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Curr Allergy Asthma Rep (2012) 12:211–220
DOI 10
...
Miller

Published online: 27 March 2012
# Springer Science+Business Media, LLC 2012

Abstract Environmental epigenetic regulation in asthma
and allergic disease is an exciting area that has gained a
great deal of scientific momentum in recent years
...
In addition,
several known allergy and asthma genes have been found
to be susceptible to epigenetic regulation
...
” The field has certainly advanced
significantly in the past year
...
Asthma
...
Environment
...
Histone modification
...

T-helper cell
...
Transgenerational
...
Lovinsky-Desir
Division of Pediatric Pulmonary, Columbia University
College of Physicians and Surgeons,
630 West 168th Street,
New York, NY 10032, USA
e-mail: stl2003@nyp
...
L
...
edu

Introduction
Recently, there have been numerous publications addressing
the role of epigenetic regulation in complex diseases, and
how environmental exposures may induce these molecular
events
...
They may explain immune modulation induced by
the environment even when we cannot measure the inciting
environmental exposure itself
...

All these explanations fit well with why epigenetic regulation may be an important mechanism in asthma and
allergic disease
...
Allergies
and asthma are more likely to develop in children if the mother
has allergies or asthma compared with the father, suggesting
the possibility of intrauterine programming [3, 4]
...
Furthermore, several known atopy and asthma genes have been found to be susceptible to
epigenetic regulation, including genes important to
T-effector pathways (interferon (IFN)-γ, interleukin (IL)4,
IL13, IL17) [8–13], T-regulatory pathways (forkhead box
P3 [FoxP3]) [14], and airway inflammation (arginase
[ARG], inducible nitric oxide synthase [iNOS]) [15, 16]
...


212

Curr Allergy Asthma Rep (2012) 12:211–220

Table 1 Mechanisms of epigenetic regulation
Site(s) of action
DNA methylation

Histone modification

Noncoding RNAs

Mechanism(s) of action

Effect(s)

CpG islands (stretches of DNA
>200 bp with >50% GC content)
and other CpG regions (<200 bp)
Histone proteins (H2A, H2B, H3,
and H4) that form the nucleosome
core

Addition of methyl group to the 5′ position
of cytosines by DNMTs

Turn off gene transcription

Chromatin remodeling by methylation,
acetylation (via HAT, HDAC),
phosphorylation, or ubiquitylation
of histone tails
Regulatory transcripts: binding of miRNA
to the 3′ untranslated regions of mRNA

Regulate accessibility of DNA
to RNA polymerase II
and transcription factors

miRNAs (21–23 nucleotide long
regulatory RNAs)

Induce degradation
of target mRNA

CpG, cytosine-phosphate-guanine, DNMT, DNA methyltransferase; HAT, histone acetyltransferases, HDAC, histone deacetylases; miRNA,
microRNA

The scientific literature in recent years has benefited from
the publication of numerous comprehensive review articles
and call for more studies on epigenetic regulation in allergic
disease and asthma [17–19]
...
The published experimental work, with few exceptions [15, 16, 20], mostly has comprised small observational
studies and models in cell systems and animals [21–23]
...
Advances were made in many areas, including 1)
better characterization of how several environmental asthma
triggers induce epigenetic changes, 2) better characterization
of how allergic immune pathways and regulatory pathways
important to asthma undergo epigenetic regulation, 3) growing evidence of active epigenetic regulation in asthma experimental models and the production of asthma
biomarkers, 4) experimental evidence of transmission of
an asthma-related phenotype across multiple generations,
and 5) “pharmaco-epigenetics
...


Environmental Asthma Triggers
Among the airborne pollutants, the one most associated with
the induction of epigenetic changes is tobacco smoke
...
Blocking deacetylation or removal of acetyl
groups on the histone presumably permitted greater access
of the DNA to RNA polymerases and transcription factors,
augmented the inflammatory cytokine gene transcription,
and thereby reduced the efficacy of anti-inflammatory therapy such as glucocorticoids in chronic obstructive lung
disease [24]
...
Liu and colleagues [27•], in an
informative experimental model using primary and immortalized human airway epithelial cells chronically exposed to
cigarette smoke condensate, found that smoke condensate
induced dose- and time-dependent histone alterations that
were associated with decreased expression of DNA methyltransferase (DNMT)1 and increased expression of
DNMT3b, enzymes that catalyze the transfer of methyl
groups to DNA
...
In addition, prenatal exposure to cigarette smoke in
a pediatric cohort was associated with decreased DNA
methylation globally, as indicated by reduced methylation
of Alu sequences (the short interspersed nucleotide elements) and in CpG regions in the promoter of receptor
tyrosine kinase (AXL), protein tyrosine phosphatase receptor
type (PTPRO), and other genes [28•]
...
Ambient levels of another combustion
traffic emission, namely polycyclic aromatic hydrocarbons
(PAH), measured from backpacks worn by pregnant women
were associated with asthma and allergy candidate genespecific changes in DNA methylation [31]
...
Nadeau and

