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Has Critical Roles in Epithelial Dysfunction in Airway Disease JBC Papers in Press. Published on May 1, 2017 as Manuscript M117.775304 The latest version is at http://www.jbc.org/cgi/doi/10.1074/jbc.M117.775304 EHF has critical roles in airway epithelial dysfunction Ets Homologous Factor (EHF) has critical roles in epithelial dysfunction in airway disease Sara L Fossum1,2, Michael J. Mutolo1,2, Antonio Tugores3, Sujana Ghosh1,2, Scott H. Randell4, Lisa C. Jones4, Shih-Hsing Leir1,2,5, Ann Harris1,2,5 1Human Molecular Genetics Program, Lurie Children’s Research Center, Chicago, IL 60614, USA, 2Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA, 3 Unidad de Investigación, Complejo Hospitalario Universitario Insular Materno Infantil, Las Palmas de Gran Canaria, Spain, 4Marsico Lung Institute, University of North Carolina Cystic Fibrosis Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA, 5 Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44016, USA Running title: EHF has critical roles in airway epithelial dysfunction Downloaded from To whom correspondence should be addressed: Ann Harris, Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio, 44106; Email: [email protected] http://www.jbc.org/ Keywords: genomics, gene regulation, epithelium, lung, transcription factor at University of North Carolina Chapel Hill on August 16, 2019 ABSTRACT The airway epithelium forms a barrier between the internal and external environments. The airway epithelium plays a critical role Epithelial dysfunction is critical in the pathology in lung function in both normal and pathological of many respiratory diseases including cystic states. It forms an active barrier between the fibrosis (CF). Ets homologous factor (EHF) is a external and internal environments, responding to key member of the transcription factor (TF) a wide range of stimuli. Because this cell layer is network that regulates gene expression in the constantly exposed to the outside atmosphere, it airway epithelium in response to endogenous and has developed mechanisms to respond rapidly to exogenous stimuli. EHF, which has altered external insults. Following mechanical damage, expression in inflammatory states, maps to the 5’ the epithelial cells proliferate and migrate to close end of an intergenic region on Chr11p13 that was the resulting wound (1). In response to foreign implicated as a modifier of CF airway disease. pathogens and particles, the cells release immune Here we determine the functions of EHF in factors (2). The airway epithelium also drives the primary human bronchial epithelial (HBE) cells mucociliary escalator, which physically removes and relevant airway cell lines. Using EHF debris from the lungs (3,4). In the presence of chromatin immunoprecipitation followed by deep chronic damage or infection, these pathways can sequencing (ChIP-seq) and RNA-seq after EHF malfunction and contribute to lung pathology in depletion, we show that EHF targets in HBE cells diseases such as cystic fibrosis (CF) (3,5,6). are enriched for genes involved in inflammation CF is a common autosomal recessive and wound repair. Furthermore, changes in gene disorder caused by mutations in the cystic fibrosis expression impact cell phenotype, since EHF transmembrane conductance regulator (CFTR) depletion alters epithelial secretion of a neutrophil gene. The main cause of morbidity and mortality chemokine and slows wound closure in HBE cells. in CF is lung disease (7). Airway dysfunction in EHF activates expression of the SAM pointed CF patients is complex, but altered ion transport domain-containing ETS transcription factor leads to a decreased ability to clear (SPDEF), which contributes to goblet cell microorganisms, chronic infection, and hyperplasia. Our data reveal a critical role for EHF inflammation. Neutrophil-dominant inflammation in regulating epithelial function in lung disease. is present early in the disease (8). There is 1 Copyright 2017 by The American Society for Biochemistry and Molecular Biology, Inc. EHF has critical roles in airway epithelial dysfunction increased secretion of cytokines including modifier of lung disease in CF patients. We interleukin-13 (IL-13) and interleukin-17a (IL- hypothesize that EHF regulates genes involved in 17a) in the lungs, which is exacerbated in patients cellular processes that impact the severity of infected with Pseudomonas aeruginosa, the epithelial pathology in airway disease, including predominant pathogen in the CF airway (11-13). inflammation and wound repair. IL-13 augments mucin production by the lung This study investigates the role of EHF in epithelium and triggers goblet cell hyperplasia primary human bronchial epithelial (HBE) cells. (14). IL-17a induces