Epigenetic regulation of asthma and allergic disease

Abstract

Epigenetics of asthma and allergic disease is a field that has expanded greatly in the last decade. Previously thought only in terms of cell differentiation, it is now evident the epigenetics regulate many processes. With T cell activation, commitment toward an allergic phenotype is tightly regulated by DNA methylation and histone modifications at the Th2 locus control region. When normal epigenetic control is disturbed, either experimentally or by environmental exposures, Th1/Th2 balance can be affected. Epigenetic marks are not only transferred to daughter cells with cell replication but they can also be inherited through generations. In animal models, with constant environmental pressure, epigenetically determined phenotypes are amplified through generations and can last up to 2 generations after the environment is back to normal. In this review on the epigenetic regulation of asthma and allergic diseases we review basic epigenetic mechanisms and discuss the epigenetic control of Th2 cells. We then cover the transgenerational inheritance model of epigenetic traits and discuss how this could relate the amplification of asthma and allergic disease prevalence and severity through the last decades. Finally, we discuss recent epigenetic association studies for allergic phenotypes and related environmental risk factors as well as potential underlying mechanisms for these associations.

Keywords: Allergy; Amplification hypothesis; Asthma; Atopy; Epigenetic; Histone; Inheritance; Methylation; Th2; Transgenerational.

Figure 1

Structure of methylcytosine and its by-products. 5-mC = 5’methylcytosine; 5-hmC = 5’-hydroxymethylcytosine; 5-fC = 5’-formylcytosine; 5-caC = 5’-carboxymethylcytosine.

Figure 2

Replication of methylated DNA. The palindromic nature of CpG sites is key to their inheritance (A). With replication, each separated strand carries one methylated cytosine (B). The daughter hemi-methylated DNA (C) is recognised by DNMT isoform 1 which methylates CpG sites on the new strand using the old one as a template (D).

Figure 3

Euchromatin and heterochromatin. Unmethylated CpG islands (blank circles), permissive histone modifications (green stars) and loose chromatin structure promote gene transcription in the euchromatin state. Conversely, DNA methylation (red circles), repressive histone modifications (red stars) and condensed structure prevent transcription in the heterochromatin state. Although governed by distinct enzymes, cooperativity and interaction between the different epigenetic modifications provide a self-reinforcing mechanism for epigenetic regulation. TET=Ten-eleven translocation dioxygenase; DNMT=DNA methyltransferase.

Figure 4

Epigenetic control of the Th2 locus. Master regulator GATA-3 is induced by TCR and IL-4 receptor activation and maintains its own expression with a positive feedback mechanism. GATA-3 induces repressive histone modifications at Th1 loci (TBET, IFNG). It interacts with HAT enzyme p300 with chromatin remodeling complex component Chd to induce permissive histone and chromatin changes at the Th2 LCR. Distribution of main epigenetic marks at the Th2 LCR [23] are presented in the lower box.

Figure 5

Transgenerational amplification hypothesis. Panel A depicts a purely environmental model for the rise of atopic disease, in which a change in environment increases baseline genetic risk for the disease. Panel B depicts an epigenetic transgenerational inheritance model, in which a persistent change in environment does not only increase baseline risk but induces transmittable epigenetic changes leading to amplification of the phenotype with every subsequent generation. Return to a normal environment, will lead to resolution of the phenotype but only after 2 generations.

Figure 6

Loci identified from previous DNA methylation association studies for asthma, atopy and related exposures.