Chromatin regions, genes and pathways that confer susceptibility to chemical-induced DNA damage

导致对化学诱导的 DNA 损伤易感性的染色质区域、基因和途径

• 批准号: 10330422
• 负责人: Ivan Rusyn
• 金额: $ 65.58万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330422
• 关键词: 1,3-Butadiene; ATAC-seq; African; Air; Animal Model; Asian; Biological Assay; Butadiene; Carcinogens; Cell Line; Cells; Chemical Exposure; Chemicals; Chromatin; Chromosome Mapping; Complex; Coupled; DNA; DNA Adducts; DNA Damage; DNA Sequence; DNA sequencing; Data; Decision Making; Dependence; Development; Disease; Dose; Enhancers; Environment; Environmental Health; Epigenetic Process; European; Exposure to; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic Variation; Genome; Genotype-Tissue Expression Project; Goals; Human; In Vitro; Individual; Individual Differences; Industrialization; Inhalation Exposure; Inherited; Kidney; Libraries; Link; Liver; Lung; Maps; Mediating; Mediator of activation protein; Metabolism; Modeling; Molecular; Molecular Toxicology; Mus; Outcome; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Poison; Population; Predisposition; Quantitative Trait Loci; Reproducibility; Resistance; Rodent; Rubber; Series; Susceptibility Gene; Techniques; Testing; Time; Tissues; Toxic effect; Toxicology; Transcriptional Regulation; Variant; Work; adduct; base; carcinogenesis; cigarette smoke; computerized tools; cost effective; cytotoxic; cytotoxicity; environmental chemical; experience; genotoxicity; histone modification; human disease; human model; in vitro Model; in vivo; inter-individual variation; lymphoblast; male; novel; open data; population based; promoter; response; sex; toxicant; transcriptome sequencing

Chromatin regions, genes and pathways that confer susceptibility to chemical-induced DNA damage ABSTRACT Genetic variability has a major impact on susceptibility to common diseases, responses to drugs and toxicants, and influences disease-related outcomes. In addition, the links between genetic variability, toxicity outcomes and epigenetics are being actively explored. However, studies of Gene × Environment × Epigenetics are difficult as they involve interrogation of multiple individuals, exposure doses/times, tissue types, -omics endpoints and various toxicity phenotypes. This proposal aims to identify and validate chromatin regions, genes and pathways that confer susceptibility to environmental chemical-induced and metabolism-associated DNA damage. We will perform a series of proof-of-principle studies of the interplay between DNA damage induced by 1,3-butadiene, a genotoxic carcinogen, genetics, and epigenetics. We have extensive experience performing toxicology studies in the mouse (Collaborative Cross, CC) and human (1000 Genomes lymphoblast cell lines) population-based models. First, we will determine expression and chromatin quantitative trait loci (QTL) of butadiene genotoxicity in mouse tissues. We will test the hypothesis that strain- and tissue-specific variation in butadiene-induced DNA damage is controlled by the genetic variability-dependent background states in chromatin and gene expression. We will use tissues (liver, lung and kidney) from a study of 50 CC strains exposed to butadiene and will evaluate butadiene DNA damage and identify regions of active/repressed enhancers and promoters. Second, we will determine dose- and time-effects of butadiene-induced DNA damage in the context of background and treatment-induced chromatin and transcriptional states. We will test the hypothesis that butadiene exposure modifies strain- and tissue-specific epigenetic states in a dose-dependent manner and that DNA damage-associated effects on chromatin persist. We will examine inter- vs intra-strain variability, dose- and time-dependency in select CC strains. Third, we will characterize the extent of population variability in response to butadiene metabolites in a human in vitro population model. We will test the hypothesis that human lymphoblasts can be used to map susceptibility loci for butadiene genotoxicity. Fourth, we will validate the discoveries of the transcriptional and epigenetic mediators of strain-dependent DNA damage by butadiene in a human in vitro population-based model. We will test the hypothesis that genetic background- dependent transcriptional and epigenetic states confer susceptibility/resistance to butadiene-induced DNA damage. We will evaluate chromatin states and expression coupled with assays for DNA adducts. Overall, this work will demonstrate the interplay among environment (i.e., chemical exposure), genetics, and epigenetics by studying effects of 1,3-butadiene, an industrial toxicant and model genotoxic carcinogen. Human relevance and feasibility are justified by the focus on a fundamental mechanism of toxicity and carcinogenesis, the fact that butadiene is a known human and rodent carcinogen, and our previous work demonstrating butadiene effects of chromatin, histone modifications and other epigenetic states in a strain- and tissue-dependent manner.

染色质区域，基因和途径赋予易感性的化学诱导的DNA损伤