Profiling of H3K27Ac Reveals the Influence of Asthma on the Epigenome of the Airway Epithelium
Peter McErlean, Audrey Kelly, Jaideep Dhariwal, Max Kirtland, Julie Watson, Ismael Ranz, Janet L. Smith, Alka Saxena, David J. Cousins, Antoon van Oosterhout, Roberto Solari, Michael R. Edwards, Sebastian L. Johnston, Paul Lavender
Abstract
Background 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. Methods We piloted genome-wide profiling of the enhancer-associated histone modification H3K27ac in BECs from people with asthma ( n = 4) and healthy controls ( n = 3). Results We identified n = 4,321 (FDR < 0.05) regions exhibiting differential H3K27ac enrichment between asthma and health, clustering at genes associated predominately with epithelial processes (EMT). We identified initial evidence of asthma-associated Super-Enhancers encompassing genes encoding transcription factors ( TP63 ) and enzymes regulating lipid metabolism ( PTGS1 ). We integrated published datasets to identify epithelium-specific transcription factors associated with H3K27ac in asthma ( TP73 ) and identify initial relationships between asthma-associated changes in H3K27ac and transcriptional profiles. Finally, we investigated the potential of CRISPR-based approaches to functionally evaluate H3K27ac-asthma landscape in vitro by identifying guide-RNAs capable of targeting acetylation to asthma DERs and inducing gene expression ( TLR3 ). Conclusion Our small pilot study validates genome-wide approaches for deciphering epigenetic mechanisms underlying asthma pathogenesis in the airways.