Ten-eleven translocation 1 (TET1) methylation is associated with childhood asthma and traffic-related air pollution Hari K. Somineni, MS, Xue Zhang,

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Ten-eleven translocation 1 (TET1) methylation is associated with childhood asthma and traffic-related air pollution Hari K. Somineni, MS, Xue Zhang, PhD, MsPH, Jocelyn M. Biagini Myers, PhD, Melinda Butsch Kovacic, PhD, MPH, Ashley Ulm, BA, Noelle Jurcak, BA, Patrick H. Ryan, PhD, Gurjit K. Khurana Hershey, MD, PhD, Hong Ji, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 3, Pages 797-805.e5 (March 2016) DOI: 10.1016/j.jaci.2015.10.021 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Study schematic. There were 35 sibling pairs in the discovery ESS population. Of these, nasal samples from 12 pairs were selected to run on the Infinium HumanMethylation450 BeadChips. We then verified the results using pyrosequencing on PBMCs and saliva in these same 12 pairs and in nasal epithelial samples from all 35 sibling pairs. We also measured 5-hmC levels in saliva from 18 pairs. To replicate our findings, we performed pyrosequencing on 186 saliva samples from children participating in the PEES cohort. qPCR, Quantitative PCR. Journal of Allergy and Clinical Immunology 2016 137, 797-805.e5DOI: (10.1016/j.jaci.2015.10.021) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Hypomethylation of cg23602092 located at the TET1 promoter is associated with childhood asthma in the ESS cohort. A, Differentially methylated cg23602092 on the Infinium HumanMethylation450 BeadChip. β Values and differences of each of the asthma-control pairs are shown as gray dots. The mean β value for control subjects or asthmatic patients is shown as the black bar. The mean difference is shown as a black triangle together with the SEM. B, Correlation between bisulfite pyrosequencing and bead array measurements. Control subjects and asthmatic patients are represented by solid triangles and open dots, respectively. C, Bland-Altman plot showing limits of agreement. Solid line, Mean difference; dotted lines, 95% confidence limits of the mean. D, DNA methylation in all ESS participants. Journal of Allergy and Clinical Immunology 2016 137, 797-805.e5DOI: (10.1016/j.jaci.2015.10.021) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Influences of TRAP on cg23602092 methylation and the association between cg23602092 methylation and asthma. Percentage methylation was shown for control subjects (solid triangles) and asthmatic patients (open circles). Model-predicted relationship between TRAP exposure (current ECAT value) and methylation was shown in control subjects (solid line) and asthmatic patients (dashed line). Distance between the dashed and solid lines represents the differences in methylation between control subjects and asthmatic patients at different levels of current ECAT exposure. Journal of Allergy and Clinical Immunology 2016 137, 797-805.e5DOI: (10.1016/j.jaci.2015.10.021) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Methylation of cg23602092 is correlated among 3 tissues. Shown are comparisons of cg23602092 methylation between nasal cells and saliva (A), nasal cells and PBMCs (B), and saliva and PBMCs (C) in the ESS cohort. Control subjects and asthmatic patients are represented by solid triangles and open dots, respectively. Journal of Allergy and Clinical Immunology 2016 137, 797-805.e5DOI: (10.1016/j.jaci.2015.10.021) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Hypomethylation of cg23602092 is associated with childhood asthma in the PEES cohort. Methylation levels were measured by means of locus-specific bisulfite pyrosequencing in the saliva of asthmatic (n = 158) and nonasthmatic (n = 28) children enrolled in the PEES cohort. A statistically significant association between TET1 hypomethylation and asthma was detected, thus replicating our finding from the ESS cohort. Bars represent means ± SEMs. Journal of Allergy and Clinical Immunology 2016 137, 797-805.e5DOI: (10.1016/j.jaci.2015.10.021) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 cg23602092 methylation is negatively correlated with TET1 expression in nasal mucosa samples. A, Bimodal distribution of cg23602092 methylation shown as a histogram (gray bars) and as density (solid curve). Solid triangles, Control subjects; open circles, asthmatic patients. B, TET1 expression levels in nasal epithelial cells. HighM, Methylation greater than 20%; LowM, methylation less than 20%. Values are presented as means ± SEMs. C-E, TET1 expression (Fig 6, C), cg23602092 methylation (Fig 6, D), and global 5-hmC levels (Fig 6, E) in HBECs treated with 1 μmol/L 5-aza-2′-deoxycytidine. Data represent 2 technical duplicates of 3 biological replicates and are shown as means ± SDs. F, 5-hmC levels in saliva DNA from 18 pairs of siblings from the ESS cohort. Values are presented as means ± SEMs. Journal of Allergy and Clinical Immunology 2016 137, 797-805.e5DOI: (10.1016/j.jaci.2015.10.021) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 DEP exposure induced changes in cg23602092 methylation, TET1 expression, and 5-hmC. A, TET1 expression in HBECs cultured with DEPs (5 μg/cm2) was measured and normalized to that in untreated control subjects at indicated time points. B, Percentage methylation values were measured and normalized to those of control subjects. C, 5-hmC ELISA. Data represent 3 technical replicates of biological duplicates and are shown as means ± SDs. Journal of Allergy and Clinical Immunology 2016 137, 797-805.e5DOI: (10.1016/j.jaci.2015.10.021) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 DEP exposure in HBECs induced expression of genes encoding cytoprotective enzymes and proinflammatory cytokines. HBECs were treated with 5 μg/cm2 DEPs, and cells were harvested at 4 hours for RNA extraction and quantitative PCR. Mean values from technical duplicates of 3 biological replicates are presented as means ± SDs. ***P < .001 and ****P < .0001. Journal of Allergy and Clinical Immunology 2016 137, 797-805.e5DOI: (10.1016/j.jaci.2015.10.021) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions