PT - JOURNAL ARTICLE AU - Peter McErlean AU - Audrey Kelly AU - Jaideep Dhariwal AU - Max Kirtland AU - Julie Watson AU - Ismael Ranz AU - David J. Cousins AU - Roberto Solari AU - Michael R. Edwards AU - Sebastian L. Johnston AU - Paul Lavender AU - MRC-GSK Strategic Alliance Consortium TI - Genome-wide profiling of an enhancer-associated histone modification reveals the influence of asthma on the epigenome of the airway epithelium AID - 10.1101/282889 DP - 2018 Jan 01 TA - bioRxiv PG - 282889 4099 - http://biorxiv.org/content/early/2018/03/16/282889.short 4100 - http://biorxiv.org/content/early/2018/03/16/282889.full AB - Asthma is a chronic airway disease driven by complex genetic-environmental interactions. The role of epigenetic modifications in bronchial epithelial cells (BECs) in asthma is poorly understood. We undertook genome-wide profiling of the enhancer-associated histone modification H3K27ac in BECs from people with asthma and healthy controls. We identified 49,903 regions exhibiting differential H3K27ac enrichment in asthma, clustered at genes associated with type-2-high asthma (CLCA1) and epithelial processes (EMT). Asthma dramatically influenced the BEC enhancer landscape and we identified asthma-associated Super-Enhancers encompassing genes encoding transcription factors (TP63) and enzymes regulating lipid metabolism (NOX4). We integrated published protein, epigenomic and transcriptomic datasets and identified epithelium-specific transcription factors associated with H3K27ac in asthma (TP73) and dynamic relationships between asthma-associated changes in H3K27ac, DNA methylation, genetic susceptibility and transcriptional profiles. Finally, we used a CRISPR-based approach to recapitulate the H3K27ac-asthma landscape in vitro and provide proof of principal that asthma-associated gene expression (SERPINB2) is driven in part by aberrant histone acetylation, validating the combination of genome-wide and epigenome-editing approaches in deciphering the molecular mechanisms underlying asthma pathogenesis.