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. Author manuscript; available in PMC: 2021 Jun 1.
Published in final edited form as: Curr Opin Allergy Clin Immunol. 2018 Apr;18(2):132–138. doi: 10.1097/ACI.0000000000000429

The Role of Epigenetics in the Development of Childhood Asthma

Elizabeth J Davidson 1, Ivana V Yang 1,2,3,*
PMCID: PMC8169082  NIHMSID: NIHMS971622  PMID: 29389731

Abstract

Purpose of review

Epigenetic marks are emerging as mediators of genetics and the environment on complex disease phenotypes, including childhood asthma and allergy.

Recent findings

Epigenome-wide association studies (EWAS) over the past year have added to the growing body of evidence supporting significant associations of epigenetic regulation of gene expression and asthma and allergy. Studies in children have identified signatures of eosinophils in peripheral blood, Th2 cell transcription factors and cytokines in peripheral blood mononuclear cells, and epithelial dysfunction in the respiratory epithelium. Importantly, studies at birth have begun to decipher the contribution of epigenetic marks to asthma inception. Few studies have also begun to address the contribution of genetics and the environment to these associations.

Summary

Next generation of EWAS that will deal with confounders, study the influence of the genetics and environment, and incorporate multiple datasets to provide better interpretation of the findings are on the horizon. Identification of key epigenetic marks that are shaped by genetics and the environment, and impact transcription of specific genes will help us have a better understanding of etiology, heterogeneity and severity of asthma, and will also empower us to develop biologically driven therapeutics and biomarkers for secondary prevention of this disease.

Keywords: DNA methylation, gene expression, genetics, environment

Introduction to Epigenetics

Epigenetics, as a mechanism of control of gene expression without changes to underlying DNA sequence, has long been studied in cancer, where it was established that hypermethylation of cytosines within CpG islands in gene promoters leads to gene silencing and hypomethylation leads to active transcription[1,2]. Recent studies have demonstrated that the relationship between methylation and transcription is more complex. Methylation of less CpG dense regions near islands (‘shores’)[3,4] and within gene bodies[5,6] is also important in regulation of gene expression and alternative splicing. Large-scale data from international consortia (ENCODE[7], FANTOM5[8], and Roadmap Epigenomics[9]) have identified enhancers as critical regions involved in regulation of gene expression in addition to promoters. Promoters and enhancers are also characterized by the presence of a large number of histone modifications, with histone methylation and acetylation being the most common[10,11]. A common acetylation mark, that of lysine 27 on the histone H3 (H3K27ac) is a mark of active enhancers and active promoters. H3K4me1 is present at poised and active enhancers while H3K4me3 marks poised or active promoters. Non-coding RNAs such as micro RNAs (miRNAs) and long intergenic noncoding RNAs (lncRNAs) are sometimes viewed as a part of the epigenome as they are involved in regulation of gene expression[12], but they will not be discussed in the current review and are reviewed elsewhere[13]. Table 1 provides definitions for commonly used terms in human cohort studies of epigenetics.

Table 1.

Commonly used terms in studies of epigenetics in human cohorts. (Original)

Term Definition
CpG site DNA sequence where a cytosine nucleotide is followed by a guanine nucleotide. CpG is shorthand for 5′—C—phosphate—G—3′, that is, cytosine and guanine separated by only one phosphate group in the 5′ to 3′ direction.
Chromatin DNA wrapped around histone core proteins for the purpose of tight packaging of DNA into a small volume to fit into the nucleus of a cell and protect the DNA structure and sequence.
Differentially Methylated Position A single CpG site that is statistically significantly differentially methylated among study groups.
Differentially Methylated Region A group of CpG sites across a region of DNA that is statistically significantly differentially methylated among study groups.
DNA methylation DNA methylation is a process by which methyl groups are added to the DNA molecule. Methylation can change transcriptional activity of a DNA segment without changing the sequence.
Epigenome Collection of epigenetic marks throughout the genome. Genome-wide distribution of transcriptional regulators believed to mediate the memory of past cellular events.
Epigenome-wide Association Study (EWAS) A study of the epigenome that looks for association between epigenetic variation and a high-level trait such as disease status across individuals, or for association of a difference in organization of a genomic regulator.
Genome-wide Association Study (GWAS) A study that looks for association between genetic variation and a high-level trait such as disease across individuals, typically scanning millions of genetic variants genome-wide for association signals.
Histone modification A histone modification is a covalent post-translational modification (PTM) to histone proteins. The PTMs made to histones can impact gene expression by altering chromatin structure or recruiting histone modifiers.
Quanatitative Trait Locus (QTL) Loci in the genome at which genetic variation is associated with molecular variation across individuals. For example, individuals with a particular single nucleotide variant have altered expression levels of a gene (eQTL), altered DNA methylation (mQTL) or altered chromatin state (chromQTL).
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Both genetics and the environment are important determinants of epigenetic marks. An individual’s genetic background impacts epigenetic marks in two ways – by direct inheritance (imprinted loci)[14] and by genetic variants that segregate with disease exerting their effects through epigenetic modifications; this has been documented for both DNA methylation[15–18] and histone modifications[15–17]. Environmental influences on the epigenome have been documented both prenatally and postnatally[18]. Epigenetic processes translate environmental exposures associated with disease risk into regulation of chromatin, which shapes the identity, gene expression profile, and activity of specific cell types that participate in disease pathophysiology[19]. We have previously proposed that epigenetic marks may be the missing link that connects environmental exposures (exposome) in genetically predisposed individuals (genome) to transcriptional changes (transcriptome) associated with development of asthma[20] (Figure 1).

