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

Authors: Somineni, Hari K; Zhang, Xue; Biagini Myers, Jocelyn M; Kovacic, Melinda Butsch; Ulm, Ashley; Jurcak, Noelle; Ryan, Patrick H; Khurana Hershey, Gurjit K; Ji, Hong

Published In J Allergy Clin Immunol, (2016 Mar)

Abstract: 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.

PubMed ID: 26684294

MeSH Terms: 5-Methylcytosine/analogs & derivatives; Adolescent; Air Pollution/adverse effects*; Alleles; Asthma/etiology*; Asthma/metabolism; Case-Control Studies; Child; CpG Islands; Cytosine/analogs & derivatives; Cytosine/metabolism; DNA Methylation*; DNA-Binding Proteins/genetics*; Epigenesis, Genetic; Epithelial Cells; Female; Gene Expression; Humans; Male; Mixed Function Oxygenases; Nasal Mucosa/metabolism; Promoter Regions, Genetic; Proto-Oncogene Proteins/genetics*; RNA, Messenger/genetics; RNA, Messenger/metabolism; Risk Factors; Vehicle Emissions*