neutrophil chemokine Using chromatin immunoprecipitation followed by production by the epithelial cells (15). The sequencing (ChIP-seq) and RNA-sequencing amplified mucus and cytokine levels cause (RNA-seq) after EHF depletion, we identified destruction of lung tissue by initiating remodeling putative direct targets of EHF in HBE cells. These and fibrosis, which correlate with pulmonary genes are enriched in processes that are involved dysfunction (16-19). Similar pathways are in lung pathology. Cellular assays determined that Downloaded from activated in other airway diseases, including EHF-modulated changes in gene expression alter chronic obstructive pulmonary disease (COPD) epithelial phenotypes. Our results suggest that and asthma (20,21). Modulation of gene EHF is involved in multiple processes that expression underlies the response of the lung influence lung function in disease. Of particular http://www.jbc.org/ epithelium to the environment, both in normal and relevance to CF are the release of neutrophil disease states, so it is critical to understand the chemokines and wound repair. causative mechanisms. Pivotal to these processes is the transcription factor (TF) network that RESULTS regulates development, normal function, and ChIP-seq generates a genome-wide at University of North Carolina Chapel Hill on August 16, 2019 response to disease in respiratory epithelial cells. binding signature for EHF in primary HBE cells− TFs respond to normal and aberrant stimuli by To identify genome-wide binding sites for EHF, binding to the genome at regulatory sites, thereby ChIP-seq was performed on cultures from two altering gene expression. Ets homologous factor tissue donors. The antibody specific for EHF was (EHF) is a member of the epithelial-specific Ets used previously for ChIP-seq in Calu-3 lung transcription factor subfamily that is expressed in adenocarcinoma cells (31). The HOMER the bronchial epithelium (22-24). In response to irreproducible discovery rate pipeline (32) was inflammatory mediators including interleukin-1β used to call a total of 11,326 peaks with an (IL-1β) and tumor necrosis factor-α (TNF-α), irreproducible discovery rate (IDR) < 0.05 (Table bronchial EHF expression is increased in an NF- S1). Sonicated input DNA was used as κB-dependent manner, suggesting a role for EHF background. The normalized tag counts at each in the epithelial response to inflammation (25). In called peak were significantly correlated between prostate cancer, loss of EHF leads to epithelial-to- the two biological replicates (r=0.29, p<0.0001). mesenchymal transition (EMT) and increased The Cis-regulatory Element Annotation metastatic potential (26). In EMT, epithelial cells System (CEAS) software (33) was used to lose contact with adjacent cells and become more annotate peaks based on genomic location (Fig motile (27). Similar pathways may be involved in 1A) and determined that EHF sites were enriched lung fibrosis (28). at promoters (-1 kb relative to the transcription Recent genome-wide association studies start site) and 5’ untranslated regions (UTRs) of (GWAS) led to an interest in EHF as a potentially genes (Fig 1B). Consistent with its role as a TF important factor in CF lung pathology. These controlling cell-type specific gene expression, studies identified intergenic single nucleotide peaks of EHF occupancy were also found in polymorphisms (SNPs) at chr11p13 that strongly intergenic and intronic regions, which may associate with lung disease severity in CF patients represent cis-regulatory elements such as carrying the most common disease-causing enhancers. These regulatory sites are marked by mutation, F508del (29,30). These SNPs are likely specific histone modifications. Active or poised within or close to cis-regulatory elements for promoters and enhancers are enriched for histone nearby genes. EHF maps immediately adjacent 3 lysine 4 trimethylation (H3K4me3) and (5’) to this intergenic region, suggesting a role as a H3K4me1, respectively, while active regions are 2 EHF has critical roles in airway epithelial dysfunction specifically marked by histone 3 lysine 27 version 6.26 (Fig 2D). The overlapping sites are acetylation (H3K27ac) (34,35). To determine found near loci involved in differentiation, whether EHF peaks are found in regions with development and wound repair, suggesting they these histone modifications, as predicted by their may have a combined role in regulating genomic locations, ChIP-seq was performed using phenotypes important for lung pathology. antibodies against H3K4me1, H3K4me3 and EHF regulates genes involved in lung H3K27ac in HBE cells. EHF sites were enriched pathology −To detect genes that are directly and for all marks with
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