Figure 1.

Figure 1

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Conceptual overview of epigenetic regulation of gene expression in asthma and allergy. Underlying genetic variation (genome) and environmental exposures (exposome) influence epigenetic marks which in turn regulate gene expression. Alterations in epigenetic marks have consequences on expression of key genes and pathways in asthma (transcriptome). It should be noted that genetics and exposure can influence gene expression by other mechanisms. (Original)

Studies of Epigenetics in Childhood Asthma and Allergy

Early studies of DNA methylation in human cohorts demonstrated an association of DNA methylation in a few candidate genes in peripheral blood[21], buccal[22,23] and nasal[24] cells with childhood asthma phenotypes. The next wave of studies performed epigenome-wide association studies (EWAS) in peripheral blood. A study by Liang et al. demonstrated association of serum IgE and low methylation at 36 loci in three independent non-hispanic white (NHW) adult cohorts[25]. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors, and mitochondrial proteins. The authors also confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without high IgE levels. A more recent follow-up study extended these associations of hypomethylation, driven by higher eosinophil counts, with serum IgE to Hispanic children from two independent cohorts, Puerto Rico Genetics of Asthma and Lifestyle Study (PR-GOAL) and the Genes-environments and Admixture in Latino Americans (GALA II)[26]. Using data collected in the Avon Longitudinal Study of Parents and Children (ALSPAC), associations of asthma and wheeze with DNA methylation at 7.5 and 16.5 years were shown to be largely driven by higher eosinophil cell counts in asthma cases[27]. Collectively, these studies have identified signatures associated with higher numbers of eosinophils, and some intrinsic changes in DNA methylation in eosinophils, in peripheral blood.

Our work in African American inner city children identified 81 differentially methylated regions (DMRs) in peripheral blood mononuclear cells (PBMCs) associated with allergic asthma[28]. Several immune genes were hypomethylated and overexpressed in asthma, including IL-13, IL-4, RUNX3, ST2, and TIGIT; while consistently hypomehtylated, methylation changes in PBMCs are small in magnitude (median 1.3%; range 0.02%-3.1%). Another publication identified asthma-specific enhancers in primary CD4+ T cells, marked by gaining the histone H3K4me2 mark during Th2 cell development[29]. These findings build on our knowledge of the importance of T cells, especially Th2 immune response in allergic asthma[30], and epigenetic regulation of T cell lineage commitment[31].

In the nasal epithelia of the subset of the inner city African American children, we identified much larger (median 9.5%, range: 2.6-29.5% methylation change) methylation changes, both in the form of single CpG methylation (differentially methylated probes[DMPs]) and regions (DMRs) that are associated with their disease and changes in gene expression[32]. 60% of genes that are differentially expressed in the asthmatic nasal epithelium have significant associations between DNA methylation and gene expression; these include asthma genes (ALOX15, CAPN14, POSTN), genes involved in inflammation and immunity, cell adhesion, extracellular matrix, obesity and autophagy, and epigenetic regulators, among others. 30% of the genes we identified were also found in an IL-13 DNA methylome signature of cultured airway epithelial cells of asthmatics, additionally demonstrating the relevance of our findings to allergic asthma[33]. Our more recent work demonstrates that nasal epithelia capture disease activity seen in the lung airway epithelia but that there are many more significant associated DNA methylation changes in the nasal epithelia, suggesting an important role for the environment in influencing these epigenetic changes[34] and the need to understand environmental exposures that are driving these changes.

