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Mammalian Genome (2018) 29:153–167
https://doi.org/10.1007/s00335-018-9739-6
Tissue- and strain-specific effects of a genotoxic carcinogen
1,3-butadiene on chromatin and transcription
Jennifer W. Israel
1
· Grace A. Chappell
2,3
· Jeremy M. Simon
1
· Sebastian Pott
4
· Alexias Sa
5
· Lauren Lewis
2
·
Paul Cotney
1
· Hala S. Boulos
4
· Wanda Bodnar
3
· Jason D. Lieb
4
· Gregory E. Crawford
5
· Terrence S. Furey
1,6,7
·
Ivan Rusyn
2
Received: 27 December 2017 / Accepted: 3 February 2018 / Published online: 10 February 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Epigenetic effects of environmental chemicals are under intense investigation to fill existing knowledge gaps between envi-
ronmental/occupational exposures and adverse health outcomes. Chromatin accessibility is one prominent mechanism of
epigenetic control of transcription, and understanding of the chemical effects on both could inform the causal role of epige-
netic alterations in disease mechanisms. In this study, we hypothesized that baseline variability in chromatin organization
and transcription profiles among various tissues and mouse strains influence the outcome of exposure to the DNA damag-
ing chemical 1,3-butadiene. To test this hypothesis, we evaluated DNA damage along with comprehensive quantification
of RNA transcripts (RNA-seq), identification of accessible chromatin (ATAC-seq), and characterization of regions with
histone modifications associated with active transcription (ChIP-seq for acetylation at histone 3 lysine 27, H3K27ac). We
collected these data in the lung, liver, and kidney of mice from two genetically divergent strains, C57BL/6J and CAST/EiJ,
that were exposed to clean air or to 1,3-butadiene (~600 ppm) for 2 weeks. We found that tissue effects dominate differences
in both gene expression and chromatin states, followed by strain effects. At baseline, xenobiotic metabolism was consistently
more active in CAST/EiJ, while immune system pathways were more active in C57BL/6J across tissues. Surprisingly, even
though all three tissues in both strains harbored butadiene-induced DNA damage, little transcriptional effect of butadiene
was observed in liver and kidney. Toxicologically relevant effects of butadiene in the lung were on the pathways of xenobi-
otic metabolism and inflammation. We also found that variability in chromatin accessibility across individuals (i.e., strains)
only partially explains the variability in transcription. This study showed that variation in the basal states of epigenome and
transcriptome may be useful indicators for individuals or tissues susceptible to genotoxic environmental chemicals.
Introduction
Chemical exposure-associated epigenetic events are gain-
ing attention in toxicology as providing important mecha-
nistic information for human health assessments (Chappell
Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s0033 5-018-9739-6) contains
supplementary material, which is available to authorized users.
* Terrence S. Furey
tsfurey@email.unc.edu
* Ivan Rusyn
irusyn@tamu.edu
1
Department of Genetics, University of North Carolina,
Chapel Hill, NC, USA
2
Department of Veterinary Integrative Biosciences, College
of Veterinary Medicine and Biomedical Sciences, Texas
A&M University, College Station, TX, USA
3
Department of Environmental Sciences and Engineering,
University of North Carolina, Chapel Hill, NC, USA
4
Department of Human Genetics, University of Chicago,
Chicago, IL, USA
5
Department of Pediatrics, Duke Center for Genomic
and Computational Biology, Duke University, Durham, NC,
USA
6
Department of Biology, University of North Carolina,
Chapel Hill, NC, USA
7
UNC Lineberger Comprehensive Cancer Center, University
of North Carolina School of Medicine, Chapel Hill, NC,
USA
@Phil_Robichaud
@deepthiw
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