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Keywords:

  • asthma;
  • epigenetic;
  • fetus;
  • remodeling

Abstract

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

Asthma has been associated with an exaggerated T-helper type 2 (Th2) over Th1 responses to allergic and nonallergic stimuli, which leads to chronic airway inflammation and airway remodeling. In the present article, we propose that many of the genes involved in IgE synthesis and airways (re)modeling in asthma are persistent or reminiscent fetal genes which may not be silenced during early infancy (or late pregnancy). Genes of the embryologic differentiation of ectodermic and endodermic tissues may explain some of the patterns of airway remodeling in asthma. In utero programming leads to gene expression, the persistence of which may be associated with epigenetic inheritance phenomena induced by nonspecific environmental factors. Clear delineation of these issues may yield new information on the mechanisms of asthma and new targets for therapeutic intervention and primary prevention.

Asthma is a heterogeneous and multifactorial disease and although classically two different pathologic entities, allergic and nonallergic asthma, have been described, the differences are not clearly understood yet (1). Asthma has been associated with an exaggerated T-helper type 2 (Th2) over Th1 responses to allergic and nonallergic stimuli (2, 3), which leads to chronic airway inflammation (4, 5). Alternative hypotheses may be that the innate immune system may also be specially programmed for anti-infectious defense and abnormally programmed in inflammatory disease such as asthma (6, 7).

Allergic asthma usually starts early in life (8, 9) and most asthmatic children are allergic. The early occurrence of allergic asthma suggests that prenatal influences are of importance (10, 11) and it is likely that defects in early development of the lung, as well as the immune system are involved in the pathogenesis of asthma.

Epidemiologic surveys indicate that there has been a notable increase in the prevalence of both asthma and other allergic diseases within the past 30–40 years in developed countries (12) and within the past 10–15 years in developing countries (13). Environmental factors interact early in life with gene susceptibility to induce allergenic sensitization and may determine whether sensitization eventually leads to clinical disease (14). It is thought that new environmental factors have lead to the increased prevalence of allergy and asthma. It is however unlikely that these new environment–gene interactions have lead to major changes in the sequence of DNA since only few unknown sensitizations have occurred within the past decades. However, these interactions may have induced epigenetic inheritance of ‘allergy’ and/or ‘asthma genes’.

In the present article, we propose that many of the genes involved in IgE synthesis and airways (re)modeling in asthma are reminiscent or persistent fetal genes (15), which may not be silenced during early infancy (or late pregnancy) by epigenetic mechanisms and we hypothesize that their gene products might play an important role in the induction and maintenance of the pathogenesis of allergic asthma.

Perinatal influences on IgE-mediated allergy

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

It has been hypothesized that during pregnancy the immunologic milieu of the placenta is constitutively skewed away from Th1 dominated response and shifted towards the Th2 phenotype (16–18).

Allergy may start during fetal life and that the risk of such a development may be amplified by prenatal exposure to allergens (10). In some infants who will later develop atopy, these Th2-cytokine-mediated immune responses appear to be preserved in early periods of infancy (19, 20) and may be perpetuated in those who will develop persistent atopic disease (21). On the contrary, a generalized immaturity or suppression of both Th1 and Th2 type immune responses may occur at birth in atopy-prone babies (22), followed by a delayed maturation of the Th1 pathways leading to an enhanced release of Th2 cytokines which will perpetuate Th2-driven responses (19). Postnatal IFN-γ upregulation is usually delayed until the age of 1 year and rises steadily thereafter (18). It is therefore possible that there is a persistence of the fetal state in children who are developing atopy, because of a defect in Th2-dampening mechanisms.

The postnatal maturation of the immune system characterized in allergic asthmatics by the development of an imbalanced Th2 immunity is genetically determined and modified by the environment (23). Several hypotheses have been proposed to explain the rise in allergy and asthma observed in young children. These are based on early life events acting on genetic susceptibility. They include the ‘hygiene hypothesis’ associated with the lack of ‘natural’ infections (24–28), a change in the composition of the gastrointestinal flora (29) and an increase in IgE production by automobile pollution (30). On the contrary, there are environmental exposures which were found to reduce the prevalence of atopy. These include a down-regulation of the IgE immune response by endotoxins (31–36) or a complex anthroposophic lifestyle associating a lack of vaccinations and a particular diet (37).

