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

• Research Article

First posted online April 23, 2013, doi: 10.1242/dmm.011247Dis. Model. Mech. April 23, 2013, doi: 10.1242/dmm.011247

Epigenetic changes associated with disease 

progression in a model of childhood allergic asthma

1. Adam Collison1, 
2. Jessica S. Siegle2, 
3. Nicole G. Hansbro1,
4. Chau-To Kwok2, 
5. Cristan Herbert2, 
6. Joerg Mattes1, 
7. Megan Hitchins2,
8. Paul S. Foster1 and 
9. Rakesh K. Kumar2,*

+Author Affiliations

1. ¹ University of Newcastle and Hunter Medical Research Institute, Newcastle, Australia;
2. ² University of New South Wales, Sydney, Australia

1. ↵*Author for correspondence (r.kumar@unsw.edu.au)

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 may involve epigenetic changes. To investigate this, we employed a novel 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 down-regulated 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 microRNA exhibited marked up- or down-regulation 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 microRNA included genes involved in immune/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 may play a role in the development of childhood asthma.

Research Article:

• Adam Collison, 
• Jessica S. Siegle, 
• Nicole G. Hansbro, 
• Chau-To Kwok,
• Cristan Herbert, 
• Joerg Mattes, 
• Megan Hitchins, 
• Paul S. Foster,
• and Rakesh K. Kumar

Epigenetic changes associated with disease progression in a model of childhood allergic asthmaDis. Model. Mech. 2013 dmm.011247; First posted online April 23, 2013,doi:10.1242/dmm.011247

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• Received November 2, 2012.
• Accepted April 16, 2013.

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