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Baseline Chromatin Modification Levels May Predict Interindividual Variability in Ozone-Induced Gene Expression
McCullough, Shaun D., E. Bowers, D. On, D. Morgan, Lisa A. Dailey, Ronald N. Hines, Robert B. Devlin, AND D. Diaz-Sanchez. Baseline Chromatin Modification Levels May Predict Interindividual Variability in Ozone-Induced Gene Expression. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 150(1):216-224, (2016).
The role of chromatin modifications in regulating basal and induced pro-inflammatory and oxidative stress gene expression in the context of toxicology has received little attention. As the relationship between the epigenome, exposure effects, and susceptibility becomes better defined, the field of epigenetics has the potential to transform our understanding of the mechanisms underlying inter-individual variability, establish new risk assessment paradigms, and identify modifiable factors that can be leveraged to mitigate the adverse health effects of toxicant exposures. To explore this potential we sought to determine the role that both baseline histone modifications and 5-hmC play in basal and toxicant-mediated induction expression of pro-inflammatory and oxidative stress genes in a primary cell ALI model of the human airway. Here, we demonstrate that baseline levels of specific chromatin modifications correlate with the inter-individual variability in both basal and O3-induced expression of pro-inflammatory stress genes. The findings from this study are the first to link the baseline relative abundance of specific histone modifications and DNA hydroxymethylation to the inter-individual variability in pro-inflammatory and oxidative stress gene induction following toxicant exposure.
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 (03)-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), panacetyl H4 (H4ac), histone H3K27 di/trimethylation (H3K27me2/3), unmodified H3, and5-hydroxymethylcytosine (5-hmC)-and the variability in the 03-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 03-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.