Curr Allergy Asthma Rep (2012) 12:211–220

colleagues [33•] found while studying asthmatic children
living in either the relatively polluted Fresno area (ie, airborne fine particulate matter concentrations that exceeded
federal annual standards) versus cleaner Stanford areas of
California that children with greater exposure to air pollution were more likely to have evidence of increased DNA
methylation of the forkhead box P3 (FoxP3) transcription
factor and impaired T-regulatory (Treg) function
...
Moreover, changes in the
expression of several miRNAs have been reported in association with exposure to particulate matter
...
They
found in foundry workers from an electrical furnace steel
plant that estimated individual levels of exposure to fine
particulate matter and metals were associated with both
upregulation and downregulation of an array of miRNAs
important in inflammation and oxidative stress [36••]
...

Given the presumption that folic acid supplementation is a
source of methyl donors that could alter DNA methylation
and thereby gene expression, its use has become the focus of
several studies
...
The allergic
phenotype was associated with altered DNA methylation of
several genes, including the T-cell suppressor runt related
transcription factor 3 (RUNX3) [39]
...
However, data on folic
acid supplementation in humans and associated allergic
disease have been mixed
...
This debate arguably continued this past year,
when Haberg and colleagues [44], in follow-up studies now
looking at nonfasting plasma folate levels in their cohort of
pregnant mothers, reported a trend of increasing risk of
asthma in children across quintiles of plasma folate levels
during pregnancy
...
[45••] found
that folic acid use during pregnancy was not associated with

213

a greater risk of wheeze, asthma, or eczema
...
Therefore, the weight of
current evidence is insufficient to recommend any change
from the current practice of periconceptional folic acid
supplementation to protect children from neural tube
defects
...
Indeed, higher
intake of vitamin D during pregnancy has been associated
with some protection from wheeze in children at age 5 years
[46]
...
Evidence of epigenetic regulation of these
processes thus far is limited, though in one recent study,
the active metabolite, 1,25-dihydroxyvitamin D3, upregulated histone H4 acetylation and participated in other chromatin remodeling events important to the expression of
proinflammatory genes [48]
...
In one paper, the promoter of
the peanut allergen Ara h 3 underwent changes in histone
acetylation influencing its gene expression in early- and
late-maturation embryos [49]
...


Allergic Immune and Regulatory Pathways Important
to Asthma
Growing fundamental cellular and experimental work continues to provide strong biological support for the premise
that key pathways important to the allergic immune response, such as T-cell differentiation and Treg function,
are susceptible to distinct epigenetic modifications
...
For example, we now are learning that proallergic T-helper type 2 (Th2) or counterregulatory Th1
cytokine production such as IFN-γ by human effector T
cells can be flexible or plastic [52]
...
New findings also have emerged
detailing the induction of FoxP3, a Treg-specific transcription factor, and its dependence on DNA methylation and
histone modifications [14, 54, 55]
...
[58]

Th2

Chromatin remodeling of the Th2 cytokine locus critical to systemic and airway
inflammation
HDAC1 important to early Th2 cell differentiation and development of allergic airway
inflammation

Grausenburger et al
...
[60]

CTLA-4

miR-155 upregulated in atopic dermatitis and its overexpression associated with
decreased CTLA-4

Lim et al
...
[70]

IL-13

Polikepahad et al
...
[62••]

STAT6

Inhibition of DNMT increased STAT6 expression

Tanaka et al
...
[65]

IL4, IL13
IL17

Targeted deletion of HS sites in the IL-4–IL-13 locus inhibited GATA-3 activation
Th17 cell lineage is not stable and mediated epigenetically through chromatin
remodeling

FoxP3

Differential FoxP3 methylation in thymus derived nTreg versus peripheral
TGF-β–induced Treg

Treg pathway responses
Lal and Bromberg [67•]

Th and Treg pathway responses
Janson et al
...
[68]

Th2, Treg

Epigenetic immune lineage analysis profiled CD4+ cells in rheumatoid arthritis,
multiple sclerosis
Memory antigen-specific Th2 cells can redifferentiate into functional Tregs

