Integrative transcriptional and epigenomic modeling of xenobiotic-activated gene regulatory networks

外源物质激活基因调控网络的综合转录和表观基因组模型

基本信息

批准号：
10657411
负责人：
Sudin Bhattacharya
金额：
$ 45.69万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-03 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657411
关键词：
ATAC-seq Adverse effects Aryl Hydrocarbon Receptor B-Lymphocytes Binding Binding Sites Biological Biological Assay Body Burden Breastfed infant CRISPR interference Cells ChIP-seq Chemical Exposure Chemicals Chromatin Chromatin Interaction Analysis by Paired-End Tag Sequencing Computer Models Congenital Abnormality DNA DNA Sequence Data Data Set Development Dioxins Environmental Pollutants Epigenetic Process Exposure to Fishes Food Food Chain Gene Expression Gene Expression Regulation Genes Genetic Transcription Genome Genomics Goals Hepatocyte Hepatotoxicity Human Human Cell Line Immunosuppression Infant Ingestion Knowledge Ligands Liver Maps Mediating Medical center Michigan Modeling Mus Nucleic Acid Regulatory Sequences Outcome Poison Population Promoter Regions Public Health Receptor Activation Receptor Signaling Regulator Genes Regulatory Pathway Response Elements Risk Risk Assessment Risk Estimate Rodent Role Statistical Models Testing Tetrachlorodibenzodioxin Tissue Model Tissues Toxic effect Training United States National Institutes of Health Universities Vulnerable Populations Wasting Syndrome Work Xenobiotics adverse outcome computational basis differential expression epigenome editing epigenomics experimental study exposed human population functional genomics gene regulatory network genome-wide health assessment histone modification improved in utero innovation multidisciplinary novel predictive modeling receptor binding response sensor species difference toxicant transcription factor transcription regulatory network transcriptome sequencing virtual

项目摘要

PROJECT SUMMARY/ABSTRACT The environmental contaminant 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most potent and persistent toxicants known. TCDD and other dioxin-like chemicals are primarily ingested through food, and can cause various adverse effects ranging from immune suppression to hepatotoxicity and developmental alterations. Despite gradually decreasing environmental and body burdens, dioxin exposure remains of particular concern in utero, in breastfed infants, and specific populations reliant for food on locally caught fish and wildlife. The aryl hydrocarbon receptor (AHR), a ligand-inducible transcription factor, mediates virtually all of the toxic effects of dioxins. Nearly four decades after its discovery, the AHR remains an enigmatic molecule with a variety of endogenous roles in addition to its function as an environmental sensor. Our recent analysis of the AHR signaling network in mouse liver showed that direct AHR binding to cognate sequences in promoter regions of target genes explains only about 10% of TCDD-induced gene perturbations. In addition, it is unclear why humans are much less sensitive in responses to TCDD than rodents. These gaps in our knowledge make it difficult to estimate the risks of human exposure to dioxins. Our overarching hypothesis is that tissue- and species-specific alterations in gene expression induced by AHR activation, which in turn lead to dioxin toxicity, are determined by a combination of local chromatin accessibility, AHR binding in gene regulatory regions, and AHR-mediated long-range chromatin interactions. We propose to use an innovative combination of functional genomic experiments, computational modeling, and targeted epigenome editing (CRISPRi) to develop a predictive model for AHR-mediated tissue- and species-specific gene regulation, and to reconstruct the AHR transcriptional regulatory network in human vs. mouse liver and B cells. We will draw on both AHR-specific data generated in this project, and the NIH ENCODE and Roadmap Epigenomics projects, which have collectively made available 10,000+ genomic and epigenomic data sets from more than 400 human cell lines and tissue types. In Aim 1, we will compare genome-wide chromatin accessibility of mouse and human hepatocytes and B cells in the absence and presence of TCDD. In Aim 2, a novel predictive model for genome-wide AHR binding will be developed based on ChIP-Seq, chromatin accessibility and histone modification data. In Aim 3, we will identify and predict the differential expression of AHR target genes in mouse and human from AHR binding sites in regulatory DNA and AHR-mediated long-range interactions. The overall impact of our model will be improved mechanistic understanding of tissue-and species-specific gene regulation by the AHR in unprecedented genome-wide detail. Our long-term goal is to develop a genome- based quantitative framework for human risk assessment of chemicals that dysregulate core transcriptional regulatory pathways.

项目摘要/摘要环境污染物2,3,7,8-四氯迪本佐-P-二恶英（TCDD）是最有效的一种，持续的有毒物质已知。 TCDD和其他类似二恶英的化学物质主要通过食物摄入，并且可以引起各种不良反应，从免疫抑制到肝毒性和发育改变。尽管逐渐减轻了环境和身体负担，但仍有二恶英的暴露在子宫内特别关注的是母乳喂养的婴儿和依赖于当地捕获的鱼类食物的特定种群和野生动植物。芳基烃受体（AHR）是一种可诱导的转录因子，几乎全部介导二恶英的毒性作用。发现近四十年后，AHR仍然是一个神秘的分子除了其作为环境传感器的功能外，还具有多种内源性作用。我们最近对小鼠肝脏中的AHR信号网络表明，直接AHR与启动子中的同源序列结合靶基因区域仅解释了约10％的TCDD诱导的基因扰动。另外，还不清楚为什么人类对TCDD的敏感性比啮齿动物敏感得多。这些差距在我们的知识中很难估计人类暴露于二恶英的风险。我们的总体假设是组织和 AHR激活诱导的基因表达中的物种特异性改变，进而导致二恶英毒性，由局部染色质可及性，基因调节区域的AHR结合和 AHR介导的远程染色质相互作用。我们建议使用功能的创新组合基因组实验，计算建模和靶向表观基因组编辑（CRISPRI）开发 AHR介导的组织和物种特异性基因调节的预测模型，并重建AHR 人与小鼠肝脏和B细胞中的转录调节网络。我们将利用两个特定的AHR 该项目生成的数据以及NIH的编码和路线图表观基因组学项目，从400多个人类细胞系中共同提供了10,000多个基因组和表观基因组数据集和组织类型。在AIM 1中，我们将比较小鼠和人类的全基因组染色质的可及性在不存在和存在TCDD的情况下，肝细胞和B细胞。在AIM 2中，一个新颖的预测模型全基因组AHR结合将基于ChIP-Seq，染色质可及性和组蛋白开发修改数据。在AIM 3中，我们将识别并预测AHR靶基因的差异表达在调节性DNA和AHR介导的远距离相互作用中，来自AHR结合位点的小鼠和人。这我们模型的总体影响将改善对组织和物种特异性基因的机械理解 AHR在空前的全基因组细节中对AHR进行调节。我们的长期目标是开发基因组 - 基于对核心转录失调的化学物质的人类风险评估的定量框架监管途径。