The timing of environmental exposures may be critical. Thus, although the feto-maternal interface and early life events seem of importance for the development and persistence of atopy (38), there may be later environmental exposures which can modify the atopic status. Such an ‘allergic breakthrough’ may be a consequence of disturbance in normal ‘damping’ of IgE antibody production (39; Fig. 1).

image

Figure 1. ‘Allergic breakthrough’: in 1979, Katz (39) proposed the concept of the ‘allergic breakthrough’. Immunoglobulin E antibodies against environmental allergens are synthesized when ‘damping’ mechanisms are down-regulated either in infancy or later in life. The synthesis of IgE can be reduced or even abolished if these ‘damping’ mechanisms are increased by environmental factors. This concept is still valid 20 years later but needs some modification as allergic diseases may start in utero and the increased prevalence of allergic diseases is probably associated with perinatal environment–gene interactions.

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It was thought that atopy was a persistent state which was not reversible. However, there are several epidemiologic studies suggesting that some atopic individuals may loose their propensity to respond to environmental allergens by an IgE immune response (40, 41).

Bronchial remodeling in asthma

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

In asthma, tissue modeling and remodeling co-exist in a dynamic process (4). Features of airways remodeling in asthma encompass epithelial activation, the presence of myofibroblasts beneath the basement membrane, reticular basement membrane pseudo-thickness, increase in smooth muscle mass and mucous gland enlargement (for review see 4, 42).

Airways inflammation and remodeling already exist in infants who will subsequently develop asthma (43). Reticular basement membrane thickening is already present in children with difficult asthma and to a similar extent to that seen in adults with asthma (44). Thus, important questions are whether remodeling of the airway wall precedes asthma (45), and if airways remodeling is in fact associated with the persistence of fetal processes (15).

Processes of wound healing and airway remodeling in asthma have common features as cell proliferation and differentiation involved in the restoration of the normal tissue architecture are to a certain degree reminiscent of the embryonic development of the corresponding tissue (46).

The complex process of lung formation is determined by the action of numerous genes that influence cell commitment, differentiation, and proliferation (47). The pattern of branching of the lung endoderm is regulated by the surrounding mesenchyme leading to the concept of the epithelial–mesenchymal trophic unit (48–50).

In asthma, abnormal signaling between the epithelium, in contact with the environment, and the underlying (myo)fibroblasts and dendritic cells may reactivate the epithelial–mesenchymal trophic unit, which is involved in fetal lung development and branching (42, 51). There are several features of the developing lung which are present in asthma, and it has been observed that allergen exposure induces the expression of some of the these embryologic features such as enhanced expression of tenascin (52) or the development of myofibroblasts (53). Moreover, positional cloning in asthmatics has identified a number of candidate molecules that are probably fundamental to asthma pathogenesis. These include ESE-3 (54–56), ADAM33 (57, 58) and SPINK5 (59, 60). Each of these genes may influence the epithelial–mesenchymal trophic unit (42).

Genes of the embryologic differentiation may govern airway remodeling in asthma

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

The differences in nasal and bronchial remodeling in patients with concomitant rhinitis and asthma may be related to differences in the embryologic origin of the nose and bronchi. The chronology of the embryologic development of the upper and lower airways is similar. It begins during the fourth week of gestation and continues for many years after birth. However, the nose develops from the ectoderm [nasal placode and the nasal prominence (66)], with the larynx, trachea, bronchi, and lungs developing from the endoderm (laryngotracheal groove in the ventral wall of the primitive pharynx) (67). Genes of the embryologic development may therefore be associated with prevention or induction of airway remodeling, and airway remodeling in asthma may be associated with the persistence and/or later reactivation of some of these genes.

Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

It has been suggested that a reactivation of the epithelial–mesenchymal trophic unit may exist in asthma (51). We would like to extend this notion by proposing that this trophic unit still exists at birth in the neonate who will develop asthma, suggesting the persistence of immature features of the developing lung. Two nonexclusive hypotheses may then be proposed.

