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.

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

“…Significantly, environmental inputs can affect gene transcription via heritable epigenetic regulation that does not require alterations in gene sequence, including DNA and histone modifications, as well as changes in noncoding RNAs 69 . One of the notable epigenetic changes in asthmatic epithelium involves hypo-methylation of KRT5 69 , which increases keratin 5 expression in basal epithelium and may therefore lead to dysregulated epithelial differentiation 70–72 . The potential for epigenetic “reprogramming” is evident when asthmatic epithelium cultured in normal media still retains persistent indicators of defects in junctional maintenance, “immaturity” and repair ex vivo 73 .…”

Mechanisms and treatments for severe, steroid‐resistant allergic airway disease and asthma

“…Increasing evidence implicates miRNAs in asthma pathogenesis, as well as other chronic respiratory diseases, and as potential therapeutic targets for treatments . Given the potential for miRNAs to regulate a large number of cellular processes that are crucial to the pathogenesis of disease, targeting alterations in miRNA expression in the asthmatic lung may have greater efficacy for the treatment of disease than steroids.…”

Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients

“…Furthermore, a number of genes associated with epithelial homeostasis, differentiation, or barrier immunity have been identified, including protocadherin 1 (PCDH1) , 169 cadherin-related family member 3 (CDHR3) , 170 HLA-DQ , 10 SPINK5 , 171 GPRA , 172 and orosomucoid-like 3 (ORMDL3)/GSDMB 10 at the 17q12-21 locus. However, it should be noted that asthma-associated alleles have small effect sizes and account for little of the prevalence of asthma, and it is likely that a significant portion of the genetic risk for asthma and its exacerbations results from genotype-specific responses to environmental exposures, including allergens, pollution, and viral infections, especially at particular stages of life 173, 174, 175, 176, 177. Here we have attempted to place some of the asthma susceptibility genes in the context of epithelial barrier dysregulation, with a view to highlighting potential epithelial endotypes of disease linked to reduced barrier defenses, dysregulated immune responses, and/or abnormal repair responses (Fig 5).…”