CBP, cAMP-responsive element binding protein; CTLA, cytotoxic T-lymphocyte antigen; DNMT, DNA methyltransferases; FoxP3, forkhead box
P3; GATA-3, trans-acting T-cell–specific transcription factor 3; HDAC, histone deacetylases; HS, DNase I-hypersensitive site; IL, interleukin;
miRNA, microRNA; nTreg, natural Treg; STAT6, signal transducer and activator of transcription 6; Th, T helper; Treg, regulatory T cell

methylation, histone changes, and miRNA in these pathways, as well as better localization of the sites involved
...
The
method involves profiling each lineage in an isolated population of human CD4+ T cells based on the specific CpG
methylation status of signature cytokine and transcription
factor loci
...
Their technique holds some interesting promise for
future studies in the ability to define epigenomes relevant to
a cell population and possibly many clinical diseases, including allergy and asthma [57]
...
These cLCR

knockout mice experienced a loss of general H3 acetylation
and histone H3-K4 methylation and demethylation of the
DNA in the Th2 cytokine locus
...
Grausenburger et al
...
Using ChIP
assays in nonactivated naïve CD4+ T cells, they also showed
that HDAC was bound to the IL-4 gene locus, suggesting
HDAC may be particularly important during early T-cell
differentiation [59]
...
miR-155 was one of the most upregulated
miRNA in atopic dermatitis lesions and was most expressed
in the infiltrating immune cells
...

Major advances describing epigenetic regulation of the
pro-allergic cytokine IL-13 were made this year as well
...
Inhibition of HDAC (using culture of primary esophageal
epithelial cells with trichostatin A) and induction of acetylated histone 3 increased IL-13–induced, and CBPmediated, eotaxin-3 gene expression
...
The critical IL-4 signaling transcription
factor STAT6 also appears susceptible to DNA methylation
...
In a recent study by Tanaka
and colleagues [63••], a greater understanding was gained
regarding chromosome modification of the IL-4 locus during Th2 differentiation
...
Targeted deletion of a
series of HS sites in the IL4–IL13 locus led to functional
impairment of epigenetic regulation of the IL4 locus in mice
...

Th17 cells comprise a relatively recently discovered subset of T-helper cells producing IL-17 that provide host
defense against extracellular bacteria, especially at the mucosa
...
More recent work this year
by Mukasa and colleagues [65] focused on the stability
versus plasticity of IL-17 epigenetic changes
...
The experiments were
intended to shift toward a Th1 phenotype (after IL-12)
versus maintain the Th17 phenotype (after TGF-β)
...
However,
STAT4- and Th1-specific T box transcription factor (T-bet)
silenced the pro-IL17 RAR-related orphan receptor gamma
(RORC) gene when the cells were stimulated with IL-12
...

In recent studies, Treg cell function and regulation of
FoxP3 transcription have emerged as targets of epigenetic
modifications
...
Since then, the FoxP3 promoter has been
shown to undergo both histone acetylation and DNA methylation affecting gene transcription (reviewed in [14])
...
FoxP3 methylation
also distinguished natural Treg (nTregs), found in the thymus, from TGF-β–induced Tregs, found in the periphery
[67•]
...
These new Tregs functioned as usual Tregs and were
able to downregulate key transcription factors such as
GATA-3 and IRF-4, suppress T-cell proliferation, and suppress pro-allergic cytokine production
...
Also, they were able to home very efficiently
to the airways [68]
...
In attempt to identify epigenome-wide
DNA methylation, Fedulov and Kobzik [69] isolated splenic
DCs from their neonatal asthma–susceptible murine model
...
They found an increase in the
overall methylation and increased allergen presentation in
the sensitized DCs compared with DCs isolated from control mice that were not sensitized but were otherwise genetically and environmentally identical
...


Asthma Experimental Models and Asthma Biomarkers
The recent literature, using animal models for asthma and
biomarkers as surrogates of the human disease processes,
has brought us exciting new support for epigenetic regulation in asthma
...
Intranasal administration of let-7 reduced the allergic
phenotype (airway inflammation, airway hyperresponsiveness, mucus metaplasia, and subepithelial fibrosis) in sensitized mice [70]
...
Short RNAs and miRNAs were very enriched in both
naïve and allergen-sensitized and challenged mouse lungs,
with the most abundant ones belonging to the let-7 family
...
The authors attributed these
unexpected findings to the large (>800) repertoire of targets
of let-7 miRNAs and possible secondary effects [71•]
...
Interestingly, the authors identified significantly elevated levels of miR-145, miR-21, and
let-7b in the HDM-induced allergic airways
...
Of the miRNAs identified, they
found that the most significant proinflammatory role was
played by miR-145 that, when specifically inhibited, suppressed allergic inflammation and airway remodeling
...
These informative studies are among the
few to identify altered regulation of specific miRNAs in
allergic-mediated inflamed airways and point to potential future therapeutic targets directed at airway inflammation [72]
...
Under the
auspices of the Children’s Health Study, methylation levels of
several CpG loci located in the promoter regions of the iNOS
and ARG genes were compared with levels of fractional
exhaled nitric oxide (FeNO), an established asthma biomarker
associated with airway inflammation and lung function decrements, among their asthmatic children
...

