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

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

doi:10.1152/ajplung.00021.2015

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

Am J Physiol Lung Cell Mol Physiol. 2015 May 1;308(9):L962-72. doi: 10.1152/ajplung.00021.2015. Epub 2015 Feb 20.

Authors

Rachel L Clifford¹, Jamie K Patel¹, Alison E John¹, Amanda L Tatler¹, Lisa Mazengarb¹, Christopher E Brightling², Alan J Knox³

Affiliations

¹ Department of Respiratory Medicine and Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom; and.
² Institute for Lung Health, Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, United Kingdom.
³ Department of Respiratory Medicine and Nottingham Respiratory Research Unit, University of Nottingham, Nottingham, United Kingdom; and alan.knox@nottingham.ac.uk.

Abstract

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.

Keywords: BET protein; CXCl8; airway smooth muscle; asthma; bromodomain; histone acetylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Airway Remodeling / immunology
Asthma / metabolism*
CCAAT-Enhancer-Binding Protein-beta / metabolism
Cell Cycle Proteins
Cells, Cultured
DNA Methylation
DNA-Binding Proteins / metabolism
Histones / metabolism
Humans
Inflammation / immunology
Interleukin-8 / antagonists & inhibitors
Interleukin-8 / genetics
Interleukin-8 / metabolism*
Muscle, Smooth / metabolism*
Myocytes, Smooth Muscle / metabolism*
Nerve Tissue Proteins / antagonists & inhibitors
Nerve Tissue Proteins / metabolism*
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / metabolism
Primary Cell Culture
Promoter Regions, Genetic
Protein Binding
RNA Polymerase II / metabolism
RNA-Binding Proteins / antagonists & inhibitors
RNA-Binding Proteins / metabolism
Transcription Factor RelA / metabolism
Transcription Factors / antagonists & inhibitors
Transcription Factors / metabolism
Transcription, Genetic
p300-CBP Transcription Factors / metabolism

Substances

BRD3 protein, human
BRD4 protein, human
CCAAT-Enhancer-Binding Protein-beta
CEBPB protein, human
CXCL8 protein, human
Cell Cycle Proteins
DNA-Binding Proteins
Histones
Interleukin-8
Nerve Tissue Proteins
Nuclear Proteins
RELA protein, human
RNA-Binding Proteins
Transcription Factor RelA
Transcription Factors
p300-CBP Transcription Factors
p300-CBP-associated factor
RNA Polymerase II

Abstract

Publication types

MeSH terms

Substances

Grants and funding