CXCL8 histone H3 acetylation is dysfunctional in airway smooth muscle in asthma: Regulation by BET

Clifford, Rachel L.; Patel, Jamie K.; John, Alison E.; Tatler, Amanda L.; Mazengarb, Lisa; Brightling, Christopher E.; Knox, Alan J.

Abstract

© 2015 The American Physiological Society. Asthma is characterized by airway inflammation and remodeling and CXCL8 is a CXC chemokine that drives steroid-resistant neutrophilic airway inflammation. We have shown that airway smooth muscle (ASM) cells isolated from asthmatic individuals secrete more CXCL8 than cells from nonasthmatic individuals. Here we investigated chromatin modifications at the CXCL8 promoter in ASM cells from nonasthmatic and asthmatic donors to further understand how CXCL8 is dysregulated in asthma. ASM cells from asthmatic donors had increased histone H3 acetylation, specifically histone H3K18 acetylation, and increased binding of histone acetyltransferase p300 compared with nonasthmatic donors but no differences in CXCL8 DNA methylation. The acetylation reader proteins Brd3 and Brd4 were bound to the CXCL8 promoter and Brd inhibitors inhibited CXCL8 secretion from ASM cells by disrupting Brd4 and RNA polymerase II binding to the CXCL8 promoter. Our results show a novel dysregulation of CXCL8 transcriptional regulation in asthma characterized by a promoter complex that is abnormal in ASM cells isolated from asthmatic donors and can be modulated by Brd inhibitors. Brd inhibitors may provide a new therapeutic strategy for steroid-resistant inflammation.

Citation

Clifford, R. L., Patel, J. K., John, A. E., Tatler, A. L., Mazengarb, L., Brightling, C. E., & Knox, A. J. (2015). CXCL8 histone H3 acetylation is dysfunctional in airway smooth muscle in asthma: Regulation by BET. AJP - Lung Cellular and Molecular Physiology, 308(9), L962-L972. https://doi.org/10.1152/ajplung.00021.2015

• Journal Article Type: Article
• Acceptance Date: Feb 13, 2015
• Online Publication Date: Feb 20, 2015
• Publication Date: May 1, 2015
• Deposit Date: Oct 16, 2019
• Journal: American Journal of Physiology - Lung Cellular and Molecular Physiology
• Print ISSN: 1040-0605
• Electronic ISSN: 1522-1504
• Publisher: American Physiological Society
• Peer Reviewed: Peer Reviewed
• Volume: 308
• Issue: 9
• Pages: L962-L972
• DOI: https://doi.org/10.1152/ajplung.00021.2015
• Keywords: Physiology (medical); Cell Biology; Physiology; Pulmonary and Respiratory Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/2847491