Journal article
Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue
Scientific reports, Vol.10(1), pp.20553-20553
11/25/2020
DOI: 10.1038/s41598-020-76347-0
PMCID: PMC7689470
PMID: 33239626
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.
Details
- Title: Subtitle
- Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue
- Creators
- Rachel A Hodos - Courant Institute of Mathematical SciencesMatthew D Strub - University of IowaShyam Ramachandran - Editas Medicine (United States)Li Li - Icahn School of Medicine at Mount SinaiPaul B McCray Jr - Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA, USA. paul-mccray@uiowa.eduJoel T Dudley - Icahn School of Medicine at Mount Sinai
- Resource Type
- Journal article
- Publication Details
- Scientific reports, Vol.10(1), pp.20553-20553
- DOI
- 10.1038/s41598-020-76347-0
- PMID
- 33239626
- PMCID
- PMC7689470
- NLM abbreviation
- Sci Rep
- ISSN
- 2045-2322
- eISSN
- 2045-2322
- Grant note
- T32 GM-008629 / NIGMS NIH HHS R01 HL-118000 / NHLBI NIH HHS P01 HL-51670 / NHLBI NIH HHS P01 HL-091842 / NHLBI NIH HHS P30 DK-54759 / NIDDK NIH HHS P30 DK054759 / NIDDK NIH HHS
- Language
- English
- Date published
- 11/25/2020
- Academic Unit
- Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Internal Medicine
- Record Identifier
- 9984297432502771
Metrics
14 Record Views