Ten-eleven translocation 1 (TET1) methylation is associated with childhood asthma and traffic-related air pollution

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Background Asthma is a complex disorder influenced by genetics and the environment. Recent findings have linked abnormal DNA methylation in T cells with asthma; however, the potential dysregulation of methylation in airway epithelial cells is unknown. Studies of mouse models of asthma have observed greater levels of 5-hydroxymethylcytosine (5-hmC) and ten-eleven translocation 1 (TET1) expression in lungs. TET proteins are known to catalyze methylation through modification of 5-methylcytosine to 5-hmC. Objective We sought to examine the association of TET1 methylation with asthma and traffic-related air pollution (TRAP). Methods TET1 methylation levels from DNA derived from nasal airway epithelial cells collected from 12 African American children with physician-diagnosed asthma and their nonasthmatic siblings were measured by using Illumina 450K arrays. Regions of interest were verified by means of locus-specific pyrosequencing in 35 sibling pairs and replicated in an independent population (n = 186). Exposure to TRAP in participants' early life and at current home addresses was estimated by using a land-use regression model. Methylation studies in saliva, PBMCs, and human bronchial epithelial cells were done to support our findings. Results Loss of methylation at a single CpG site in the TET1 promoter (cg23602092) and increased global 5-hmC levels were significantly associated with asthma. In contrast, TRAP exposure at participants' current homes significantly increased methylation at the same site. Patterns were consistent across tissue sample types. 5-Aza-2′-deoxycytidine and diesel exhaust particle exposure in human bronchial epithelial cells was associated with altered TET1 methylation and expression and global 5-hmC levels. Conclusions Our findings suggest a possible role of TET1 methylation in asthmatic patients and response to TRAP.




Somineni, H. K., Zhang, X., Biagini Myers, J. M., Kovacic, M. B., Ulm, A., Jurcak, N., … Ji, H. (2016). Ten-eleven translocation 1 (TET1) methylation is associated with childhood asthma and traffic-related air pollution. Journal of Allergy and Clinical Immunology, 137(3), 797-805.e5. https://doi.org/10.1016/j.jaci.2015.10.021

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