Genes, genomes, and genotoxicity: in vivo epigenetic toxicology of 1,3-butadiene

基因、基因组和遗传毒性：1,3-丁二烯的体内表观遗传毒理学

基本信息

批准号：
8584447
负责人：
GREGORY E CRAWFORD
金额：
$ 56.19万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-26 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8584447
关键词：
1,3-Butadiene Affect Alleles Animals Biological Markers Biology Butadiene Carcinogen exposure Carcinogenesis Mechanism Carcinogens Characteristics Chemicals Chromatin Chromatin Structure Coupled DNA DNA Damage DNA Packaging DNA Sequence DNA Structure Data Disease Environment Epigenetic Process Evaluation Event Exposure to Foundations Gene Expression Gene Expression Profiling Gene Mutation Genes Genetic Genetic Determinism Genetic Materials Genetic Population Study Genetic Transcription Genome Genomic Instability Genotype Hazard Assessment Health Hemoglobin concentration result Human Hypersensitivity Inbred Mouse Inbred Strain Inbred Strains Mice Indium Individual Inherited Link Malignant Neoplasms Maps Measurement Metabolism Modeling Molecular Mus Mutagenesis Mutation Occupational Outcome Pathogenesis Pathway interactions Physical condensation Population Predisposition RNA Sequences Recombinants Research Research Proposals Resistance Resources Shapes Solid Techniques Testing Tissues Toxic effect Toxicology Validation Variant base cancer cell carcinogenesis chemical carcinogen chromatin immunoprecipitation chromatin remodeling cohort deep sequencing disorder risk environmental chemical epigenome genotoxicity histone modification human disease in vivo insight mouse model novel public health relevance resistant strain response sex tool toxicant

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：已提出表观遗传电子编程是“基因组不稳定性”的组成部分，从而使癌细胞具有特征。化学引起的表观遗传变化可能是DNA损伤的结果，也可能是致癌作用的非生物毒性机制的一部分。我们最近的研究为癌变的遗传毒性和表观遗传机制之间的联系提供了关键的其他见解。首先，使用人口的多晶体小鼠模型，我们表明，经典遗传毒性致癌物1、3-丁二烯和其他化学物质的遗传毒性和表观毒素作用都存在重要的个体间（例如，间菌株）差异。其次，我们证实了以下假设：染色质重塑反应是丁二烯诱导的DNA损伤的晶体间差异的基本机制。这些新发现的结果塑造了该项目的总体目标，即揭示基因组（例如DNA序列变体），表观基因组（例如染色质状态）和分子启动事件（例如DNA损伤）之间的机械联系，这是由遗传毒性癌基因基因基因基因基因组的，在Vivo Invivo鼠标中引起的。两个具体的目的将检验以下假设：遗传变异性相关的染色质重塑事件会影响丁二烯的遗传毒性潜力。在特定的目标1中，我们将扩展我们令人兴奋的发现，即近交小鼠菌株之间丁二烯诱导的DNA损伤程度的主要差异是表观遗传控制的染色质状态的结果。我们将利用基于深层测序的DNASEI超敏反应图和染色质免疫沉淀分析，这些分析是对调节染色质状态的代表性组蛋白修饰的分析，以及培养RNA测序的基因表达分析和丁二烯特异性DNA损伤的测量。这些数据将使对丁二烯敏感和抗性菌株中毒物诱导的染色质变化的更深入了解。我们将在性别，靶标组织中探测这些事件，以示丁二烯诱导的癌变。在特定的目标2中，使用类似的实验技术，我们将将丁二烯的染色质变异和遗传毒性作用与DNA序列变化联系起来。为此，我们将使用合作交叉资源的大量重组近交小鼠系列，这是一种独特而有力的实验动物种群遗传学研究的工具。总而言之，该提案不仅会使用最新颖的工具来研究致癌物对基因组生物学的影响，而且还将为范式转移概念提供实验性证明，该概念概念可以调节遗传性的染色质状态调节疾病的风险。