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: 10091978
• 负责人: Ivan Rusyn
• 金额: $ 65.83万
• 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/10091978
• 关键词: 1,3-Butadiene; ATAC-seq; African; Air; Animal Model; Asians; 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; 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.

对化学诱导的DNA损伤敏感的染色质区域、基因和途径 摘要 遗传变异对常见疾病的易感性、对药物和毒物的反应、 并影响与疾病相关的结果。此外，遗传变异性、毒性结果和 表观遗传学正在积极探索中。然而，基因×环境×表观遗传学的研究是困难的 它们涉及对多个人的询问、暴露剂量/时间、组织类型、组学终点和 各种毒性表型。该提案旨在识别和验证染色质区域、基因和 环境化学诱导和新陈代谢相关DNA易感性的途径 损坏。我们将对DNA损伤之间的相互作用进行一系列的原则证明研究 由1，3-丁二烯，一种遗传毒性致癌物质，遗传学和表观遗传学。我们有丰富的表演经验 小鼠(协同交叉，CC)和人类(1000个基因组淋巴母细胞系)的毒理学研究 基于人口的模型。首先，我们将确定其表达和染色质数量性状基因座(QTL)。 丁二烯对小鼠组织的遗传毒性。我们将检验这一假设，即菌株和组织特异性变异在 丁二烯诱导的DNA损伤是由遗传变异相关的背景状态控制的 染色质和基因表达。我们将使用来自50个CC菌株研究的组织(肝、肺和肾) 暴露于丁二烯，并将评估丁二烯DNA损伤并确定活跃/抑制区域 促进剂和促进剂。其次，我们将确定丁二烯引起的DNA损伤的剂量和时间效应 在背景和治疗诱导染色质和转录状态的背景下。我们将测试 丁二烯暴露以剂量依赖的方式改变应变和组织特异性表观遗传状态的假说 而且与DNA损伤相关的对染色质的影响持续存在。我们将检查内部和内部的应变 选定CC菌株的可变性、剂量和时间依赖性。第三，我们将描述人口的范围 在人类体外群体模型中丁二烯代谢物反应的可变性。我们将检验这一假设 人类淋巴母细胞可以用来定位丁二烯遗传毒性的易感基因。第四，我们将 通过以下方法验证菌株依赖DNA损伤的转录和表观遗传介体的发现 丁二烯在人类体外种群模型中的作用。我们将测试这样的假设：遗传背景- 依赖转录和表观遗传状态赋予对丁二烯诱导的DNA的敏感性/抵抗力 损坏。我们将结合DNA加合物的分析来评估染色质状态和表达。总体而言，这 工作将通过以下方式展示环境(即，化学暴露)、遗传学和表观遗传学之间的相互作用 研究1，3-丁二烯的作用，1，3-丁二烯是一种工业毒物和模型遗传毒性致癌物。人的关联性和 对毒性和致癌的基本机制的关注证明了可行性，事实是 丁二烯是一种已知的人类和啮齿动物致癌物，我们之前的工作证明了丁二烯对 染色质、组蛋白修饰和其他表观遗传状态以一种应变和组织依赖的方式。