Epigenetic Actions of Environmental Chemicals

环境化学物质的表观遗传作用

• 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
• 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

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(申请人提供)：许多工业化学品和环境污染物通过与属于核受体超家族的转录因子相互作用而产生毒性，但对导致基因转录发生广泛的、通常是长期的变化的下游表观遗传事件知之甚少。这一应用侧重于肝脏核受体和转录因子CAR(构成雄烷受体；NR1I3)的基因组和表观基因组学作用，CAR被结构上不同的环境化学物质激活，调节重要的生理和病理生理过程，包括肝脏药物和脂肪代谢、葡萄糖稳态、炎症和肿瘤促进。建议的研究利用高通量基因组学、计算生物学和表观遗传调控机制的最新进展，在完整的动物模型中阐明CAR激活对染色质结构和表观遗传状态的影响。小鼠肝脏模型将被用来解决基本的生物学问题，即典型的CAR特异性激动剂配体TCPOBOP(1，4-双[2-(3，5-二氯吡啶氧基)]苯)如何激活受体，改变染色质的可及性，并建立与广泛的，在某些情况下永久的肝脏基因表达失调相关的表观遗传环境。支持这一建议的初步研究包括：(A)开发可访问染色质区域(DNA酶超敏反应)和表观遗传特征(染色质标记)的全球图谱，以表征处于基础状态的CAR靶标；(B)发现CAR激活导致基因组中约1000个位点的染色质可及性快速变化；以及(C)发现对CAR快速反应并假设重新编程CAR靶基因及其调控元件染色质状态的富核长基因间非编码(Linc)RNA。这些发现提供了一个独特的机会，通过在基因组和表观遗传水平上阐明决定外国化学物质激活CAR的复杂转录反应的基本生物学机制，推动该领域的发展。这将通过以下发现来完成：1)CAR诱导的肝脏染色质可及性改变及其与CAR结合和靶基因失调的关系；2)CAR调节的lincRNAs在外来化学物质暴露后染色质状态和基因转录模式重新编程中的作用；以及3)新生儿激活CAR在易感靶基因建立永久表观遗传记忆的机制。总之，这些研究将确定控制复杂的、环境中依赖化学物质的CAR基因调控的关键机制特征，这些基因控制着对人类健康和疾病产生重大影响的不同代谢过程。预计所获得的结果将产生很大的影响，将环境化学作用的机制研究重点转移到表观基因组，并将成为以复杂方式改变基因组的其他外国化学激活受体的范例。