Abstract
BackgroundEpigenetic adjustments of the chromatin architecture through histone modifications are reactive to the environment and can establish chromatin states which are permissive or repressive to gene expression. Epigenetic regulation of gene expression is cell specific and therefore, it is important to understand its contribution to individual cellular responses in tissues like the airway epithelium which forms the mucosal barrier to the inhaled environment within the lung. The airway epithelium of asthmatics is abnormal with dysregulation of genes such as epidermal growth factor receptor (EGFR), the ΔN isoform of the transcription factor p63 (ΔNp63), and signal transducer and activator of transcription 6 (STAT6), integral to differentiation, proliferation, and inflammation. It is important to establish in diseases like asthma how histone modifications affect tissue responses such as proliferation and differentiation.ObjectivesTo characterize the global histone acetylation and methylation status in the epithelium of asthmatic compared to healthy subjects and to identify the impact of these variations on genes involved in epithelial functions.MethodsWhole lungs were obtained from healthy and asthmatic subjects (n = 6) from which airway epithelial cells (AECs) were isolated and airway sections were taken for analysis of histone lysine acetylation and methylation by immunohistochemistry. AECs were subjected to chromatin immunoprecipitation (ChIP) using anti-H3K18ac and anti-H3K4me2 antibodies followed by RT-PCR targeting ΔNp63, EGFR, and STAT6. AECs were also treated with TSA and changes in ΔNp63, EGFR, and STAT6 expression were determined.ResultsWe identified an increase in the acetylation of lysine 18 on histone 3 (H3K18ac) and trimethylation of lysine 9 on histone 3 (H3K9me3) in the airway epithelium of asthmatic compared to healthy subjects. We found increased association of H3K18ac around the transcription start site of ΔNp63, EGFR, and STAT6 in AECs of asthmatics. However, we were unable to modify the expression of these genes with the use of the HDAC inhibitor TSA in healthy subjects.DiscussionThe airway epithelium from asthmatic subjects displays increased acetylation of H3K18 and association of this mark around the transcription start site of ΔNp63, EGFR, and STAT6. These findings suggest a complex interaction between histone modifications and gene regulation in asthma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0254-y) contains supplementary material, which is available to authorized users.
Highlights
The sequence of the human genome is essentially the same in all cells of the body within a specific individual, yet the epigenome differs from tissue to tissue [1]
We identified an increase in the acetylation of lysine 18 on histone 3 (H3K18ac) and trimethylation of lysine 9 on histone 3 (H3K9me3) in the airway epithelium of asthmatic compared to healthy subjects
We identified a significant increase in % positive area of airway epithelium for acetylation of lysine 18 on histone 3 (H3K18ac) in asthmatic compared to healthy subjects (p = 0.02, Fig. 1m)
Summary
The sequence of the human genome is essentially the same in all cells of the body within a specific individual, yet the epigenome differs from tissue to tissue [1]. An important mechanism for altering the chromatin structure to regulate gene expression is the covalent modification of the amino acid residues of core histone N-terminal tails [3, 4]. Methylation of histone tails can be both activating and suppressive of gene expression depending on the particular residue [3]. Epigenetic adjustments of the chromatin architecture through histone modifications are reactive to the environment and can establish chromatin states which are permissive or repressive to gene expression. Epigenetic regulation of gene expression is cell specific and it is important to understand its contribution to individual cellular responses in tissues like the airway epithelium which forms the mucosal barrier to the inhaled environment within the lung. It is important to establish in diseases like asthma how histone modifications affect tissue responses such as proliferation and differentiation
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