Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue
| Autor: | Li Li, Paul B. McCray, Shyam Ramachandran, Rachel A. Hodos, Joel T. Dudley, Matthew D. Strub |
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| Rok vydání: | 2020 |
| Předmět: |
Cystic Fibrosis
Bioinformatics Science Mutant EGR1 Cystic Fibrosis Transmembrane Conductance Regulator Gene Expression Bronchi Computational biology Biology Cystic fibrosis Article Cell Line chemistry.chemical_compound Gene expression analysis Transcription (biology) Databases Genetic medicine Humans Gene Respiratory tract diseases Multidisciplinary Gene Expression Profiling Lumacaftor Computational Biology Genomics medicine.disease Protein Transport chemistry Mutation Unfolded protein response SGK1 Medicine Transcriptome |
| Zdroj: | Scientific Reports Scientific Reports, Vol 10, Iss 1, Pp 1-16 (2020) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-76347-0 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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