title: Epigenetic changes associated with disease progression in a mouse model of childhood allergic asthma.
abstract: 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.
authors.affiliation: Centre for Asthma and Respiratory Disease, University of Newcastle and Hunter Medical Research Institute, Newcastle, NSW 2308, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Collison
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Siegle
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Hansbro
authors.forename: Chau-To
authors.initials: CT
authors.lastname: Kwok
authors.forename: Cristan
authors.initials: C
authors.lastname: Herbert
authors.forename: Joerg
authors.initials: J
authors.lastname: Mattes
authors.forename: Megan
authors.initials: M
authors.lastname: Hitchins
authors.forename: Paul S
authors.initials: PS
authors.lastname: Foster
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000473:pathology* / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002648:Child; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D029122:Murine pneumonia virus / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000235:genetics
chemical_list: D035683:MicroRNAs; D015847:Interleukin-4; D007371:Interferon-gamma