Reduced mouse allergen is associated with epigenetic changes in regulatory genes, but not mouse sensitization, in asthmatic children

Miller, Rachel L.; Zhang, Hanjie; Jezioro, Jacqueline; Saguer, Mariangels de Planell; Lovinsky‐Desir, Stephanie; Liu, Xinhua; Perzanowski, Matthew S.; Divjan, Adnan; Phipatanakul, Wanda; Matsui, Elizabeth C.

doi:10.1016/j.envres.2017.04.025

Cited by 11 publications

(4 citation statements)

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“…In our cohort, we observed lower FOXP3 promoter methylation in females compared to males (Additional file 1 : Figures S4 and S5), consistent with the findings in a different cohort of children. In that cohort, differences were more striking and in the opposite direction within the FOXP3 enhancer region [ 43 ]. In this current study, the association between physical activity and FOXP3 methylation among children with high BC was most notable in females compared to males (Additional file 1 : Figures S6 and S7, Additional file 2 : Table S6).…”

Section: Discussionmentioning

confidence: 99%

“…For these exploratory analyses, we chose to stratify by the upper tertile of BC based on our previous findings that physical activity was associated with decrease airway inflammation but not among children with the highest exposure to BC (upper tertile) [ 6 ]. Lastly, given that the FOXP3 gene is located on the X-chromosome and may be susceptible to X-chromosome inactivation (XCI) resulting in sex differences in methylation patterns [ 43 , 44 ], we performed ancillary analyses stratified by sex. All final models were adjusted for the following covariates: age, sex (except in models stratified by sex), race/ethnicity, height (lung function models only), body mass index (BMI) Z-score [ 45 ], asthma, atopy (total IgE ≥80 IU/mL), personal BC concentration (except in the models stratified by BC), SHS exposure, and heating season.…”

Section: Methodsmentioning

confidence: 99%

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Physical activity, black carbon exposure, and DNA methylation in the FOXP3 promoter

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BackgroundPhysical activity is associated with improvement in lung function; however, pollution exposure during physical activity can lead to a transient reduction in lung function. This paradoxical relationship may be linked to altered T regulatory (Treg) cell activity, which increases with exercise and suppresses airway inflammation, but decreases in association with exposure to air pollution. To clarify these relationships, we investigated buccal cell DNA methylation of the forkhead box p3 (FOXP3) gene promoter, a proposed biomarker of Treg activity. We hypothesized that active urban children would have lower FOXP3 promoter methylation, associated with better lung function compared to non-active children. We also hypothesized that this relationship would be attenuated by high exposure to the air pollutant black carbon (BC).MethodsWe performed a cross-sectional study of 135 children ages 9–14 who live in New York City. Activity was measured across 6 days. BC exposure was assessed by personal monitors worn for two 24-h periods, followed by lung function assessment. Buccal swabs were collected for DNA methylation analysis of three regions (six CpG sites) in the FOXP3 promoter.ResultsIn multivariable regression models, overall, there was no significant relationship between physical activity and FOXP3 promoter methylation (p > 0.05). However, in stratified analyses, among children with higher BC exposure (≥1200 ng/m3), physical activity was associated with 2.37% lower methylation in promoter 2 (CpGs −77, −65, and −58) (β estimate = −2.37%, p < 0.01) but not among those with lower BC exposure (β estimate = 0.54%, p > 0.05). Differences across strata were statistically significant (p interaction = 0.04). Among all children, after controlling for BC concentration, promoter 2 methylation was associated with reduced FEV1/FVC (β estimate = −0.40%, p < 0.01) and reduced FEF25–75% (β estimate = −1.46%, p < 0.01).ConclusionsPhysical activity in urban children appeared associated with lower FOXP3 promoter methylation, a possible indicator of greater Treg function, under conditions of high BC exposure. Reduced FOXP3 promoter methylation was associated with higher lung function. These findings suggest that physical activity may induce immunologic benefits, particularly for urban children with greater risk of impaired lung function due to exposure to higher air pollution. FOXP3 promoter buccal cell methylation may function as a useful biomarker of that benefit.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0364-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Physical activity, black carbon exposure, and DNA methylation in the FOXP3 promoter

et al. 2017

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“…We investigated the effect of mouse allergen-targeted integrated pest management and education (versus education only) on asthma morbidity. Although no significant difference was observed in asthma morbidity between the two groups after intervention, a decrease in buccal DNA, Forkhead box P3 promoter methylation was observed in the mousespecific integrated pest management group (40).…”

