The genetic and epigenetic landscapes of the epithelium in asthma

Abstract

Asthma is a global health problem with increasing prevalence. The airway epithelium is the initial barrier against inhaled noxious agents or aeroallergens. In asthma, the airway epithelium suffers from structural and functional abnormalities and as such, is more susceptible to normally innocuous environmental stimuli. The epithelial structural and functional impairments are now recognised as a significant contributing factor to asthma pathogenesis. Both genetic and environmental risk factors play important roles in the development of asthma with an increasing number of genes associated with asthma susceptibility being expressed in airway epithelium. Epigenetic factors that regulate airway epithelial structure and function are also an attractive area for assessment of susceptibility to asthma. In this review we provide a comprehensive discussion on genetic factors; from using linkage designs and candidate gene association studies to genome-wide association studies and whole genome sequencing, and epigenetic factors; DNA methylation, histone modifications, and non-coding RNAs (especially microRNAs), in airway epithelial cells that are functionally associated with asthma pathogenesis. Our aims were to introduce potential predictors or therapeutic targets for asthma in airway epithelium. Overall, we found very small overlap in asthma susceptibility genes identified with different technologies. Some potential biomarkers are IRAKM, PCDH1, ORMDL3/GSDMB, IL-33, CDHR3 and CST1 in airway epithelial cells. Recent studies on epigenetic regulatory factors have further provided novel insights to the field, particularly their effect on regulation of some of the asthma susceptibility genes (e.g. methylation of ADAM33). Among the epigenetic regulatory mechanisms, microRNA networks have been shown to regulate a major portion of post-transcriptional gene regulation. Particularly, miR-19a may have some therapeutic potential.

Keywords: Asthma; DNA methylation; Epithelial cells; Genes; Histone acetylation; microRNA.

Fig. 1

Epigenetic regulatory factors in airway epithelium. a DNA methylation; white circles represent unmethylated CpGs that induces gene expression (e.g. KRT5) while black circles represent methylated CpGs that suppresses gene expression (e.g. STAT5A). b Histone acetylation; green circles refer to acetylated histone tail that stimulate gene expression (e.g. ΔNp63) while red circles indicate free histone tails that suppressed gene expression. c Noncoding RNA; miRNAs affect gene expression by either RNA degradation or translational inhibition. miRNAs hence (e.g. miR-19a) may suppress mRNA expression (e.g. TGF-β receptor 2)

Fig. 2

Role of miRNAs in airway epithelial cells regeneration. a In healthy airway epithelial cells, miR-449 suppresses NOTCH1 mRNA and encourages differentiation of ciliated cells compared with goblet cells. miR-203 may paly essential role in epithelial cell homeostasis by suppressing p63 which is expressed in basal cells. b The level of miR-449 and miR-203 are reduced in asthmatic airway epithelial cells, which may result in increase in goblet cells and compromising epithelial cells regeneration, respectively. Solid lines and bold fonts represent strong effect and dashed lines and normal font represent weak effect

Fig. 3

Overview of the key genes and epigenetic regulatory mechanisms associated with asthma in airway epithelial cells. Environmental insults (e.g. allergens or viruses) may damage the integrity of airway epithelial cells. Some of the susceptibility genes expressed in the airway epithelial cells (e.g. ADAM33) may further deteriorate this structural damage through the process of epithelial–mesenchymal trophic unit (EMTU) and hence encouraging airway remodelling and hyper-responsiveness. Whereas other asthma susceptibility genes (e.g. IRAKM) may promote (Th2)-immunity result in activation of inflammatory responses. Some of the genes have more protective roles (e.g. SPINK5 and TSLP). Furthermore, epigenetic regulatory mechanisms may affect some of these genes (e.g. hyper-methylation of ADAM33, and HLA-G suppression by miRNAs)