In the 1940s, Conrad Waddington used the term epigenetics to describe how the genotype manifests itself as a phenotype . In 1958, Nanney  borrowed the term to describe inherited phenomena that could not be explained by conventional genetics. Recently, epigenetics has been defined concisely by Ptashne in 2007 by three criteria: a change in the activity of a gene that does not involve a mutation, that is initiated by a signal, and that is inherited (mitotically or meiotically) in the absence of the signal that initiated the change [3▪]. Classically, four epigenetic mechanisms have been identified: DNA methylation, histone modification, chromatin remodeling, and small (21–26-nt) and noncoding RNAs.
There is ample evidence that DNA methylation fulfills all three criteria required for it to be considered as an epigenetic mechanism [4–6]. Histone modifications fulfill some of the criteria for being epigenetic mechanisms in that they can result from exogenous signals such as cigarette smoke and that they alter gene activity [7–9]. However, meiotic inheritance has only been demonstrated in Caenorhabditis elegans, a transparent nematode . DNA methylation usually works hand in hand with histone modifications to activate or silence genes by influencing chromatin structure and its accessibility by transcription factors . So, it is possible that DNA methylation constitutes a mechanism of inheritance for some histone modifications. Given the complex and ever-changing structure of chromatin, there is little information on chromatin remodeling regarding initiation, alteration of gene activity, and inheritance [12–14]. MicroRNAs (miRNAs) also have been shown to be caused by exogenous factors and to alter gene activity by either inhibiting translation or degrading messenger RNAs (mRNA) [15,16]. For instance, in humans, miRNAs have been demonstrated to be differentially expressed in current and never smokers and to be related to particulate matter exposure [7,17]. Currently, there is little evidence that miRNAs can be inherited . However, because miRNAs are part of the genetic code, it is possible that DNA methylation affects the activity of miRNAs and thus facilitates inheritance. Hence, in the following, we concentrate on the truly and well established epigenetic mechanism, DNA methylation.
DNA METHYLATION AND ASTHMA PHENOTYPES
Asthma is the most common chronic disease among children and has a complex etiology including genetic and environmental factors. Human studies have investigated the role of DNA methylation more often than other epigenetic marks due to practical and biological reasons . Table 1 gives a summary of recent population-based studies investigating the association between DNA methylation and asthma [20–22,23▪,24,25▪▪]. Sood et al. investigated the role of DNA methylation of 12 genes selected due to their involvement in oxidative stress pathways in sputum of 695 older adults. They found that the PCDH20 gene coding protocadherin-20, a protein involved in cell adhesion and signal transduction, was statistically more highly methylated in sputum cells from asthma patients. In a subsample of 36 of 637 children, Isidoro-Garcia et al. studied methylation of the D prostanoid receptor (PTGDR) gene. Prostaglandin D2, a metabolite of arachidonic acid, inhibits the apoptosis, prolonging eosinophilic survival, and biases the development of naive T lymphocytes to T helper 2 cells. Isidoro-Garcia et al. showed that genetic variants of the PTGDR gene altered adjacent DNA methylation levels, which was related to hypomethylation of the promoter of the PTGDR gene among asthmatic participants. In gene expression analyses, the authors were able to demonstrate that hypomethylation caused by underlying sequence variants in patients was associated with increased PTGDR expression . A limitation of these two studies is that DNA methylation may not constitute a risk for asthma but may reflect a response due to the disease (reverse causation).
Among 182 children with asthma, high methylation levels of adrenergic-receptor beta-2 (ADRB2) gene, an important regulator of airway smooth muscle tone, have been associated with severe childhood asthma . Taking environmental exposures into account, an increased risk of severe asthma was associated with the joint effect of indoor NO2 exposure and high levels of ADRB2 methylation, which suggests that DNA methylation can act as an effect modifier for the association between NO2 levels and asthma severity . An environmental study focused on the effects of particulate matter conducted among 940 southern California school children. Salam et al.[23▪] investigated the fraction of exhaled nitric oxide (FeNO) produced by the bronchial epithelium and the NOS2 gene that codes the nitric oxide synthase. The results demonstrated two-way interactions between ‘exposure to particulate matter with an aerodynamic diameter of 2.5 μm or less (PM2.5) × NOS2 genetic variants’ and ‘PM2.5 exposure × NOS2 methylation’ and a three-way interaction between ‘PM2.5 exposure × NOS2 genetic variants × CpG methylation levels’ that jointly influenced FeNO levels [23▪]. In another investigation of this cohort, Breton et al. reported associations between differential DNA methylation of arginase-1 (ARG1) and ARG2 and significantly higher levels of FeNO in children with asthma. The authors suggest that differential methylation of ARG genes may play a role in modifying FeNO production in individuals whose inflammatory and oxidative stress pathways are already upregulated.
