Profiling of H3K27Ac Reveals the Influence of Asthma on the Epigenome of the Airway Epithelium

oleh: Peter McErlean, Peter McErlean, Audrey Kelly, Audrey Kelly, Jaideep Dhariwal, Jaideep Dhariwal, Max Kirtland, Max Kirtland, Julie Watson, Julie Watson, Ismael Ranz, Ismael Ranz, Janet Smith, Alka Saxena, David J. Cousins, David J. Cousins, Antoon Van Oosterhout, Roberto Solari, Roberto Solari, Michael R. Edwards, Michael R. Edwards, Sebastian L. Johnston, Sebastian L. Johnston, Paul Lavender, Paul Lavender

Format: Article
Diterbitkan: Frontiers Media S.A. 2020-12-01

Deskripsi

BackgroundAsthma 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.MethodsWe piloted genome-wide profiling of the enhancer-associated histone modification H3K27ac in BECs from people with asthma (n = 4) and healthy controls (n = 3).ResultsWe 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).ConclusionOur small pilot study validates genome-wide approaches for deciphering epigenetic mechanisms underlying asthma pathogenesis in the airways.