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：
10559536
负责人：
Ivan Rusyn
金额：
$ 65.32万
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 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10559536
关键词：
1,3-Butadiene ATAC-seq African Air Asian Biological Assay Butadiene Carcinogens Cell Line Cells Chemical Exposure Chemicals Chromatin Chromosome Mapping Complex Coupled DNA DNA Adduction 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 Metabolism Modeling Molecular Molecular Toxicology Mus Outcome Pathway interactions Persons Pharmaceutical Preparations Phenotype Poison Population Predisposition Quantitative Trait Loci Repression 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 model organism 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.

导致对化学诱导的 DNA 损伤易感性的染色质区域、基因和途径抽象的遗传变异对常见疾病的易感性、对药物和毒物的反应、此外，遗传变异性、毒性结果和疾病相关结果之间的联系。表观遗传学正在被积极探索，然而，基因×环境×表观遗传学的研究是困难的。它们涉及对多个个体的询问、暴露剂量/时间、组织类型、组学终点和该提案旨在识别和验证染色质区域、基因和赋予对环境化学诱导和代谢相关 DNA 易感性的途径我们将对 DNA 损伤之间的相互作用进行一系列原理验证研究。 1,3-丁二烯（一种基因毒性致癌物）、遗传学和表观遗传学方面我们拥有丰富的经验。小鼠（Collaborative Cross，CC）和人类（1000 Genomes 淋巴母细胞系）的毒理学研究首先，我们将确定表达和染色质数量性状基因座（QTL）。我们将检验小鼠组织中丁二烯基因毒性的假设，即菌株和组织特异性变异。丁二烯诱导的 DNA 损伤是由依赖于遗传变异的背景状态控制的我们将使用来自 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 损伤并识别活性/抑制区域其次，我们将确定丁二烯诱导的 DNA 损伤的剂量和时间效应。我们将在背景和治疗诱导的染色质和转录状态的背景下进行测试。假设丁二烯暴露以剂量依赖性方式改变菌株和组织特异性表观遗传状态方式，并且 DNA 损伤相关的染色质影响持续存在，我们将检查菌株间和菌株内。选定 CC 菌株的变异性、剂量和时间依赖性第三，我们将描述群体范围的特征。我们将在人类体外群体模型中检验该假设。第四，人类淋巴母细胞可用于绘制丁二烯遗传毒性的易感位点。验证菌株依赖性 DNA 损伤的转录和表观遗传介质的发现我们将在基于人类体外群体的模型中检验丁二烯的遗传背景假设。依赖的转录和表观遗传状态赋予对丁二烯诱导的 DNA 的敏感性/抗性我们将评估染色质状态和 DNA 加合物的表达耦合分析。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（一种工业毒物和模型遗传毒性致癌物）的影响和人类相关性。可行性的合理性是通过关注毒性和致癌的基本机制来证明的，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的影响以菌株和组织依赖性方式调节染色质、组蛋白修饰和其他表观遗传状态。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Refining risk estimates for lead in drinking water based on the impact of genetics and diet on blood lead levels using the Collaborative Cross mouse population.

使用协作交叉小鼠群，根据遗传学和饮食对血铅水平的影响，完善饮用水中铅的风险估计。

DOI：
发表时间：
2023-07-28
期刊：
影响因子：
0
作者：
Cuomo, Danila;Nitcher, Megan;Barba, Estefania;Feinberg, Andrew P;Rusyn, Ivan;Chiu, Weihsueh A;Threadgill, David W
通讯作者：
Threadgill, David W

Non-alcoholic fatty liver disease-associated DNA methylation and gene expression alterations in the livers of Collaborative Cross mice fed an obesogenic high-fat and high-sucrose diet.

喂食导致肥胖的高脂肪和高蔗糖饮食的 Collaborative Cross 小鼠肝脏中与非酒精性脂肪肝相关的 DNA 甲基化和基因表达改变。

DOI：
发表时间：
2022-11
期刊：
影响因子：
3.7
作者：
Tryndyak, Volodymyr P;Willett, Rose A;Avigan, Mark I;Sanyal, Arun J;Beland, Frederick A;Rusyn, Ivan;Pogribny, Igor P
通讯作者：
Pogribny, Igor P

Model systems and organisms for addressing inter- and intra-species variability in risk assessment.

用于解决风险评估中物种间和物种内变异性的模型系统和生物体。

DOI：
发表时间：
2022-07
期刊：
影响因子：
0
作者：
Rusyn, Ivan;Chiu, Weihsueh A.;Wright, Fred A.
通讯作者：
Wright, Fred A.

A resource for integrated genomic analysis of the human liver.

人类肝脏综合基因组分析的资源。

DOI：
发表时间：
2022-09-07
期刊：
影响因子：
4.6
作者：
Zhou, Yi;Gallins, Paul J;Etheridge, Amy S;Jima, Dereje;Scholl, Elizabeth;Wright, Fred A;Innocenti, Federico
通讯作者：
Innocenti, Federico

Lipidomic profiling of the hepatic esterified fatty acid composition in diet-induced nonalcoholic fatty liver disease in genetically diverse Collaborative Cross mice.

遗传多样性协作交叉小鼠饮食诱导的非酒精性脂肪肝病中肝酯化脂肪酸成分的脂质组学分析。

DOI：
10.1016/j.jnutbio.2022.109108
发表时间：
2022-11
期刊：
The Journal of nutritional biochemistry
影响因子：
0
作者：
Nagumalli, Suresh K.;Willett, Rose A.;de Conti, Aline;Tryndyak, Volodymyr P.;Avigan, Mark I.;da Costa, Goncalo Gamboa;Beland, Frederick A.;Rusyn, Ivan;Pogribny, Igor P.
通讯作者：
Pogribny, Igor P.