Morales et al.[25▪▪] addressed a burgeoning question, namely whether dichlorodiphenyldichloroethylene (DDE), a metabolite of the pesticide DDT, is related to the development of asthma [26,27]. Their results suggest that prenatal DDE exposure and genetic variants were associated with DNA hypomethylation of ALOX12 gene. In turn, this hypomethylation was a risk for persistent wheezing up to 6 years of age [25▪▪].
THE INTERPLAY OF GENETIC VARIANTS, ENVIRONMENTAL FACTORS, AND DNA METHYLATION
The epidemiological investigations (Table 1) demonstrate that both environmental and genetic factors may influence DNA methylation levels and could act as effect modifiers for asthma-related phenotypes. Hence, environmental exposures and genetic factors are both essential elements that determine epigenetic state in asthma [28,29]. Multiple past and current exposures have been linked to levels of DNA methylation such as the Dutch famine [30,31], low birth weight and fetal alcohol syndrome [32,33], maternal gestational stress in third trimester , gestational folate levels [35–38], early life socio-economic position , infections [40–43], and smoking [44–52]. Similarly genetic variants have been shown to affect the susceptibility to DNA methylation, a process named allele-specific or genotype-dependent DNA methylation [53–59]. Such genetic variants have recently been named methylation quantitative trait loci (methQTL) [60,61▪▪].
Hence, we do not only need to understand the mechanisms by which alterations in the epigenome alter phenotype but also to test different models of interplay between genetic variants, environmental factors, and DNA methylation in the etiology of asthma. A common idea is that the epigenome is an integrator of multiple signals in the pathway to diseases. Although different steps seem to be involved in structuring the DNA methylation profiles, the integrative role often remains a black box (Fig. 1, model A) [62,63]. Here, we propose a two-stage model (Fig. 1, model B), allowing these stages to develop in different phases of life. In stage 1, specific exposures and methQTLs interact within one gene and change the DNA methylation status of specific genetic elements (either promoter or intragenic). Once a methylation change close to a methQTL has been established, for instance, at the promoter site, the gene may be differentially regulated. The response to additional exposures that interact with other genetic variants of the same gene depends on whether, for example, the promoter is silenced or activated. To contrast these other genetic variants, whose response may be modified as a consequence of prior DNA methylation, from methQTLs, we call these modifiable genetic variants (modGV). The three-way interaction in the study by Salam et al.[23▪] in children in southern California showed that NOS2 genetic variants were modifiable (Table 1). Similarly, the study of asthma severity by Fu et al. demonstrates that DNA methylation is an effect modifier for the association between indoor exposure to NO2 and severe asthma. Recently for eczema, Ziyab et al.[64▪] demonstrated that the haploinsufficiency of the filaggrin gene can be modified by DNA methylation within the intragenic region that worsens the insufficiency. Experimentally, in lymphoblastoid cell lines, similar models have been identified by Berlivet et al.[65▪] for the asthma-associated locus 17q12–q21.
Comparable to the studies described above that have focused on gene promoter methylation, these models also apply to intragenic methylation. DNA methylation is more frequent within gene bodies (intragenic) than in promoters. Whereas hypermethylation of promoter sites has been associated with transcriptional silencing, intragenic methylation has been observed to have a positive or a bell-shaped correlation with gene expression . Recently, for the CD45 transcript, it has been demonstrated that intragenic DNA methylation is related to alternative premRNA splicing . In particular, it has been suggested that a specific binding factor was involved in splicing regulation . We speculate that methQTLs and exposure may also affect intragenic DNA methylation (stage 1) and then modify premRNA splicing (stage 2).
DNA methylation is likely to have contributed to discrepancies found among genome-wide association studies. Both methQTL and modGV are part of the set of genetic variants (e.g. SNP: single nucleotide polymorphism, haplotypes) that are the focus of genome-wide association studies. The detection of associations between such genetic variants and phenotypes may therefore depend on other modifiers of DNA methylation levels such as environmental exposure. For instance, a SNP may facilitate DNA methylation in an exposed study group but not in the unexposed group. As stage 1 changes may penetrate through stage 2 to some extent, a methQTL in the exposed group may be associated with increased risk of the disease. However, in another study group, a different genetic sequence (nonrisk genotype) in the same methQTL may not be favoring DNA methylation, and thus not establishing a risk for a disease. Also, modGV with the same genetic code may be masked by DNA methylation in one study group but unmasked in another study. Such settings lead to disagreements between genetic studies and reduce the chance to replicate candidate genes . Hence, a methQTL cannot be assessed without knowing the exposure and modGV cannot be assessed without taking the methylation of other SNPs/haplotypes into account that may influence gene regulation or splicing.
