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

基本信息

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
项目类别：
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

项目摘要

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，会议对化学诱导的DNA损伤的敏感性抽象的遗传变异性对对常见疾病的易感性，对药物和毒物的反应有重大影响，并影响与疾病有关的结果。此外，遗传变异性，毒性结果与正在积极探索表观遗传学。但是，基因×环境×表观遗传学的研究很困难，因为它们涉及对多个个体的询问，暴露剂量/时间，组织类型， - 组学终点和各种毒性表型。该建议旨在识别和验证染色质区域，基因和会议对环境化学诱导和代谢相关的DNA的敏感性损害。我们将对DNA损伤诱导的相互作用进行一系列原则研究证明 1,3-丁二烯，一种遗传毒性致癌，遗传学和表观遗传学。我们有丰富的表现经验小鼠（协作十字，CC）和人（1000个基因组淋巴细胞细胞系）中的毒理学研究基于人群的模型。首先，我们将确定表达和染色质定量性状位置（QTL）小鼠组织中的丁二烯遗传毒性。我们将测试菌株和组织特异性变化的假设丁二烯诱导的DNA损伤受遗传变异性背景状态的控制染色质和基因表达。我们将从50 cc菌株的研究中使用组织（肝脏，肺和肾脏）暴露于丁二烯，并将评估丁二烯DNA损伤并确定活跃/抑制的区域增强剂和促进者。其次，我们将确定丁二烯诱导的DNA损伤的剂量和时间效应在背景和治疗引起的染色质和转录状态的背景下。我们将测试假设丁二烯暴露修饰剂应变和组织特异性表观遗传态在剂量依赖性方式和DNA损伤相关的对染色质的影响持续存在。我们将检查与局体之间的互换选择CC菌株中的变异性，剂量和时间依赖性。第三，我们将表征人口的程度响应于人类体外种群模型中丁二烯代谢产物的变异性。我们将检验假设人类淋巴细胞可用于绘制丁二烯基因毒性的易感性位置。第四，我们会的验证通过菌株依赖性DNA损伤的转录和表观遗传介质的发现丁二烯在人类基于人群的模型中。我们将测试遗传背景的假设依赖的转录和表观遗传状态会议易感性/对丁二烯诱导的DNA的敏感性/抗性损害。我们将评估染色质状态和表达与DNA加合物的测定。总体而言，这工作将证明环境之间的相互作用（即化学暴露），遗传学和表观遗传学研究1,3-丁二烯的作用，一种工业毒物和遗传毒性致癌物的作用。人类的相关性和可行性是通过关注毒性和癌变的基本机制的合理性，这一事实是丁二烯是已知的人类和啮齿动物的致癌物，我们以前的工作证明了丁二烯的影响染色质，组蛋白修饰和其他表观遗传态以应变和组织依赖性方式。