Studies of Epigenetics at Birth

Studies of DNA methylation at birth are especially important, as they would address the question of whether epigenetic marks contribute to asthma inception. The idea of DNA methylation being important in asthma inception is supported by (1) potential of transgenerational inheritance and the influence of in utero exposures on epigenetic marks, and (2) maternal imprinting of allergic asthma[35] and IgE[36]. DeVries et al. were the first to show that DNA methylation in cord blood mononuclear cells (CBMCs) was associated with childhood asthma (age 9)[37]. Of the large number of DNA methylation changes they identified, increased methylation in SMAD3 was: (1) associated with childhood asthma risk, a result that was replicated in two independent cohorts; (2) was the most connected node within the network of asthma-associated DMRs; and (3) was strongly and positively associated with neonatal production of IL-1β, an innate inflammatory mediator. Two other recent studies contributed to this growing area of research by identifying DNA methylation changes in candidate genes AXL[38] and GATA3[39] at birth that are associated with childhood asthma. Interestingly, AXL hypermethylation was only associated with wheeze at age 6 in girls but not in boys[38]. In addition to association of higher methylation of GATA3 and a reduced risk of asthma at ages 3 and 6-7, Barton and collegues also observed associations of IL4R methylation with atopic eczema at 12 months and TBX21(TBET) methylation with atopy at 6-7 years of age [39]. These results complement our observations of inverse relationships of DNA methylation in Th2 genes and risk of childhood allergic asthma[28], and suggest that these changes are likely causative and not the result of disease activity. However, longitudinal studies of DNA methylation and asthma phenotypes are needed to better understand these observed associations and to fully address the issue of reverse causation[40].

Second Generation EWAS in Asthma and Allergy – Future Perspective

A challenge for all EWAS, including those that have been performed in asthma and allergy, is the interpretation of the results obtained. In addition to reverse causation, some of the challenges include accounting for the the effect of genetic variants on methylation levels and distinguishing inherent changes in DNA methylation within a cell versus a change in methylation observed due to differences in cell proportions[40].

Genome-wide association studies in asthma and allergy have identified genetic loci that are risk factors for these complex disorders. For example, meta-analysis of GWAS identified seven asthma genetic risk loci (HLA-DQ, IL33, ORMDL3/GSDMB, IL1RL1/IL18R1, IL2RB, SMAD3, and TSLP [41,42]) and ten loci near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL-2, and HLA-B that influence allergic sensitization [43]. These and other genetic variants could potentially influence DNA methylation levels, and be at least in part responsible for the EWAS signal. A recent study showed this type of interplay between genetics and epigenetics in the control of circulating levels of the chitinase-like protein YKL-40[44]. Alleles linked to lower YKL-40 levels were associated with higher methylation levels, and high YKL-40 levels were associated with increased odds for asthma. Using genetic and DNA methylation data from airway epithelial cells from 115 adults (74 asthmatics and 41 nonasthmatics), Nicodemus-Johnson et al. showed cis methlation quantitative loci (mQTLs) were enriched among genes that were differentially methylated between asthmatics and controls, and mQTLs are also enriched for asthma-associated SNPs[45]. These early studies highlight the importance of incorporating genetic variants in studies of DNA methylation. Second generation EWAS in asthma and allergy will need to integrate DNA methylation with genetic variants, chromatin accessibility (by ATAC-seq or a similar technique), and transcription factor binding data to provide further insight into the true function of the epigenome, as recently proposed[40].

Another important aspect of the next generation of EWAS studies will be proper incorporation of cell heterogeneity in the analysis. Methylation and gene expression signal, measured in a mixed population of cells can reflect a change in the pattern of methylation and expression of the molecules measured within a certain cell type, a change in the cellular composition, or in many cases a combination of both. There are three main approaches to deal with this issue. One approach is to perform statistical deconvolution of epigenomic profiles by relying on features that are known to be cell specific, known as reference datasets. This approach has been used widely in peripheral blood profiling studies[46] and more recently on complex tissues[47] but is highly dependent on known markers and difficult to implement for lung cell populations due to the complexity of collection of appropriate reference datasets. The second approach is to isolate cell types based on cell surface markers by flow cytometry, often used in immunological studies, but limited by the need for known cell markers and antibodies for all cell populations of interest, as well as concerns that cell sorting may affect cellular methylation and expression patterns. The recently developed single cell technologies provide the best solution to identification of all relevant cell populations albeit they also have technical limitations at the present time[48].

Environmental Epigenetics in Asthma and Allergy – Future Perspective

Asthma prevalence has been on the increase, especially in North America compared to other continents. However, the prevalence of asthma differs worldwide and in many countries the prevalence of asthma is stable or decreasing. This highlights the influence of environmental exposures, such as allergens, air pollution, and environemtnal tobacco smoke (ETS), on disease etiology and pathogenesis. Formal mediation or two-step Mendelian randomization analyses[49], that test the effect of exposures on DNA methylation and then of DNA methylation on asthma and allergy phenotypes will be needed in the future to fully address the impact of the environment and the epigenome in asthma. Some early studies, outlined in the following sections have begun to address the link of the environment and the epigenome.

