Environmental epigenetics of asthma: an update

Abstract

Asthma, a chronic inflammatory disorder of the airway, is influenced by interplay between genetic and environmental factors now known to be mediated by epigenetics. Aberrant DNA methylation, altered histone modifications, specific microRNA expression, and other chromatin alterations orchestrate a complex early-life reprogramming of immune T-cell response, dendritic cell function, macrophage activation, and a breach of airway epithelial barrier that dictates asthma risk and severity in later life. Adult-onset asthma is under analogous regulation. The sharp increase in asthma prevalence over the past 2 or 3 decades and the large variations among populations of similar racial/ethnic background but different environmental exposures favors a strong contribution of environmental factors. This review addresses the fundamental question of whether environmental influences on asthma risk, severity, and steroid resistance are partly due to differential epigenetic modulations. Current knowledge on the epigenetic effects of tobacco smoke, microbial allergens, oxidants, airborne particulate matter, diesel exhaust particles, polycyclic aromatic hydrocarbons, dietary methyl donors and other nutritional factors, and dust mites is discussed. Exciting findings have been generated by rapid technological advances and well-designed experimental and population studies. The discovery and validation of epigenetic biomarkers linked to exposure, asthma, or both might lead to better epigenotyping of risk, prognosis, treatment prediction, and development of novel therapies.

Figure 1

Environmental factor–induced T cell regulation of allergic airway responses. Inhaled allergens derived from environmental factors such as tobacco smoke, polycyclic aromatic hydrocarbons (PAH), endotoxin, diesel exhaust particles (DEP), particulate matter (PM), and dust mites in the immature or leaky airways are sampled by dendritic cells. The allergen-activated dendritic cells serve to prime the naïve CD4⁺ T cells to differentiate into pro-inflammatory T helper 2 type (Th2) cells instead of the infection-fighting Th1 cells in the T cell repertoire. The progressive increase in the commitment of CD4⁺ T cells towards a Th2 phenotype is driven by Th2 cytokines such as interleukin (IL)-4, IL-5, IL-9, and IL-13 and heightened expression of GATA3. In parallel, the Th2 cells shut off the expression of interferon-γ (IFNγ) and other Th1 cytokines such as IL-2. In neutrophilic, corticosteroid-resistance asthma, Th17 differentiation is increased. TGF-β-driven naïve CD4⁺ T cells differentiating into Foxp3+ T regulatory cells confers immune tolerance and dampens allergic responses. Alveolar macrophages play a dual role in pathogen/allergen elimination and suppression of the responses for airway repair and remodeling. Allergen-triggered oxidative stress, dietary methyl donors, and nutritional factors such as vitamin D modulate these immune/airway reprogramming events. Cytokines and transcriptional factors colored red are known to be modulate by epigenetic events. RORγt, GATA-3, T-bet, and Foxp3 are transcriptional factor promoting the differentiation of the respective T cells. IL, interleukin; IFN-γ, interferon-γ; Th cell, T helper cell; Treg cell, T regulatory cell; DC, dendritic cell; TGF-β, transforming growth factor-β.

Figure 2. DNA methylation and histone modification collaborate in regulating gene expression

DNA methylation refers to the covalent addition of a methyl group to a cytosine (C) residue in a CpG dinucleotide (black circles = methylated C; open circles = unmethylated C). The carboxyl ends of histones have specific amino acids that are sensitive to post-translational modifications. These two major epigenetic mechanisms collaborate to package genes in euchromatin (active chromatin) or heterochromatin (silenced chromatin), a packaging that determines whether a gene or a set of genes is silenced or activated. CpG sites are underrepresented in the mammalian genome but tend to cluster as CpG islands (CGIs) in gene promoter regions. Hypermethylation of promoter CGIs is associated with transcriptional silencing (red X) because of loss of affinity for transcriptional factors (TF) and accessibility by the transcriptional machinery (represented by Pol II in this figure). The heterochromatin has increased affinity for methylated DNA-binding proteins (MBPs), which further recruit histone deacetyltransferases (HDACs), DNA methylases (DNMTs,) and other corepressors. Methylated promoters are associated with unique repressive histone markers, which classically include trimethylation of histone 3 (H3), lysine (K) 9, and H3-K27. Unmethylated promoters are associated with gene activation (green arrow). They have reduced affinity for MBPs, increased affinity for histone acetylases (HATs), and histone marks associated with active chromatin, including acetylated H3-K9 and trimethylated H3-K4. Histone modifications are believed to mediate more rapid responses to environmental influences, whereas DNA methylation provides gene silencing over a longer time frame. Pol II, polymerase II; M, methylation; A, acetylation; H3, histone 3.