Ets Homologous Factor Regulates Genes Involved in Airway Epithelial Development, Function and Response to Injury

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The airway epithelium forms an active barrier between the internal and external environments and has multiple roles critical to normal function of the lung. Its development and function are controlled by a network of transcription factors that regulate gene expression in response to varying stimuli. Dysfunction of this tissue plays an important role in pathogenesis of multiple pulmonary diseases, including cystic fibrosis (CF). Ets homologous factor (EHF) is a transcription factor that is expressed in the airway epithelium, and its levels are altered in inflammatory states. EHF maps adjacent to an intergenic region that has been implicated as a modifier of CF airway disease through a replicated genome-wide association study. The role of EHF in regulation of gene expression in the bronchial epithelium was investigated. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) identified a binding signature for EHF in Calu-3 lung adenocarcinoma and primary human bronchial epithelial (HBE) cells. EHF binding sites were enriched at promoters and for corresponding histone modifications. In Calu-3 cells, regions of EHF occupancy overlap those of activator protein-1 (AP-1) genome-wide, and these sites are found near loci important for epithelial differentiation and wound repair. EHF modulation followed by RNA-sequencing (RNA-seq) in Calu-3 cells and A549 lung carcinoma cells altered expression of genes involved in epithelial differentiation, barrier function and response to wounding. RNA-seq after EHF depletion in primary HBE cells identified putative direct targets that are enriched for genes involved in degradation of response to wounding, the immune response, and gene regulation. EHF expression is increased by the Th2 interleukin IL-13. EHF increases levels of the SAM pointed domain-containing ETS transcription factor (SPDEF), a target of IL-13-induced signaling that contributes to goblet cell hyperplasia in the airway epithelium. Furthermore, EHF represses the cystic fibrosis transmembrane conductance regulator (CFTR) locus. Changes in gene expression correspond to alterations in cell phenotype; EHF depletion slows wound repair and alters secretion of a neutrophil chemokine. In summary, these results support a strong role for EHF in regulating epithelial function in CF and other airway diseases

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  • 02/20/2018
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