Ets homologous factor (EHF) has critical roles in epithelial dysfunction in airway disease
Ets homologous factor (EHF) has critical roles in epithelial dysfunction in airway disease
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DOI：
10.1074/jbc.m117.775304
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发表时间：
2017-06-30
影响因子：
4.8
通讯作者：
Harris, Ann
中科院分区：
文献类型：
--
作者：
Fossum, Sara L.;Mutolo, Michael J.;Harris, Ann
气道上皮在内部和外部环境之间形成屏障。上皮功能障碍在许多呼吸系统疾病的病理学中是至关重要的，包括囊性纤维化。Ets同源因子（EHF）是转录因子网络中的一个关键成员，它调节气道上皮细胞对内源性和外源性刺激的基因表达。EHF在炎症状态下表达改变，定位于Chr 11 p13基因间区域的5'端，该区域与囊性纤维化气道疾病的修饰有关。在这里，我们确定EHF在原代人支气管上皮（HBE）细胞和相关气道细胞系的功能。使用EHF ChIP，然后在EHF耗尽后进行深度测序（ChIP-seq）和RNA测序，我们表明HBE细胞中的EHF靶点富含参与炎症和伤口修复的基因。此外，基因表达的变化影响细胞表型，因为EHF耗竭改变了上皮细胞中性粒细胞趋化因子的分泌，减缓了HBE细胞的伤口闭合。EHF激活含有SAM指向结构域的ETS转录因子的表达，这有助于杯状细胞增生。我们的数据揭示了EHF在肺疾病中调节上皮功能的关键作用。
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. Ets homologous factor (EHF) is a key member of the transcription factor 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 is implicated as a modifier of cystic fibrosis airway disease. Here we determine the functions of EHF in primary human bronchial epithelial (HBE) cells and relevant airway cell lines. Using EHF ChIP followed by deep sequencing (ChIP-seq) and RNA sequencing 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 because 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, which contributes to goblet cell hyperplasia. Our data reveal a critical role for EHF in regulating epithelial function in lung disease.