First, there may be an early defect involving Th2 and branching genes leading to a permanent abnormality of the epithelial–mesenchymal trophic unit. This would suggest that gene defects in asthma do not allow the full maturation of fetal tissues and that there is a delayed maturation of the fetal lung in asthma before and just after birth. This concept is in line with the in utero programming of chronic disease proposed by Barker (68, 69). In this hypothesis, any human fetus has to adapt to a limited supply of nutrients. In doing so, it permanently changes its structure and metabolism. These ‘programmed’ changes may be the origin of a number of diseases later in life including coronary heart disease and the related disorders such as stroke, diabetes and hypertension. Programming agents might include growth factors, hormones, and nutrients (70, 71; Fig. 2).

image

Figure 2. In utero programming and perinatal environment–gene interactions in allergic asthma. (A) Normal subject: in normal infants, the Th2/Th1 imbalance of pregnancy is rapidly reversed towards the normal Th1/Th2 balance preventing the synthesis of IgE against environmental allergens. (B) allergic asthmatic: in infants who will subsequently develop allergic asthma, the Th2/Th1 imbalance of pregnancy is maintained (by different mechanisms) and leads to the synthesis of IgE against environmental allergens. In utero programming induces some patterns of airway remodeling (1). This is further increased by airway inflammation which occurs following the IgE-mediated immune response (2).

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Alternatively, in atopic asthma, some genes expressed in the fetus may not be repressed prenatally or in early infancy under the influence of the environment. This proposal would lead to the concept of the persistence of the epithelial–mesenchymal trophic unit. Certain genes in the developing lung which are unwanted after birth would therefore persist associated with a defect in gene silencing.

Gene silencing

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

If fetal genes are expressed during childhood and later in life in allergic asthma, several mechanisms including gene silencing and epigenetic phenomena may be involved.

Gene expression in eukaryotes in response to environmental and developmental stimuli is a complex phenomenon involving the coordinated silencing and activation of gene expression by the actions of many factors, including transcriptional (72) and post-transcriptional mechanisms.

Chromatin modification and DNA methylation are two important and interrelated mechanisms that regulate gene expression.

Histones and chromatin

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

In eukaryotes, the DNA of all chromosomes is packaged in an ordered way into a compact structure with the aid of histones (73; Fig. 3). Not all DNA is folded in exactly the same way and the manner in which a region of the genome is packaged into chromatin affects the activity of the genes contained in this region (74). Around 10% of the chromatin is highly condensed (heterochromatin) and transcriptionally inactive. New functions of heterochromatin including gene silencing have been described (75). The rest of the chromatin is less condensed (euchromatin), with 15% being transcriptionally active and 85% being inactive. The four nucleosomal histones appear to be unusually acetylated in active chromatin (76). The traditional view of active and inactive chromatin may however be too simple as recent evidence showed that combinations of diverse histone tail modifications represent a spectrum of chromatin states (77).

image

Figure 3. Role of histones acetylation in gene transcription. TF, transcription factor; HAT, histone acetyltransferase; HDAC, histone deacetylase. Adapted from Ref. (79).

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Transcriptionally active genes reside in chromosomal domains characterized by an elevated rate of digestion by DNase I, increased acetylation of histone tails and well defined boundaries. These features are not simply a consequence of transcription, but rather relate to a more general property such as decondensation of the chromatin domain (74).

Histone acetylation–deacetylation

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

The structure of the flexible and charged histone tails that extend from the hydrophobic nucleosome core (78) has a key role in transcription. Histone tails are modified by acetylation and deacetylation, phosphorylation, methylation, and ubiquitination (79, 80). These modifications regulate functions as diverse as transcription, DNA-dependent chromatin assembly, DNA repair, mitosis and silencing (81). Histone acetylation contributes to the formation of transcriptionally competent environment by ‘opening’ chromatin and allowing general transcription factors to gain access to the DNA template (78). Conversely, histone deacetylation mainly contributes to a ‘closed’ chromatin state and transcriptional repression (82). Many enzymes that catalyze either acetylation of the lysine residues of the histone tails (histone acetyl transferase, HATs) (83) or histone deacetylation (histone deacetyl transferase, HDACs) have been identified (84, 85).

DNA methylation

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

The cytidine phosphate guanosine (CpG) sequence is depleted about fivefold in the human genome. There are, however, regions of the genome that maintain a normal density of CpG dinucleotides. These regions are called CpG islands and are frequently found at the 5′ ends of the genes (86; Fig. 4). Deoxyribonucleic acid methylation is important in the control of gene transcription and chromatin structure (87). Chromatin remodeling enzymes and histone methylation are essential for proper DNA methylation patterns.

image

Figure 4. Role and transmission of methylated cytidine phosphate guanosine (CpG).