THE ROLE OF DIFFERENT LIFE PHASES
As exemplified by the study by Morales et al.[25▪▪], it is important to consider the timing of exposure, measurement of DNA methylation, and phenotypic outcome assessment with reference to the life course. In the study by Morales et al.[25▪▪], first, change in methylation related to prenatal DDE in DNA obtained at 4 years of age was assessed (replication study: cord blood), and second, the altered DNA methylation was linked to wheezing. This approach avoids the problem of reverse causation that can result if DNA methylation may either result as a response to the disease or may be considered as a risk factor. The concept of the ‘developmental programming’ has been well accepted [69–71] and there is increasing awareness of its importance in asthma . Environmental pollutants may influence crucial cellular functions during critical periods of fetal development and permanently alter the structure or function of specific organ systems.
Some studies [73,74] suggest that intrauterine and early life exposures to a farming environment are associated with decreased risk of allergic disorders, including asthma. This protective effect is believed to be associated with epigenetic mechanisms that are induced during early developmental stages. Recently, Slaats et al. demonstrated that profiles of promoter DNA methylation of CD14 gene measured in placentas were different among mothers living on a farm compared with mothers not living on a farm. However, this finding needs to be replicated in a larger sample and the biological pathway underlying the protective effect needs further elucidation.
Another example of prenatal exposure is maternal smoking. Using the Norwegian Mother and Child Cohort Study (cord blood), Joubert et al.[76▪▪] reported that DNA methylation in cord blood derived DNA of genes including the cytochrome P450 aryl-hydrocarbon-hydroxylase CYP1A1 gene and the aryl hydrocarbon receptor repressor gene (AHRR) are differentially methylated after gestational exposure to cigarette smoking. The CYP1A1 gene codes an enzyme that catalyzes the conversion of chemical species into reactive intermediates such as quinones; AHRR competes with AHR for binding at xenobiotic response elements and is related to active smoking. In addition, Karmaus et al. (unpublished observation) have demonstrated that these genes were also differentially methylated in individuals exposed to in-utero cigarette smoke in blood DNA samples at 18 years of age in the Isle of Wight Birth cohort. Given that early life DNA methylation leads to a cell memory [77,78], children may be programmed to metabolize xenobiotics differently, which can increase their disease risk due to smoke exposure later in life. Hence, DNA methylation builds gene-activation memories during key periods of development (e.g. in utero and adolescence) producing aberrant activation patterns later in life, which may elevate disease risk.
To date, only a few studies have reported associations between epigenetic marks and the diverse asthma-related phenotypes. Although most studies have focused on different candidate genes, they have shown similar models of interactions between genetic variants (methQTLs and modGV), environmental exposures, and DNA methylation. There is a need to improve our knowledge about the black box of epigenetics with regard to exposures and diseases. The biological mechanisms that lead to specific changes in gene regulation in response to specific exposures are not known. We need to determine whether epigenetics should be considered as a major integrator of multiple signals, or, alternatively, whether DNA methylation acts differently at various developmental stages depending on genetic variants and exposures, such as in the proposed two-stage model. In addition, as there is a lack of critical knowledge on which genes are programmed or re-programmed at what time during gestation and in which developmental phase, birth cohort studies need to trace DNA methylation over time, and ideally over generations. This will provide critical information about which phases in the course of life are most suitable to prevent deviant DNA methylation (preventive epigenomics) or intervene to normalize DNA methylation to prevent disease (pharmacoepigenomics) . Given that patterns of DNA methylation can be inherited through meiosis, future research will provide a unique chance to not only prevent and treat asthma in the current generation but also prevent it in subsequent generations.
The authors’ work was funded and supported by the National Institute of Allergy and Infectious Diseases under award number R01 AI091905. Research reported in this review was supported by the National Institute of Allergy and Infectious Diseases under Award Number R01 AI091905-01 (PI: W.K.).
Conflicts of interest
The authors have no conflicts of interest to declare in connection with this work.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 122).
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