Alterations of the lung methylome in allergic airway hyper‐responsiveness

Abstract

Asthma is a chronic airway disorder characterized by recurrent attacks of breathlessness and wheezing, affecting 300 million people around the world (available at: www.who.int). To date, genetic factors associated with asthma susceptibility have been unable to explain the full etiology of asthma. Recent studies have demonstrated that the epigenetic disruption of gene expression plays an equally important role in the development of asthma through interaction with our environment. We sensitized 6-week-old C57BL/6J mice with house-dust-mite (HDM) extracts intraperitoneally followed by 5 weeks of exposure to HDM challenges (three times a week) intratracheally. HDM-exposed mice showed an increase in airway hyper-responsiveness (AHR) and inflammation together with structural remodeling of the airways. We applied methylated DNA immunoprecipitation-next generation sequencing (MeDIP-seq) for profiling of DNA methylation changes in the lungs in response to HDM. We observed about 20 million reads by a single-run of massive parallel sequencing. We performed bioinformatics and pathway analysis on the raw sequencing data to identify differentially methylated candidate genes in HDM-exposed mice. Specifically, we have revealed that the transforming growth factor beta signaling pathway is epigenetically modulated by chronic exposure to HDM. Here, we demonstrated that a specific allergen may play a role in AHR through an epigenetic mechanism by disrupting the expression of genes in lungs that might be involved in airway inflammation and remodeling. Our findings provide new insights into the potential mechanisms by which environmental allergens induce allergic asthma and such insights may assist in the development of novel preventive and therapeutic options for this debilitative disease.

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

“…However, how the persistent epigenetic alteration of PDE4D is established in asthmatic ASMCs remains unknown. We previously demonstrated the changes in mRNA level of the DNA methylation modulators, including Dnmt3A, methyl-CpG-binding domain proteins (Mbd2 and Mbd3), and ten-eleven translocation proteins (Tet1) in mouse chronically exposed to house allergen (26). It will be informative to further examine how PDE4D is epigenetically regulated by these DNA methylation modulators, and how these modifications persist in the presence or absence of stimuli as in our cultured 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.…”

Epigenetic targets for novel therapies of lung diseases

“…Differences in DNA methylation might be intrinsic to asthma phenotypes, but they also might have been induced by allergen exposure. The latter possibility is supported by results from mouse models of asthma showing dynamic changes in DNA methylation from allergen challenge (Cheng et al, 2014; Shang et al, 2013). In support of allergen-induced changes in DNA methylation, ovalbumin sensitization of mice decreased DNA methyltransferase 1 (DNMT1) mRNA abundance which correlated with increased methylation of the DNMT1 gene (Verma et al, 2013).…”

Mechanisms of Experimental Mouse Models of Airway Hyperresponsiveness

“…Moreover, adoptive transfer of these DCs from pups of allergic mothers into offspring from nonatopic mothers transferred increased susceptibility to allergic disease to recipients despite there being no differences in DNA sequences. Although the specific genes conferring susceptibility in this study were not identified, more recent studies have shown that alterations in the lung methylome particularly in genes involved in the TGFB2 signaling pathway are associated with alterations in airway smooth muscle remodeling and the subsequent development of AHR (Cheng et al, 2014). As the study of the methylome in asthma is in its infancy, there will undoubtedly be more knowledge to be gained in this area.…”