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confidence: 69%

Understanding Root Causes of Asthma. Perinatal Environmental Exposures and Epigenetic Regulation

Miller

Lawrence

2018

Annals ATS

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A common explanation for the origins and rising prevalence of asthma is that they involve complex interactions between hereditary predispositions and environmental exposures that are incompletely understood. Yet, emerging evidence substantiates the paradigm that environmental exposures prenatally and during very early childhood induce epigenetic alterations that affect the expression of asthma genes and, thereby, asthma itself. Here, we review much of the key evidence supporting this paradigm. First, we describe evidence that the prenatal and early postnatal periods are key time windows of susceptibility to environmental exposures that may trigger asthma. Second, we explain how environmental epigenetic regulation may explain the immunopathology underlying asthma. Third, we outline specific evidence that environmental exposures induce epigenetic regulation, both from animal models and robust human epidemiological research. Finally, we review some emerging topics, including the importance of coexposures, population divergence, and how epigenetic regulation may change over time. Despite all the inherent complexity, great progress has been made toward understanding what we still consider reversible asthma risk factors. These, in time, may impact patient care.

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“…Zhang et al identified changes in methylome and hydroxymethylome after HDM challenges in human airway bronchial epithelial cells, and these epigenetic changes are located in genes related to oxidative stress response, epithelial function and immune responses [94]. Lower mouse allergen level was identified to be associated with reduced FOXP3 DNA promoter methylation in buccal cells from asthmatic children, and methylation of FOXP3 gene was previously associated with asthma [95]. miR-155 was identified to be increased in cockroach-extract-treated human bronchial epithelial cells, and also increased in plasma of asthmatics with cockroach allergy compared with those without cockroach allergy [96].…”

Section: Environmental Allergensmentioning

confidence: 99%

The role of epigenetics in the development of childhood asthma

Koppelman

2019

Expert Review of Clinical Immunology

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Introduction: The development of childhood asthma is caused by a combination of genetic factors and environmental exposures. Epigenetics describes mechanisms of (heritable) regulation of gene expression that occur without changes in DNA sequence. Epigenetics is strongly related to aging, is cell-type specific, and includes DNA methylation, noncoding RNAs, and histone modifications. Areas covered: This review summarizes recent epigenetic studies of childhood asthma in humans, which mostly involve studies of DNA methylation published in the recent five years. Environmental exposures, in particular cigarette smoking, have significant impact on epigenetic changes, but few of these epigenetic signals are also associated with asthma. Several asthma-associated genetic variants relate to DNA methylation. Epigenetic signals can be better understood by studying their correlation with gene expression, which revealed higher presence and activation of blood eosinophils in asthma. Strong associations of nasal methylation signatures and atopic asthma were identified, which were replicable across different populations. Expert commentary: Epigenetic markers have been strongly associated with asthma, and might serve as biomarker of asthma. The causal and longitudinal relationships between epigenetics and disease, and between environmental exposures and epigenetic changes need to be further investigated. Efforts should be made to understand cell-type-specific epigenetic mechanisms in asthma.

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Reduced mouse allergen is associated with epigenetic changes in regulatory genes, but not mouse sensitization, in asthmatic children

Cited by 11 publications

References 46 publications

Physical activity, black carbon exposure, and DNA methylation in the FOXP3 promoter

Physical activity, black carbon exposure, and DNA methylation in the FOXP3 promoter

Understanding Root Causes of Asthma. Perinatal Environmental Exposures and Epigenetic Regulation

The role of epigenetics in the development of childhood asthma

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