The airway epithelium is the interface between the environment and the submucosa of the lung and thus is the first line of defense against inhaled exogenous agents. In addition to maintaining a structural barrier through homeostasis and repair, the airway epithelium is involved in co-ordination of the mucosal immune response to the inhaled environment. In asthma it is now understood that the airway epithelium is abnormal with dysregulation of genes integral to differentiation, proliferation, and inflammation. Alteration of the chromatin architecture through epigenetic modifications including DNA methylation and histone modifications is 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, as such, it is important to understand epigenetic regulation in cells that are thought to play a central role in asthma.
As epigenetic processes are critical to cellular specificity and disease susceptibility the overarching hypothesis of this thesis is that alterations to the epigenome of asthmatic airway epithelial cells contribute to the dysregulation of genes involved in key epithelial functions.
To investigate this hypothesis, we performed analysis of DNA methylation, expression of epigenetic modifying genes, and histone acetylation and methylation in airway epithelial cells, airway fibroblasts, and peripheral blood mononuclear cells from asthmatic and healthy subjects.
We identified unique signatures of both DNA methylation and expression of epigenetic modifying enzymes in airway epithelial cells and showed that epithelial cells were epigenetically distinct from other cell types. Furthermore, we found that airway epithelial cells from asthmatic subjects displayed changes in DNA methylation, expression of histone kinases, acetylation of lysine 18 on histone 3, and occupancy of this histone modification at genes important to epithelial functions.
Therefore, epigenetic differences between tissue types were more evident and plentiful than within cell types highlighting the importance of the epigenome to cell specificity, yet subtle differences within each tissue were determined and may play a role in disease pathogenesis. Thus, these findings enhance our understanding of the unique epigenetic landscape which may contribute to the airway epithelial phenotype in health and disease.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat