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Cytosine methylation of CpG dinucleotides exerts a major influence on transcription (88, 89). Methylation of promoter-associated CpG islands can inhibit transcription by restricting the access of transcription factors and inducing histone deacetylation (88, 90). It is not a prerequisite for the initiation of transcriptional gene silencing but it is required for its maintenance (91). Once established in somatic cells, CpG methylation-associated repression is very stable and this type of repression is used as a global silencing device to shut off all sequences in the genome, with the exception of housekeeping genes and tissue- and stage-specific genes that are destined to be expressed at the right time and in the right place. In contrast, DNA methylation is remarkably dynamic in the fetus during early mammalian development (92). Later in life, stable methylation can be alleviated either by demethylation of the DNA or by a strong activator that can override the methylation effect.

Cytidine phosphate guanosine methylation is the most common epigenetic modification of vertebrate genomes and is present in at least some members of all phylogenetic groups, suggesting that it is conserved (93).

Chromatin remodeling

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

Although histone acetylation counteracts the condensation of nucleosomes in chromatin fibers, it is unlikely to disrupt the structure of the core particle for transcription as the sites of acetylation in the tails lie outside the core particles and make little, if any, contribution to its structure. The assembly of genes into chromatin generally suppresses transcription by inhibiting the binding of key components of the transcriptional apparatus (94). To facilitate the function of such factors, there are a variety of ATP-utilizing chromatin remodeling factors whose fundamental function is the mobilization of nucleosomes via the alteration of histone–DNA contacts (95).

Chromatin remodeling complexes are factors which promote gene activation. However, they can also have a repressive activity. They comprise an ATPase subunit along with other polypeptides responsible for the regulation, efficiency and assembly of each complexes.

Chromatin remodeling factors can enhance the access of DNA-binding factors and nucleases to DNA packaged into chromatin. These activities also disrupt histone–DNA interactions in the nucleosome.

Gene silencing and epigenetic inheritance

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

Genes are sensitive to silencing. Normal development in plants and animals requires the stable inactivation of genes not needed in specific cell types. Stable gene repression is associated with the establishment and maintenance of silenced genetic states which are inherited through mitotic divisions (96).

Epigenetic inheritance is the ability of different states to be inherited without any change in the sequence of DNA. These are heritable, alternative states of gene activity that are not explained by mutation, changes in gene sequence or normal developmental regulation.

The epigenetic inheritance at the chromosomal level of gene silencing includes two global mechanisms that are involved in regulating gene expression: DNA methylation and histone modifications (97, 98).

Deoxyribonucleic acid may be modified by the covalent attachment of a moiety that is then perpetuated (99). Methylation establishes epigenetic inheritance as long as the maintenance methylase acts constitutively to restore the methylated state after each cycle of replication. A state of methylation can be perpetuated through an indefinite series of somatic mitoses. Methylation can also be perpetuated through meiosis.

Chromatin configuration can be modulated by various reversible alterations of histones including acetylation, and by energy-dependent chromatin remodeling complexes. Changes in DNA methylation and chromatin structure are intimately linked, suggesting that similar signals can elicit changes in both methylation and chromatin structure.

Transgene silencing

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

Various transgene silencing phenomena reflect the activity of diverse host defense responses that act ordinarily on natural foreign or parasitic sequences such as transposable elements, viroids, RNA and DNA viruses, and bacterial DNA. Analysis of transgene silencing has revealed novel mechanisms of epigenetic regulation based on the recognition of nucleic acid sequence homology. Depending on whether homology between interacting copies is confined to promoter regions of transcribed sequences, silencing can take place at the transcriptional or post-transcriptional level (96, 100).

Putative mechanisms of gene silencing in atopy and asthma

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

Active genes are found in regions of ‘decondensed’ chromatin associated with acetylated histones and are hypomethylated. The environment may then direct early in life the IgE immune response and the (re)modeling of the airways (Fig. 5) by several mechanisms:

image

Figure 5. From in utero programming to epigenetic inheritance in allergic asthma.

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  • By selecting for a hypermethylating phenotype. As this is an epigenetic phenomenon it can be transmitted and make the defect persistent.
  • By inducing histone deacetylation (101). This also may be an epigenetic phenomenon as it is associated with DNA methylation. The increase in HAT activity and reduced HDAC activity in asthma may underlie the increased expression of multiple inflammatory genes, and this is reversed, at least in part, by treatment with inhaled steroids (102).
  • By acting on transcription factors regulating histone acetylation/deacetylation and DNA methylation or oncogenes. This may not be an epigenetic phenomenon and only repeated exposures may induce a persistent atopic phenotype (103). However, when committed to the Th2 phenotype, the release of Th2 cytokines can perpetuate the atopic state.
  • By regulating chromatin remodeling (104).
  • By acting on DNA polymerases as this has been recently reported for the regulation of glucocorticosteroids.
  • On the contrary, strong environmental pressures may reverse later in life this phenotype and induce demethylation or histone acetylation explaining the allergic breakthrough and the disappearance of atopy in a subset of the population. Such demethylation patterns exist in some cancers (105).
  • Transgene silencing may also operate to block the naturally developing Th1 response.

