Variation in DNA-Damage Responses to an Inhalational Carcinogen (1,3-Butadiene) in Relation to Strain-Specific Differences in Chromatin Accessibility and Gene Transcription Profiles in C57BL/6J and CAST/EiJ Mice.
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ABSTRACT: The damaging effects of exposure to environmental toxicants differentially affect genetically distinct individuals, but the mechanisms contributing to these differences are poorly understood. Genetic variation affects the establishment of the gene regulatory landscape and thus gene expression, and we hypothesized that this contributes to the observed heterogeneity in individual responses to exogenous cellular insults.We performed an in vivo study of how genetic variation and chromatin organization may dictate susceptibility to DNA damage, and influence the cellular response to such damage, caused by an environmental toxicant.We measured DNA damage, messenger RNA (mRNA) and microRNA (miRNA) expression, and genome-wide chromatin accessibility in lung tissue from two genetically divergent inbred mouse strains, C57BL/6J and CAST/EiJ, both in unexposed mice and in mice exposed to a model DNA-damaging chemical, 1,3-butadiene.Our results showed that unexposed CAST/EiJ and C57BL/6J mice have very different chromatin organization and transcription profiles in the lung. Importantly, in unexposed CAST/EiJ mice, which acquired relatively less 1,3-butadiene-induced DNA damage, we observed increased transcription and a more accessible chromatin landscape around genes involved in detoxification pathways. Upon chemical exposure, chromatin was significantly remodeled in the lung of C57BL/6J mice, a strain that acquired higher levels of 1,3-butadiene-induced DNA damage, around the same genes, ultimately resembling the molecular profile of CAST/EiJ.These results suggest that strain-specific changes in chromatin and transcription in response to chemical exposure lead to a "compensation" for underlying genetic-driven interindividual differences in the baseline chromatin and transcriptional state. This work represents an example of how chemical and environmental exposures can be evaluated to better understand gene-by-environment interactions, and it demonstrates the important role of chromatin response in transcriptomic changes and, potentially, in deleterious effects of exposure. https://doi.org/10.1289/EHP1937.
Variation in DNA-Damage Responses to an Inhalational Carcinogen (1,3-Butadiene) in Relation to Strain-Specific Differences in Chromatin Accessibility and Gene Transcription Profiles in C57BL/6J and CAST/EiJ Mice.
<h4>Background</h4>The damaging effects of exposure to environmental toxicants differentially affect genetically distinct individuals, but the mechanisms contributing to these differences are poorly understood. Genetic variation affects the establishment of the gene regulatory landscape and thus gene expression, and we hypothesized that this contributes to the observed heterogeneity in individual responses to exogenous cellular insults.<h4>Objectives</h4>We performed an <i>in vivo</i> study of h ...[more]
Project description:Here we introduce a test for lineage-specific selection of cis-regulation that can be applied to any gene set of interest. Applying the test to hundreds of gene sets in two diverged subspecies of mouse, we find evidence for selection acting on the cis-regulation of several functional classes, including those involved in both physiology (e.g. mitochondria-related genes and growth regulators) and behavior (e.g. locomotory-related genes and memory-related genes). These positively selected gene sets implicate potential targets of positive selection that are supported by quantitative trait loci, and accurately predict a number of phenotypic differences between the two subspecies, suggesting that the divergence in these traits may have been driven by adaptive evolution.
Project description:We have identified candidate genes from the Feml2 QTL influencing femur length through allele specific expression analysis of growth plates in C57BL/6J x CAST/EiJ F1 hybrids. This work provides the foundation to identify novel genes affecting bone geometry.
Project description:Sequencing files provided here are mouse liver RNA-seq in two mouse strains: C57BL/6J and CAST/EiJ. This is part of a larger study published in PLoS Genetics (2021) "Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model" that includes DNase-seq and H3K27ac ChIP-seq in mouse liver from the same two strains. This allows us to identify strain-shared ("core") and strain-unique sex-biased genes and enhancers.
Project description:Sequencing files provided here are mouse liver ChIP-seq for the activating histone mark H3K27ac in two mouse strains: C57BL/6J and CAST/EiJ. This is part of a larger study published in PLoS Genetics (2021) "Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model" that includes RNA-seq and DNase-seq in mouse liver from the same two strains. This allows us to identify strain-shared ("core") and strain-unique sex-biased genes and enhancers.