Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma

SUMMARY Development of asthma in childhood is linked to viral infections of the lower respiratory tract in early life, with subsequent chronic exposure to allergens. Progression to persistent asthma is associated with a Th2-biased immunological response and structural remodelling of the airways. The...

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Main Authors: Adam Collison, Jessica S. Siegle, Nicole G. Hansbro, Chau-To Kwok, Cristan Herbert, Joerg Mattes, Megan Hitchins, Paul S. Foster, Rakesh K. Kumar
Format: Article
Language:English
Published: The Company of Biologists 2013-07-01
Series:Disease Models & Mechanisms
Online Access:http://dmm.biologists.org/content/6/4/993
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author Adam Collison
Jessica S. Siegle
Nicole G. Hansbro
Chau-To Kwok
Cristan Herbert
Joerg Mattes
Megan Hitchins
Paul S. Foster
Rakesh K. Kumar
author_facet Adam Collison
Jessica S. Siegle
Nicole G. Hansbro
Chau-To Kwok
Cristan Herbert
Joerg Mattes
Megan Hitchins
Paul S. Foster
Rakesh K. Kumar
author_sort Adam Collison
collection DOAJ
description SUMMARY Development of asthma in childhood is linked to viral infections of the lower respiratory tract in early life, with subsequent chronic exposure to allergens. Progression to persistent asthma is associated with a Th2-biased immunological response and structural remodelling of the airways. The underlying mechanisms are unclear, but could involve epigenetic changes. To investigate this, we employed a recently developed mouse model in which self-limited neonatal infection with a pneumovirus, followed by sensitisation to ovalbumin via the respiratory tract and low-level chronic challenge with aerosolised antigen, leads to development of an asthmatic phenotype. We assessed expression of microRNA by cells in the proximal airways, comparing changes over the period of disease progression, and used target prediction databases to identify genes likely to be up- or downregulated as a consequence of altered regulation of microRNA. In parallel, we assessed DNA methylation in pulmonary CD4+ T cells. We found that a limited number of microRNAs exhibited marked up- or downregulation following early-life infection and sensitisation, for many of which the levels of expression were further changed following chronic challenge with the sensitizing antigen. Targets of these microRNAs included genes involved in immune or inflammatory responses (e.g. Gata3, Kitl) and in tissue remodelling (e.g. Igf1, Tgfbr1), as well as genes for various transcription factors and signalling proteins. In pulmonary CD4+ T cells, there was significant demethylation at promoter sites for interleukin-4 and interferon-γ, the latter increasing following chronic challenge. We conclude that, in this model, progression to an asthmatic phenotype is linked to epigenetic regulation of genes associated with inflammation and structural remodelling, and with T-cell commitment to a Th2 immunological response. Epigenetic changes associated with this pattern of gene activation might play a role in the development of childhood asthma.
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spelling doaj.art-329730ceb18d4a199498b2b335ceab9b2022-12-22T03:15:33ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112013-07-0164993100010.1242/dmm.011247011247Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthmaAdam CollisonJessica S. SiegleNicole G. HansbroChau-To KwokCristan HerbertJoerg MattesMegan HitchinsPaul S. FosterRakesh K. KumarSUMMARY Development of asthma in childhood is linked to viral infections of the lower respiratory tract in early life, with subsequent chronic exposure to allergens. Progression to persistent asthma is associated with a Th2-biased immunological response and structural remodelling of the airways. The underlying mechanisms are unclear, but could involve epigenetic changes. To investigate this, we employed a recently developed mouse model in which self-limited neonatal infection with a pneumovirus, followed by sensitisation to ovalbumin via the respiratory tract and low-level chronic challenge with aerosolised antigen, leads to development of an asthmatic phenotype. We assessed expression of microRNA by cells in the proximal airways, comparing changes over the period of disease progression, and used target prediction databases to identify genes likely to be up- or downregulated as a consequence of altered regulation of microRNA. In parallel, we assessed DNA methylation in pulmonary CD4+ T cells. We found that a limited number of microRNAs exhibited marked up- or downregulation following early-life infection and sensitisation, for many of which the levels of expression were further changed following chronic challenge with the sensitizing antigen. Targets of these microRNAs included genes involved in immune or inflammatory responses (e.g. Gata3, Kitl) and in tissue remodelling (e.g. Igf1, Tgfbr1), as well as genes for various transcription factors and signalling proteins. In pulmonary CD4+ T cells, there was significant demethylation at promoter sites for interleukin-4 and interferon-γ, the latter increasing following chronic challenge. We conclude that, in this model, progression to an asthmatic phenotype is linked to epigenetic regulation of genes associated with inflammation and structural remodelling, and with T-cell commitment to a Th2 immunological response. Epigenetic changes associated with this pattern of gene activation might play a role in the development of childhood asthma.http://dmm.biologists.org/content/6/4/993
spellingShingle Adam Collison
Jessica S. Siegle
Nicole G. Hansbro
Chau-To Kwok
Cristan Herbert
Joerg Mattes
Megan Hitchins
Paul S. Foster
Rakesh K. Kumar
Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma
Disease Models & Mechanisms
title Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma
title_full Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma
title_fullStr Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma
title_full_unstemmed Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma
title_short Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma
title_sort epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma
url http://dmm.biologists.org/content/6/4/993
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