Mouse strain-specific chromatin and transcriptional states modulate the DNA-damage response to an inhalational carcinogen

Genetically distinct individuals are differentially affected by the DNA damaging effects of exposure to environmental toxicants, but the mechanisms contributing to these differences are poorly understood. It is known that genetic variation affects the establishment of the gene regulatory landscape, and we hypothesized that this may significantly contribute to the observed heterogeneity in individual responses to exogenous cellular insults. In this study, we investigated how genetic variation and chromatin organization may dictate susceptibility to DNA damage. We measured DNA damage, mRNA and miRNA expression, and chromatin accessibility genome-wide in lung tissue from two genetically-divergent inbred mouse strains, C57BL/6J and CAST/EiJ, at baseline and in response to exposure to a model DNA-damaging chemical, 1,3-butadiene (BD). Our results show that unexposed CAST/EiJ and unexposed C57BL/6J mice have very different chromatin organization and transcription profiles in the lung. Importantly, in unexposed CAST/EiJ, which is more resistant to BD-induced DNA damage, we see increased transcription and a more accessible chromatin landscape around genes involved in detoxification pathways. Upon BD exposure, chromatin is significantly remodeled in C57BL/6J around these genes to more closely resemble that found in CAST/EiJ. This suggests that strain-specific differences in baseline chromatin organization and transcription contribute to the relative resistance of CAST/EiJ to the DNA damaging effects of BD. Based on these results, we propose more generally that differences in the baseline molecular state of key tissues, driven by unique genetic backgrounds, significantly contributes to inter-individual variability in response to DNA-damaging environmental agents. Overall design: Investigation of strain-specific chromatin accessibility and gene expression differences in lung tissue from CAST/EiJ and C57BL/6J mice, and how the gene regulatory landscape changes in response to 1,3-Butadiene exposure