The role of epigenetics in the development of childhood asthma

Abstract

Introduction: The development of childhood asthma is caused by a combination of genetic factors and environmental exposures. Epigenetics describes mechanisms of (heritable) regulation of gene expression that occur without changes in DNA sequence. Epigenetics is strongly related to aging, is cell-type specific, and includes DNA methylation, noncoding RNAs, and histone modifications. Areas covered: This review summarizes recent epigenetic studies of childhood asthma in humans, which mostly involve studies of DNA methylation published in the recent five years. Environmental exposures, in particular cigarette smoking, have significant impact on epigenetic changes, but few of these epigenetic signals are also associated with asthma. Several asthma-associated genetic variants relate to DNA methylation. Epigenetic signals can be better understood by studying their correlation with gene expression, which revealed higher presence and activation of blood eosinophils in asthma. Strong associations of nasal methylation signatures and atopic asthma were identified, which were replicable across different populations. Expert commentary: Epigenetic markers have been strongly associated with asthma, and might serve as biomarker of asthma. The causal and longitudinal relationships between epigenetics and disease, and between environmental exposures and epigenetic changes need to be further investigated. Efforts should be made to understand cell-type-specific epigenetic mechanisms in asthma.

Epithelial cell dysfunction, a major driver of asthma development

“…In mice, increased expression led to spontaneous airway hyper-responsiveness, 82 92 Therefore, we here focus on the studies in upper (nasal) airway brushes, that mainly consist of epithelial cells, 93 and which were shown to have the best correlation to the DNA methylation patterns in bronchial epithelial cells. 94 In four studies reported to date, [95][96][97][98] methylation of the GJA4 gene, encoding Connexin37, a protein capable of forming heterotypic gap junctions, was consistently found to be reduced, although an association with altered gene expression levels was not detected. 97 Other genes relevant to epithelial barrier function (CDH26, CDHR3) were also found differentially methylated.…”

“…As the epigenetic signature of the airway epithelium integrates genetic susceptibility with the life history of relevant environmental exposures, it can be expected to be a strong biomarker for asthma development or even treatment response. 98 In addition to DNA methylation, epithelial gene expression can be ciliogenesis by targeting TGF-β1, TGF-βR2, SIRT1, SMAD2 (target of both miR-27a and miR-128) and Cp110, respectively (Figure 4). [106][107][108][109][110][111] Of interest, the discussed miRNAs were not all identified in patients with the same disease severity.…”

“…These data clearly indicate the relevance of environmental exposures for epigenetic regulation of gene expression in the airway epithelium and therefore for asthma. As the epigenetic signature of the airway epithelium integrates genetic susceptibility with the life history of relevant environmental exposures, it can be expected to be a strong biomarker for asthma development or even treatment response 98 …”

Epigenome-wide association study identifies DNA methylation markers for asthma remission in whole blood and nasal epithelium

“…Epigenetic mechanisms such as DNA methylation may help to build a link between genetic factors and the environment. DNA methylation can be regulated by SNPs, and can reflect environmental exposures, ageing, cell type constitution and activation [ 6 ]. DNA methylation refers to the addition of a methyl-group to cytosine, which usually happens when a cytosine is located next to a guanine in the 5′ to 3′ direction (CpG site), and this may relate to the regulation of gene expression [ 7 ].…”

Epigenome-wide association study identifies DNA methylation markers for asthma remission in blood and nasal epithelium

“…Epigenetic mechanisms such as DNA methylation may help to build a link between genetic factors and the environment. DNA methylation can be regulated by SNPs, and can reflect environmental exposures, ageing, cell type constitution and activation 6 . DNA methylation refers to the addition of a methyl-group to cytosine, resulting in a CpG site, which may relate to the regulation of gene expression 7 .…”