Gene activation and silencing in Th2 immune response

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

The development of the immune system and the host response to microbial infection rely on the activation and silencing of numerous, differentially expressed genes. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation (106). During the differentiation of naive Th cells into Th2 effector cells, the entire IL-4/IL-13 locus is remodeled into an accessible chromatin conformation. Activation of STAT6 promotes Th2 differentiation by inducing Th2-specific transcription factors, including GATA3. Expression of GATA3 induces Th2 differentiation and enhances the Th2 cell-specific chromatin accessibility, indicating that GATA3 is a key protein that regulates differentiation through chromatin remodeling (107, 108). The DNA methylation changes at human Th2 cytokine genes coincide with DNAse I hypersensitive site formation during CD4+ T cell differentiation (109). Changes in histone acetylation at the IL-4 and IFN-γ loci accompany Th1/Th2 differentiation (110). Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene (111). Suppressor of cytokine signaling 3 (SOCS-3) regulates proliferation and activation of Th cells as well as the onset and maintenance of T(H)2-mediated allergic responses (112).

Role of infections in the prevention of allergy

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

Several surveys in children and adults have shown significantly lower prevalences of asthma and allergic diseases in eastern Europe than in western countries (113–115). In the former East Germany tremendous changes towards western lifestyle have occurred as unification and have lead to a similar rate of atopy (116). On the contrary, children living in Estonia are still protected against the development of atopy (29, 117) and this has been attributed to the intestinal flora of these children or to the high levels of endotoxins found in the environment (118).

It has been suggested that a reduced microbial stimulation during infancy and early childhood would result in a slower postnatal maturation of the immune system and development of an optimal balance between Th1- and Th2-like immunity (25). Butyrate, a major metabolite of normal gut bacteria possesses anti-inflammatory properties inhibiting IL-12 and upregulating IL-10 production by human monocytes (119). Butyrate, a histone deacetylase inhibitor, carries information from bacteria to epithelial cells by modulating the secretion of chemokines (120).

Several studies have shown that growing up on a farm confers significant protection against the development of atopy (121–124) probably through endotoxin exposure (124). There are some experiments suggesting that endotoxins may have a role in gene silencing. Endotoxin lipopolysaccharide (LPS) is a potent inflammogen which binds to histones (125, 126). Histone acetylation/deacetylation regulates, at least in part, the endotoxin-induced expression of inflammatory genes (127).

Conclusions

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References

It is likely that atopy and asthma are associated with the persistence of fetal genes, many of which are conserved. This may be associated with epigenetic phenomena of a defect in gene silencing induced by nonspecific environmental factors. Exposure to these factors during early childhood may induce a permanent altered genetic state persisting during life which may be reversed by mechanisms still undefined. Moreover, Th2 cytokines are self-perpetuating the atopic state once IgE against environmental allergens have been produced. Clear delineation of these issues may yield new information on the mechanisms of asthma and new targets for therapeutic intervention and primary prevention. The extent to which environmental effects can provoke epigenetic responses represents an exciting area of future research.

References

  1. Top of page
  2. Abstract
  3. Perinatal influences on IgE-mediated allergy
  4. (Re)modeling of the airways in asthma and fetal lung development
  5. Bronchial remodeling in asthma
  6. Nasal remodeling in rhinitis
  7. Genes of the embryologic differentiation may govern airway remodeling in asthma
  8. Is there a delayed fetal maturation or a persistence of fetal gene expression in allergic asthma?
  9. Gene silencing
  10. Histones and chromatin
  11. Histone acetylation–deacetylation
  12. DNA methylation
  13. Chromatin remodeling
  14. Gene silencing and epigenetic inheritance
  15. Transgene silencing
  16. Lack of fetal gene silencing in allergic asthma
  17. Putative mechanisms of gene silencing in atopy and asthma
  18. Gene activation and silencing in Th2 immune response
  19. Role of infections in the prevention of allergy
  20. Conclusions
  21. References
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