Peter McErlean1,2, Audrey Kelly1,2, Jaideep Dhariwal2,3, Max Kirtland1,2, Julie Watson1,2, Ismael Ranz1,2, Janet Smith4, Alka Saxena5, David J Cousins2,6, Antoon Van Oosterhout4, Roberto Solari2,3, Michael R Edwards2,3, Sebastian L Johnston2,3, Paul Lavender1,2. 1. Peter Gorer Department of Immunobiology, King's College London, London, United Kingdom. 2. Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom. 3. Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom. 4. GlaxoSmithKline Allergic Inflammation Discovery Performance Unit, Respiratory Therapy Area, Stevenage, United Kingdom. 5. Genomics Platform, Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. 6. National Institute for Health Research (NIHR) Respiratory Biomedical Research Unit, Department of Infection, Immunity & Inflammation, Leicester Institute for Lung Health, University of Leicester, Leicester, United Kingdom.
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.
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.
Authors: Sven Heinz; Christopher Benner; Nathanael Spann; Eric Bertolino; Yin C Lin; Peter Laslo; Jason X Cheng; Cornelis Murre; Harinder Singh; Christopher K Glass Journal: Mol Cell Date: 2010-05-28 Impact factor: 17.970
Authors: Tillie-Louise Hackett; Stephanie Mary Warner; Dorota Stefanowicz; Furquan Shaheen; Dmitri V Pechkovsky; Lynne A Murray; Rochelle Argentieri; Anthony Kicic; Stephen M Stick; Tony R Bai; Darryl A Knight Journal: Am J Respir Crit Care Med Date: 2009-04-30 Impact factor: 21.405
Authors: Ivan V Kulakovskiy; Ilya E Vorontsov; Ivan S Yevshin; Anastasiia V Soboleva; Artem S Kasianov; Haitham Ashoor; Wail Ba-Alawi; Vladimir B Bajic; Yulia A Medvedeva; Fedor A Kolpakov; Vsevolod J Makeev Journal: Nucleic Acids Res Date: 2015-11-19 Impact factor: 16.971
Authors: Pablo Perez-Pinera; D Dewran Kocak; Christopher M Vockley; Andrew F Adler; Ami M Kabadi; Lauren R Polstein; Pratiksha I Thakore; Katherine A Glass; David G Ousterout; Kam W Leong; Farshid Guilak; Gregory E Crawford; Timothy E Reddy; Charles A Gersbach Journal: Nat Methods Date: 2013-07-25 Impact factor: 28.547
Authors: Fatemeh Moheimani; Alan C-Y Hsu; Andrew T Reid; Teresa Williams; Anthony Kicic; Stephen M Stick; Philip M Hansbro; Peter A B Wark; Darryl A Knight Journal: Respir Res Date: 2016-09-22