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

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• 作者：Hari K. Somineni ; MS^a ; ^&lowast ; ; Xue Zhang ; PhD ; MsPH^b ; ^&lowast ; ; Jocelyn M. Biagini Myers ; PhD^a ; Melinda Butsch Kovacic ; PhD ; MPH^a ; ^d ; ^e ; Ashley Ulm ; BA^a ; Noelle Jurcak ; BA^c ; Patrick H. Ryan ; PhD^d ; ^e ; Gurjit K. Khurana Hershey ; MD ; PhD^a ; Hong Ji ; PhD^a ; ^{Hong.Ji@cchmc.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：DNA methylation ; TET1 ; 5-hmC ; nasal epithelial cells ; cross-tissue marker ; traffic-related air pollution ; asthma
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：137
• 期：3
• 页码：797-805.e5
• 全文大小：1335 K

文摘

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.