title: Baseline Chromatin Modification Levels May Predict Interindividual Variability in Ozone-Induced Gene Expression.
abstract: Traditional toxicological paradigms have relied on factors such as age, genotype, and disease status to explain variability in responsiveness to toxicant exposure; however, these are neither sufficient to faithfully identify differentially responsive individuals nor are they modifiable factors that can be leveraged to mitigate the exposure effects. Unlike these factors, the epigenome is dynamic and shaped by an individual's environment. We sought to determine whether baseline levels of specific chromatin modifications correlated with the interindividual variability in their ozone (O3)-mediated induction in an air-liquid interface model using primary human bronchial epithelial cells from a panel of 11 donors. We characterized the relationship between the baseline abundance of 6 epigenetic markers with established roles as key regulators of gene expression-histone H3 lysine 4 trimethylation (H3K4me3), H3K27 acetylation (H3K27ac), pan-acetyl H4 (H4ac), histone H3K27 di/trimethylation (H3K27me2/3), unmodified H3, and 5-hydroxymethylcytosine (5-hmC)-and the variability in the O3-induced expression of IL-8, IL-6, COX2, and HMOX1. Baseline levels of H3K4me3, H3K27me2/3, and 5-hmC, but not H3K27ac, H4ac, and total H3, correlated with the interindividual variability in O3-mediated induction of HMOX1 and COX2. In contrast, none of the chromatin modifications that we examined correlated with the induction of IL-8 and IL-6. From these findings, we propose an "epigenetic seed and soil" model in which chromatin modification states between individuals differ in the relative abundance of specific modifications (the "soil") that govern how receptive the gene is to toxicant-mediated cellular signals (the "seed") and thus regulate the magnitude of exposure-related gene induction.
authors.affiliation: *National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and mccullough.shaun@epa.gov.
authors.forename: Shaun D
authors.initials: SD
authors.lastname: McCullough
authors.affiliation: Curriculum in Toxicology, University of North Carolina - Chapel Hill, Chapel Hill, North Carolina 27599.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Bowers
authors.affiliation: *National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and.
authors.forename: Doan M
authors.initials: DM
authors.lastname: On
authors.affiliation: *National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and.
authors.forename: David S
authors.initials: DS
authors.lastname: Morgan
authors.affiliation: *National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Dailey
authors.affiliation: *National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Hines
authors.affiliation: *National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Devlin
authors.affiliation: *National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711; and.
authors.forename: David
authors.initials: D
authors.lastname: Diaz-Sanchez
mesh_terms: D000293:Adolescent; D000328:Adult; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002843:Chromatin / Q000187:drug effects* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D064368:Healthy Volunteers; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D010126:Ozone / Q000633:toxicity*; D061251:Primary Cell Culture; D013045:Species Specificity; D055815:Young Adult
chemical_list: D002843:Chromatin; D015850:Interleukin-6; D016209:Interleukin-8; D010126:Ozone
keywords: DNA methylation; chromatin; epigenetics; histone; ozone