Epigenetic Alterations by DNA Methylation in House Dust Mite–Induced Airway Hyperresponsiveness

Abstract

Asthma is one of the most prevalent chronic lung diseases, affecting 235 million individuals around the world, with its related morbidity and mortality increasing steadily over the last 20 years. Exposure to the environmental allergen, house dust mite (HDM), results in airway inflammation with a variable degree of airway obstruction. Although there has been much experimental work in the past using HDM challenge models to understand mechanistic details in allergic inflammation and airway hyperresponsiveness (AHR), there has been no study on reprogramming of lung or airways mediated through epigenetic mechanisms in response to an acute HDM exposure. Male mice, 6 weeks of age, were administrated HDM extracts or saline at Days 1, 14, and 21. Exposure of mice to HDM extracts caused significant airway inflammation and increased AHR. These HDMchallenged mice also exhibited a change in global DNA methylation as compared with saline-exposed (control) mice. Next, by employing methylation-sensitive restriction fingerprinting, we identified a set of genes, showing aberrant methylation status, associated with the HDM-induced AHR. These candidate genes are known to be involved in cAMP signaling (pde4 d), Akt-signaling (akt1 s1), ion transport (tm6 sf1, pom121l2, and slc8a3), and fatty acid metabolism (acsl3). Slc8a3 and acsl3 were down-regulated, whereas pde4 d, akt1 s1, tm6 sf1, and pom121l2 were up-regulated in the mice exposed to HDM. Hence, our results suggest that HDM exposure induces a series of aberrant methylated genes that are potentially important for the development of allergic AHR.Keywords: airway hyperresponsiveness; DNA methylation; epigenetics; house dust mite Asthma is one of the most prevalent chronic lung diseases, affecting 235 million individuals around the world (www.who.int). Individuals with asthma experience great difficulties in breathing and have reduced quality of life, with repeated visits to clinics or emergency rooms. It is well recognized that the development of asthma is related to a combination of genetic and environmental factors, but the precise mechanisms of pathogenesis in asthma are still unclear (1, 2). There are many triggers of asthmatic attacks; most of them are associated with environmental exposure to allergens. In the inner city environment, house dust mite (HDM) allergy is reported to be the most prevalent cause of allergic sensitization in individuals with asthma (3). Exposure to HDM results in airway inflammation with a variable degree of airway obstruction. In animal studies, chronic exposure of mice to HDM leads to significant airway inflammation, increased airway hyperresponsiveness (AHR), and remodeling of bronchi (4-6). Even though much work has been done in the past using this HDM model to probe the immunologic pathways, there is no study addressing the epigenetic basis of how this environmental allergen "reprograms" the airways, thereby predisposing the animals to asthma.Epigenetics provide a promising approach for improving our understanding of complex diseases like asth...

Aberrant DNA Methylation of Phosphodiestarase 4D Alters Airway Smooth Muscle Cell Phenotypes

“…This is in agreement with our previous study showing that HDM-induced AHR was associated with the epigenetic alterations of Pde4d (25). Furthermore, we showed that the epigenetic alteration of PDE4D was associated with the abnormal increase in cell proliferation, migration, and histamine-induced Ca 21 response in asthmatic ASMCs.…”

“…DNA methylation changes are associated with asthma (19,20) and linked to specific triggers of asthma, such as pollutant exposures (21-24). We previously reported that acute exposure to house dust mite (HDM) induced AHR in a mouse model, and the AHR induction was associated with epigenetic modulations of genes related to ASMC proliferation and contraction (25,26). Specifically, we found promoter demethylation of phosphodiesterase 4D (Pde4d) gene in tracheal ASMCs isolated from HDM-exposed mice.…”

Characteristic DNA methylation profiles in peripheral blood monocytes are associated with inflammatory phenotypes of asthma

“…Hypomethylation of the PDE4D isoform was recently shown in mice and was related to house dust mite exposure. 16 However, we did not identify this in EA. The potential effects due to asthma medications may also be important in this regard as prolonged β-adrenoreceptor stimulation has been associated with increased PDE4B mRNA expression in human monocytes.…”

“…Indeed, recent studies confirmed the role of different environmental conditions on DNA methylation 13 and association of such modifications in the pathogenesis of asthma. [14][15][16][17] The genome-wide DNA methylation profiling of whole blood or PBMCs facilitated the identification of many altered gene loci. However, few studies attempted to identify the contribution of particular cell types in the disease pathogenesis.…”

Dietary or Supplementary Intake Modulates Inflammatory Response in Asthma Response in Asthma

“…Recent evidence has shown that dynamic changes in DNA methylation can provide a possible mechanistic explanation for the link between exposure to allergens and airway hyperresponsiveness [84,85]. Changes in DNA methylation can affect asthma pathogenesis [86] by modulating the expression of disease-related genes [87].…”