Epigenetic Changes Associated with Exposure to Air Pollution

Studies in adults have shown that both short[50,51] and long[52,53] term exposures to particulate matter (PM) impact DNA methylation, including genes in innate immunity (TLR4, TLR2)[51] and asthma (HLA-DOB, HLA-DPA1, CCL11, CD40LG, ECP, FCER1A, FCER1G, IL9, IL10, IL13, MBP)[53]. Exposure of BEAS-2B airways epithelial cell line to PM2.5 induced genomewide DNA methylation changes, with an enrichment for hypomethylation and transcriptional activation in pathwyas related to cytokine and immune responses, cellular motility, angiogenesis, inflammation, wound healing, cell growth, differentiation and development, and responses to exogenous matter[54]. Higher levels of black carbon (BC), assessed by personal monitoring, were associated with lower IL4 promoter methylation 5 days later in buccal cells of New York City children (age 9-14 years). The magnitude of association between BC exposure and demethylation of IL4 appeared to be greater among children sensitized to cockroach allergens[55]. Diesel exhaust particle exposure (DEP) has been associated with DNA methylation changes in peripheral blood[56] and lung epithelial cells[57]. DNA methylation in adults[58] and children both as a result of direct[59] and in utero[60] exposure is also influenced by polycyclic aromatic hydrocarbons (PAHs), a bi-product of incomplete combustion of organic materials in airborne pollution. In children, PAH exposure has been associated with increased methylation of IFNG[60] and the Treg transcription factor FOXP3 as well as impaired Treg function[61]. A study of children in Fresno, CA observed associations of high levels of CO, NO2 and PM2.5 with alterations in DNA methylation in FOXP3 and IL10 in PBMCs that persisted over time and were also associated with asthma[62]. Collectively, these studies are beginning to identify elements of the epigenome that are influenced by different components of air pollution.

Epigenetic Changes Associated with Exposure and Sensitization to Allergens

In human airway epithelial cells, controlled exposure to allergen alone, diesel exhaust alone, or allergen and diesel exhaust together (coexposure) led to significant changes in only 7 CpG sites genome-wide at 48 hours [57]. However, when the same lung was exposed to allergen and diesel exhaust but separated by approximately 4 weeks, significant changes in more than 500 sites were observed. These findings suggest that specific exposures can prime the lung for changes in DNA methylation induced by a subsequent insult. Another recent study evaluated T helper cell-secreted cytokines and DNA methylation patterns in PBMCs of children treated with Dermatophagoides pteronyssinus (Der p) allergen-specific immunotherapy (allergen-SIT) [63]. The SIT-treated children, compared with the allergic asthmatics, exhibited decreased sensitivity to the Der p allergen, IL-4 downregulation due to increased promoter DNA methylation, and inhibited T cell proliferation. These results suggest that increased IL-4 cytokine promoter methylation is a potential mechanism of Der p-specific allergen desensitization immunotherapy.

Epigenetic Changes Associated with Exposure to Cigarette Smoke

Cigarette smoke exposure has a profound influence on DNA methylation among adult smokers[64,65] and as second hand smoke exposure (environmental tobacco smoke or ETS) in childhood[66,67] and in utero,[68–70], and also affects innate immune genes (CD14)[66]. A meta-analysis of maternal smoking in pregnancy and newborn blood DNA methylation across 13 cohorts (n = 6,685) in the Pregnancy And Childhood Epigenetics (PACE) consortium identified 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults[71]. An exciting recent study sought to determine whether vitamin C supplementation reduces changes in offspring methylation in response to maternal smoking and whether methylation at specific CpGs is also associated with respiratory outcomes[72]. The majority (69.03%) of CpGs with at least 10% methylation difference between placebo and nonsmoker groups were restored (by at least 50%) toward nonsmoker levels with vitamin C treatment, with a significant portion of them also associated with phenotypic outcome.

Conclusions

A number of studies over the past year have continued to contribute to our understanding of the epigenome in asthma and allergy. Most studies have added to the growing body of evidence supporting significant associations of epigenetic regulation of gene expression and asthma and allergy phenotypes. Few studies have begun to address the contribution of genetics and environment to these associations, and we expect more progress in this area in the near future. We look forward to the next generation of EWAS that will better deal with confounders and incorporate multiple datasets to provide better interpretation of the findings. Ultimately, the goals of epigenetic studies in asthma are to establish the basic molecular profiles to develop novel molecular insights into disease etiology and clinical severity/extent, and to provide the rationale and targets/biomarkers for intervention in this disease that remains a significant public health problem, especially among children.

Key Points.

  • The epigenome, a collection of epigenetic marks, is influenced by the genome (an individual’s genetic variants) and the exposome (an individual’s exposures).

  • Published epigenome-wide association studies (EWAS) support significant associations of epigenetic regulation of gene expression and childhood asthma and allergy.

  • Next generation of EWAS will need to better address confounders, study the influence of the genetics and environment, and incorporate multiple datasets to provide better interpretation of the fidndings.

Acknowledgments

None.

Financial support and sponsorship

None.

Footnotes

Conflicts of interest

None.

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