Epigenetic eprogramming has been proposed as an integral part of the "genome instability" enabling characteristic of cancer cells. Chemical-induced epigenetic changes may be a consequence of DNA damage, or may be part of the non-genotoxic mechanisms of carcinogenesis. Our recent studies provide critical additional insights into linkages between genotoxic and epigenetic mechanisms of carcinogenesis. First, using a multi-strain mouse model of the human population, we showed that important inter-individual (e.g., inter- strain) differences exist in both genotoxic and epigenotoxic effects of the classic genotoxic carcinogen 1, 3-butadiene and other chemicals. Second, we confirmed the hypothesis that the chromatin remodeling response is an underlying mechanism for the inter-strain differences in butadiene-induced DNA damage. These novel findings shaped this project's overall objective to uncover the mechanistic linkages between the genome (e.g., DNA sequence variants), epigenome (e.g., chromatin status), and molecular initiating events (e.g., DNA damage) elicited by a genotoxic carcinogen butadiene in an in vivo mouse model.
Two Specific Aims will test the hypothesis that genetic variability-associated chromatin remodeling events affect the genotoxic potential of butadiene.
In Specific Aim 1, we will extend our exciting finding that major differences in the extent of butadiene- induced DNA damage between inbred mouse strains are the result of epigenetically-controlled chromatin status. We will utilize deep sequencing-based DNaseI hypersensitivity mapping and chromatin immunoprecipitation analyses of representative histone modifications that regulate chromatin status, coupled with RNA sequencing-enabled gene expression analysis and measurements of butadiene-specific DNA damage. This data will permit deeper understanding of the toxicant-induced changes in chromatin in butadiene-sensitive and resistant strains. We will probe these events in both sexes and in target and non- target tissues for butadiene-induced carcinogenesis.
In Specific Aim 2, using similar experimental techniques we will connect chromatin variation and genotoxic effects of butadiene with DNA sequence variation. To do so, we will use a large panel of recombinant inbred mouse lines from the Collaborative Cross resource, a unique and powerful tool for population genetics studies in experimental animals. In summary, this proposal not only will use the most novel tools to investigate carcinogen effects on genome biology, but it also will offer experimental proof to a paradigm-shifting concept that genetically-determined chromatin status modulates disease risk from genotoxic exposures.

Public Health Relevance

Environmental chemicals may cause human disease via numerous molecular pathways. Despite the complexity of the associations between exposures and adverse health outcomes, two toxicity mechanisms linked to the structure of DNA are recognized as crucial drivers in disease pathogenesis. One is the ability of chemicals to cause DNA damage and mutations, called genotoxicity, and the other is effects on DNA structure or packaging, called epigenetic events. In addition, subtle inherited variants in DNA sequence may have profound impact on the susceptibility to disease. This application aims to uncover the fundamental mechanistic linkages between the genome, epigenome, and DNA damage by an environmental and occupational carcinogen, 1, 3-butadiene. The significance of this research is in understanding the causes of human environment-associated disease, as well as in determination of genetic factors that may be responsible for individual susceptibility.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES023195-01
Application #
8584447
Study Section
Special Emphasis Panel (ZES1-LWJ-D (TG))
Program Officer
Tyson, Frederick L
Project Start
2013-08-26
Project End
2017-05-31
Budget Start
2013-08-26
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$561,930
Indirect Cost
$185,389
Name
University of North Carolina Chapel Hill
Department
Genetics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Chappell, Grace; Kutanzi, Kristy; Uehara, Takeki et al. (2014) Genetic and epigenetic changes in fibrosis-associated hepatocarcinogenesis in mice. Int J Cancer 134:2778-88