In comparison, Isidoro-Garcia and colleagues [73] compared CpG methylation levels in a small cohort of allergic
asthmatic patients with that of controls for the D prostanoid
receptor (PTGDR) gene that mediates the production of
PGD2
...
One site of differential methylation was located at the
same site as a recognized 613C>T single nucleotide polymorphism, possibly implicating genetic and epigenetic factors in the association with allergic asthma [73]
...
However,
also intriguing is the notion that these epigenetically regulated genes may be passed from parent to offspring
...
However, there was a huge
paradigm shift more than 10 years ago that disproved that
previously held belief in pivotal work involving agouti mice
performed by Morgan et al
...
Since their discoveries, there is now emerging evidence that environmental factors may alter the germline of
the epigenome, leading to transgenerational epigenetic inheritance [76]
...
This work suggests that intrauterine events yield sustained effects on the
child’s phenotype, possibly via passage of epigenetic marks
through the germline
...

Brand and colleagues demonstrated a microbial protective
effect from asthma that appears to be inherited transgenerationally in a murine model
...
Female
BALB/c mice sensitized to ovalbumin (vs negative controls)
were exposed to A
...
5 weeks
before mating and every other day during pregnancy) and
studies were performed on their offspring (who were not
exposed to A
...
They found that stimulated T cells from
the splenic mononuclear cells of these offspring had significantly decreased ability to produce Th2 cytokines such as IL4, IL-5, and IL-13, while production of the counterregulatory
IFN-γ remained intact, suggesting a blunted pro-allergic Thelper cell response
...
These experiments suggest that prenatal
A
...

Furthermore, our group hypothesized that combined prenatal in vivo exposure to Aspergillus fumigatus allergen and
diesel exhaust particles was associated with changes in the
asthma phenotype in the mouse offspring as well
...
fumigatus and mating, pregnant BALB/c mice were exposed to additional A
...
At age 9 10 weeks, the offspring were sensitized and challenged with
A
...
Adult offspring from mice that were exposed

Curr Allergy Asthma Rep (2012) 12:211–220

to A
...
Adult offspring of mice that were exposed to both
A
...

Transgenerational passages of phenotypes and differential DNA methylation also recently were published in Arabidopsis thaliana plants
...
Their findings suggest transgenerational methylation variation over multiple generations
may affect gene transcription without changing the sequence
of the genome [79]
...


Pharmaco-Epigenetics
Epigenetic regulation also has emerged as a potential mechanism for the action of asthma-related pharmacologic therapies
...
Corticosteroids bind intracellularly to glucocorticoid receptors, which become activated
and bind to glucocorticoid response elements in the promoter regions of glucocorticoid-responsive genes
...
Yet another proposed mechanism
of corticosteroid action through induction of miRNA expression was studied in a recent paper by Williams and
colleagues [81•] and found to be noncontributory
...
Although there was significant improvement in methacholine challenge following
treatment, there was no change in the miRNA pattern following treatment with inhaled corticosteroids [81•]
...


217

Finally, PGI2 analogues have emerged as potential new
asthma therapies because of their anti-inflammatory effects
...

These findings suggest that the PGI2 analogues in fact may
increase Th2 pro-allergic inflammation via histone modifications of chemokines [82]
...


Conclusions
Recent publications shed a great deal of light on several
important epigenetic responses to environmental exposures,
epigenetically regulated molecular pathways, and experimental models of allergy and asthma
...
Questions remain regarding the time
course of these epigenetic mechanisms in vivo as well as the
sustainability of their effects
...

Acknowledgments Dr
...

Dr
...

Disclosure No potential conflicts of interest relevant to this article
were reported
...
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73
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75
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77
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Curr Allergy Asthma Rep (2012) 12:211–220
production, suggesting significant complexities in these pathways
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Nat Genetics
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80
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82
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This is one of the few studies to look at the long-term
effects of prenatal allergen and environmental pollution exposure
on adult offspring mice
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fumigatus or diesel
exhaust particles
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Schmitz RJ, Schultz MD, Lewsey MG (2011) Transgenerational
epigenetic instability is a source of novel methylation variants
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Targeting the epigenome in the treatment of asthma and
chronic obstructive pulmonary disease
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2009;6:693–96
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MicroRNA expression profiling in mild asthmatic
human airways and effect of corticosteroid
...
2009;4(6):
e5889
...
They found
that iloprost had enhancing effects of histones in the Th2 pathway
(histone H3 acetylation) versus suppressive effects of the Th1
pathway
...
Effects of PGI2 analogues on Th1- and Th2-related chemokines
in monocytes via epigenetic regulation
...
2011;89:29–
41

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