Epigenetic Actions of Environmental Chemicals

环境化学物质的表观遗传作用

基本信息

批准号：
8762618
负责人：
DAVID J WAXMAN
金额：
$ 40.39万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8762618
关键词：
Abbreviations Address Affect Agonist Animal Model Benzene Binding Binding Sites Biological Biological Markers Chemical Actions Chemical Exposure Chemicals Chromatin Chromatin Structure Code Complex Computational Biology DNA Binding Deoxyribonuclease I Deoxyribonucleases Development Diabetes Mellitus Disease Distal EMSA Electrophoretic Mobility Shift Assay Enhancers Environment Environmental Pollutants Enzymes Epigenetic Process Event Feedback Functional RNA Functional disorder Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Transcription Genome Genomics Health Hepatic Histone H3 Human Hypersensitivity Immunoprecipitation Inflammation Investigation Lead Ligands Link Liver Liver diseases Malignant Neoplasms Maps Mediating Memory Metabolic Metabolic Pathway Metabolism Modeling Mus Neonatal Nuclear Nuclear Receptors Pathway interactions Pattern Physiological Physiological Processes Polycomb Pregnenolone Process Proteins RNA Receptor Activation Regulation Regulatory Element Repression Role Site Specific qualifier value Testing Time Toxic effect Transcript Transcription Elongation Transcription Initiation Site Tumor Promotion blood glucose regulation chromatin immunoprecipitation constitutive androstane receptor drug metabolism early life exposure environmental chemical epigenome epigenomics genome-wide in vivo insight lipid metabolism pregnane X receptor public health relevance receptor response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Many industrial chemicals and environmental pollutants exert toxicities via interactions with transcription factors belonging to the nuclear receptor superfamily but little is known about the downstream epigenetic events that lead to widespread, often long-term, changes in gene transcription. This application focuses on the genomic and epigenomic actions of the liver nuclear receptor and transcription factor CAR (constitutive androstane receptor; NR1I3), which is activated by structurally diverse environmental chemicals and regulates important physiological and pathophysiological processes, including hepatic drug and lipid metabolism, glucose homeostasis, inflammation and tumor promotion. The proposed studies capitalize on recent advances in high throughput genomics, computational biology and epigenetic regulatory mechanisms to elucidate in an intact animal model the impact of CAR activation on chromatin structure and epigenetic states. The mouse liver model will be used to address the fundamental biological question of how receptor activation by the prototypical CAR-specific agonist ligand TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)]benzene), a non- genotoxic hepatocarcinogen, alters chromatin accessibility and establishes an epigenetic environment associated with extensive, and in some cases permanent dysregulation of liver gene expression. Preliminary Studies supporting this proposal include (a) the development of global maps of accessible chromatin regions (DNase hypersensitivity) and epigenetic signatures (chromatin marks) that characterize targets of CAR in the basal state, (b) the finding that CAR activation induces rapid changes in chromatin accessibility at ~1,000 sites in the genome, and (c) the discovery of nuclear-enriched long intergenic non-coding (linc) RNAs that respond to CAR rapidly and are hypothesized to reprogram chromatin states of CAR target genes and their regulatory elements. These findings provide a unique opportunity to move the field forward by elucidating at the genomic and epigenetic levels the fundamental biological mechanisms that determine the complex transcriptional responses to CAR activation by foreign chemicals. This will be accomplished through the discovery of: 1) CAR- inducible changes in liver chromatin accessibility and their relationship to CAR binding and target gene dysregulation; 2) the role of CAR-regulated lincRNAs in the reprogramming of chromatin states and gene transcription patterns following foreign chemical exposure; and 3) the mechanisms that underlie the permanent epigenetic memory that neonatal activation of CAR establishes at susceptible target genes. Together, these studies will identify key mechanistic features that govern the complex, environmental chemical-dependent regulation by CAR of genes that control diverse metabolic processes with a major impact on human health and disease. The results obtained are expected to have a high impact, shifting the mechanistic focus of studies on environmental chemical action to the epigenome, and will serve as a paradigm for other foreign chemical- activated receptors that alter the genome in complex ways.

描述（由申请人提供）：许多工业化学物质和环境污染物通过与属于核受体超家族的转录因子的相互作用而施加毒性，但对下游表观遗传事件的了解鲜为人知，这些事件导致广泛的，通常长期长期的基因转录变化。该应用集中于肝核受体和转录因子CAR（组成型雄激素受体； NR1I3）的基因组和表观遗传学作用，该动作被结构上多样的环境化学物质激活，并调节重要的生理和病理生理生理和病理生理过程，包括肝药物和脂肪药物和Lipid Orposismiss，Glucolismiss和Tumormis，发炎，发炎，发炎。提出的研究利用了高通量基因组学，计算生物学和表观遗传调节机制的最新进展，以阐明完整动物模型中汽车激活对染色质结构和表观遗传状态的影响。 The mouse liver model will be used to address the fundamental biological question of how receptor activation by the prototypical CAR-specific agonist ligand TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)]benzene), a non- genotoxic hepatocarcinogen, alters chromatin accessibility and establishes an epigenetic environment associated with extensive, and in some cases permanent肝基因表达的失调。支持该建议的初步研究包括（a）（a）开发可访问染色质区域的全球图（DNase高敏性）和表观遗传签名（染色质标记），这些签名（染色质标记）表征了基础状态下汽车靶标的，（b）CAR激活的发现，该发现的发现，该发现的发现在〜1,000个位点的Chromatin disctientible car速度可及格的基因组中，以及（c），以及（c），该基因组的核能差异很长。非编码（LINC）RNA迅速响应汽车，并假设对CAR靶基因的染色质状态及其调节元件进行重编除。这些发现提供了一个独特的机会，可以通过在基因组和表观遗传水平上阐明基本生物学机制来推动该领域向前发展，从而决定了外国化学物质对汽车激活的复杂转录反应。这将通过发现：1）肝脏染色质可及性的可诱导性变化及其与CAR结合和靶向基因失调的关系； 2）在外国化学暴露后，CAR调节的LincrNA在染色质状态和基因转录模式的重编程中的作用； 3）永久表观遗传记忆的基础，即汽车的新生儿激活在易感靶基因上建立。总之，这些研究将确定关键的机械特征，该特征由汽车对控制多种代谢过程的基因的复杂，环境依赖性调节，对人类健康和疾病产生重大影响。预计获得的结果将产生很大的影响，将研究对环境化学作用的机械重点转移到表观基因组上，并将作为其他外国化学化学激活受体的范式，这些受体以复杂的方式改变了基因组。