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These vital processes are impeded in chronic inflammatory respiratory diseases, in which the epithelium typically suffers from inflammation, infections and hypoxia. An increasing body of evidence highlights the critical role of modifier genes in responses and resistance against these pathogenic processes. Here, we sought to study the transcription factor EHF, suggested by previous studies as a putative modifier gene, yet its functional role remains ambiguous. To explore this question, we knocked out EHF in human induced pluripotent stem cell-derived lung cells and examined the subsequent phenotypic and functional impacts. Loss of EHF enhanced cystic fibrosis transmembrane conductance regulator activity, led to transcriptomic changes in basal cells, increased transepithelial electrical resistance and reduced HIF-1\u03b1-mediated response to hypoxia. Here, we show that variation in EHF expression can impact lung diseases through several mechanisms, thereby highlighting prospects for novel therapies.<\/jats:p>","DOI":"10.1242\/dmm.052106","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T12:48:02Z","timestamp":1751374082000},"source":"Crossref","is-referenced-by-count":2,"title":["An <i>in vitro<\/i> model of the epithelial airway reveals a key function for EHF in lung homeostasis and disease"],"prefix":"10.1242","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2732-8949","authenticated-orcid":false,"given":"Laetitia","family":"Pinte","sequence":"first","affiliation":[{"name":"Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge 1 , Cambridge CB2 0AW ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Vila-Gonzalez","sequence":"additional","affiliation":[{"name":"Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge 1 , Cambridge CB2 0AW ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor C.","family":"Williams","sequence":"additional","affiliation":[{"name":"Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge 1 , Cambridge CB2 0AW ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Causa","sequence":"additional","affiliation":[{"name":"University of Cambridge 2 Cavendish Laboratory , , Cambridge CB3 0HE ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Fradique","sequence":"additional","affiliation":[{"name":"University of Cambridge 2 Cavendish Laboratory , , Cambridge CB3 0HE ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tekle","family":"Pauzaite","sequence":"additional","affiliation":[{"name":"Cambridge Institute of Therapeutic and Infectious Disease, University of Cambridge 3 , Cambridge CB2 0AW ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Passemar","sequence":"additional","affiliation":[{"name":"University of Cambridge 4 MRC Laboratory of Molecular Biology , , Cambridge CB2 0AW ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Becca","sequence":"additional","affiliation":[{"name":"Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge 1 , Cambridge CB2 0AW ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Gribben","sequence":"additional","affiliation":[{"name":"Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge 1 , Cambridge CB2 0AW ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiqi","family":"Ye","sequence":"additional","affiliation":[{"name":"Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge 1 , Cambridge CB2 0AW ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha","family":"Al-Thani","sequence":"additional","affiliation":[{"name":"University of Cambridge and NIHR Cambridge Biomedical Research Centre 5 Department of Surgery , , Cambridge CB2 0AW ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Bachinger","sequence":"additional","affiliation":[{"name":"Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge 1 , Cambridge CB2 0AW ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floris J. M.","family":"Roos","sequence":"additional","affiliation":[{"name":"Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge 1 , Cambridge CB2 0AW ,","place":["UK"]},{"name":"University of Cambridge and NIHR Cambridge Biomedical Research Centre 5 Department of Surgery , , Cambridge CB2 0AW ,","place":["UK"]},{"name":"Cambridge University Hospitals NHS Foundation Trust 6 Department of Surgery , , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"Nathan","sequence":"additional","affiliation":[{"name":"Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge 1 , Cambridge CB2 0AW ,","place":["UK"]},{"name":"Cambridge Institute of Therapeutic and Infectious Disease, University of Cambridge 3 , Cambridge CB2 0AW ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Mohorianu","sequence":"additional","affiliation":[{"name":"Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge 1 , Cambridge CB2 0AW ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Floto","sequence":"additional","affiliation":[{"name":"University of Cambridge 7 Stroke Research Group, Department of Clinical Neurosciences , , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Cicuta","sequence":"additional","affiliation":[{"name":"University of Cambridge 2 Cavendish Laboratory , , Cambridge CB3 0HE ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovic","family":"Vallier","sequence":"additional","affiliation":[{"name":"Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge 1 , Cambridge CB2 0AW ,","place":["UK"]},{"name":"Berlin Institute of Health, Center for Regenerative Therapies 8 , Augustenburger Platz 1, 13353 Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"2025070211320796000_DMM052106C1","doi-asserted-by":"publisher","first-page":"2889","DOI":"10.1158\/0008-5472.CAN-12-0212","article-title":"ESE3\/EHF controls epithelial cell differentiation and its loss leads to prostate tumors with mesenchymal and stem-like features","volume":"72","author":"Albino","year":"2012","journal-title":"Cancer Res."},{"key":"2025070211320796000_DMM052106C2","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/j.jcv.2014.10.004","article-title":"The roles of ADAM33, ADAM28, IL-13 and IL-4 in the development of lung injuries in children with lethal non-pandemic acute infectious pneumonia","volume":"61","author":"Baurakiades","year":"2014","journal-title":"J. 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