An in vitro model of the epithelial airway reveals a key function for EHF in lung homeostasis and disease.

In the lung airways, multiple cell types facilitate airflow to alveoli, clearing out debris, particles and pathogens. 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-1α-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.