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...

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Autores principales:	Rachel A. Hodos, Matthew D. Strub, Shyam Ramachandran, Li Li, Paul B. McCray, Joel T. Dudley
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7df26fe9ff194bfba3a28caf8cd5a311
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spelling	oai:doaj.org-article:7df26fe9ff194bfba3a28caf8cd5a3112021-12-02T12:34:06ZIntegrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue10.1038/s41598-020-76347-02045-2322https://doaj.org/article/7df26fe9ff194bfba3a28caf8cd5a3112020-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-76347-0https://doaj.org/toc/2045-2322Abstract 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.Rachel A. HodosMatthew D. StrubShyam RamachandranLi LiPaul B. McCrayJoel T. DudleyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-16 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
title	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_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_sort	integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and δf508-cftr rescue
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/7df26fe9ff194bfba3a28caf8cd5a311
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Integrative genomic meta-analysis reveals novel molecular insights into cystic fibrosis and ΔF508-CFTR rescue

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