Ets Homologous Factor (EHF) has Critical Roles in Epithelial Dysfunction in Airway Disease [Gene Regulation]

The airway epithelium forms a barrier between the internal and external environments. Epithelial dysfunction is critical in the pathology of many respiratory diseases including cystic fibrosis (CF). Ets homologous factor (EHF) is a key member of the transcription factor (TF) network that regulates gene expression in the airway epithelium in response to endogenous and exogenous stimuli. EHF, which has altered expression in inflammatory states, maps to the 5 ′ end of an intergenic region on Chr11p13 that was implicated as a modifier of CF airway disease. Here we determine the functions of EHF in primary human bronchial epithelial (HBE) cells and relevant airway cell lines. Using EHF chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) and RNA-seq after EHF depletion, we show that EHF targets in HBE cells are enriched for genes involved in inflammation and wound repair. Furthermore, changes in gene expression impact cell phenotype, since EHF depletion alters epithelial secretion of a neutrophil chemokine and slows wound closure in HBE cells. EHF activates expression of the SAM pointed domain-containing ETS transcription factor (SPDEF), which contributes to goblet cell hyperplasia. Our data reveal a critical role for EHF in regulating epithelial function in lung disease.

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