title: Ten-eleven translocation 1 (TET1) methylation is associated with childhood asthma and traffic-related air pollution.
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.
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Hari K
authors.initials: HK
authors.lastname: Somineni
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Jocelyn M
authors.initials: JM
authors.lastname: Biagini Myers
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Melinda Butsch
authors.initials: MB
authors.lastname: Kovacic
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Ashley
authors.initials: A
authors.lastname: Ulm
authors.affiliation: School of Medicine, Johns Hopkins University, Baltimore, Md.
authors.forename: Noelle
authors.initials: N
authors.lastname: Jurcak
authors.affiliation: Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Environmental Health, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Ryan
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Gurjit K
authors.initials: GK
authors.lastname: Khurana Hershey
authors.affiliation: Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: Hong.Ji@cchmc.org.
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000293:Adolescent; D000397:Air Pollution / Q000009:adverse effects*; D000483:Alleles; D001249:Asthma / Q000209:etiology* / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D018899:CpG Islands; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D044127:Epigenesis, Genetic; D004847:Epithelial Cells; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases; D009297:Nasal Mucosa / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D001335:Vehicle Emissions
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D001335:Vehicle Emissions; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human
keywords: 5-hmC; DNA methylation; TET1; asthma; cross-tissue marker; nasal epithelial cells; traffic-related air pollution