datasets characterizing transcription in human CF vs. non-CF samples from airway and whole blood. Meta-analysis yielded a core disease signature and two core rescue signatures. To interpret these through the lens of prior knowledge, we compiled a “CFTR Gene Set Library” from literature. The core disease signature revealed remarkably strong connections to genes with established effects on CFTR trafficking and function and suggested novel roles of EGR1 and SGK1 in the disease state. Our data also revealed an unexpected mechanistic link between several genetic rescue interventions and the unfolded protein response. Finally, we found that C18, an analog of the CFTR corrector compound Lumacaftor, induces almost no transcriptional perturbation despite its rescue activity. |
| first_indexed | 2024-12-17T10:01:24Z |
| format | Article |
| id | doaj.art-7df26fe9ff194bfba3a28caf8cd5a311 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-17T10:01:24Z |
| publishDate | 2020-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-7df26fe9ff194bfba3a28caf8cd5a3112022-12-21T21:53:17ZengNature PortfolioScientific Reports2045-23222020-11-0110111610.1038/s41598-020-76347-0Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescueRachel A. Hodos0Matthew D. Strub1Shyam Ramachandran2Li Li3Paul B. McCray4Joel T. Dudley5Mount Sinai School of Medicine, Institute for Next Generation HealthcareDepartment of Pediatrics, Carver College of Medicine, University of IowaDepartment of Pediatrics, Carver College of Medicine, University of IowaMount Sinai School of Medicine, Institute for Next Generation HealthcareDepartment of Pediatrics, Carver College of Medicine, University of IowaMount Sinai School of Medicine, Institute for Next Generation HealthcareAbstract Cystic fibrosis (CF), caused by mutations to CFTR, leads to severe and progressive lung disease. The most common mutant, ΔF508-CFTR, undergoes proteasomal degradation, extinguishing its anion channel function. Numerous in vitro interventions have been identified to partially rescue ΔF508-CFTR function yet remain poorly understood. Improved understanding of both the altered state of CF cells and the mechanisms of existing rescue strategies could reveal novel therapeutic strategies. Toward this aim, we measured transcriptional profiles of established temperature, genetic, and chemical interventions that rescue ΔF508-CFTR and also re-analyzed public datasets characterizing transcription in human CF vs. non-CF samples from airway and whole blood. Meta-analysis yielded a core disease signature and two core rescue signatures. To interpret these through the lens of prior knowledge, we compiled a “CFTR Gene Set Library” from literature. The core disease signature revealed remarkably strong connections to genes with established effects on CFTR trafficking and function and suggested novel roles of EGR1 and SGK1 in the disease state. Our data also revealed an unexpected mechanistic link between several genetic rescue interventions and the unfolded protein response. Finally, we found that C18, an analog of the CFTR corrector compound Lumacaftor, induces almost no transcriptional perturbation despite its rescue activity.https://doi.org/10.1038/s41598-020-76347-0 |
| spellingShingle | Rachel A. Hodos Matthew D. Strub Shyam Ramachandran Li Li Paul B. McCray Joel T. Dudley Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue Scientific Reports |
| title | Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue |
| title_full | Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue |
| title_fullStr | Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue |
| title_full_unstemmed | Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue |
| title_short | Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue |
| title_sort | integrative genomic meta analysis reveals novel molecular insights into cystic fibrosis and δf508 cftr rescue |
| url | https://doi.org/10.1038/s41598-020-76347-0 |
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