Benzo[a]pyrene-induced chromatin organization and epigenomics mediated by SATB1

SATB1介导的苯并[a]芘诱导的染色质组织和表观基因组学

• 批准号: 9043728
• 负责人: Terumi Kohwi-Shigematsu
• 金额: $ 35.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-06 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043728
• 关键词: ARNT gene; ARNT protein; Address; Affect; Air Pollution; Anchorage-Independent Growth; Apoptosis; Architecture; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Benzo(a)pyrene; Binding; Binding Sites; Biological; Biological Assay; Breast; Breast Cancer Cell; Breast Epithelial Cells; Carcinogens; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Cellular Morphology; ChIP-seq; Chromatin; Chromatin Loop; Complex; Data; Environmental Health; Enzymes; Epithelial; Epoxy Compounds; Event; Exposure to; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Genome; Genomics; Glycols; Health; Higher Order Chromatin Structure; Human; In Vitro; Individual; Lead; Ligands; MCF10A cells; Malignant - descriptor; Malignant Neoplasms; Maps; Mediating; Metabolism; Modification; Molecular Profiling; Morphology; Mutagens; Nuclear; Phase; Phenotype; Play; Process; Proteins; Pyrenes; Regulator Genes; Resistance; Role; Series; Signal Transduction; Testing; Time; Toxic Environmental Substances; Toxicant exposure; Toxicology; Tumor Promotion; Xenobiotic Metabolism; Xenobiotics; activating transcription factor; cell motility; chromatin immunoprecipitation; chromatin modification; deep sequencing; epigenomics; genome-wide; human disease; in vivo; malignant breast neoplasm; malignant phenotype; malignant state; novel; protein complex; response; toxicant; tumor initiation; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Environmental toxicants can induce changes in the epigenomic status of exposed cells, resulting in altered gene expression, which can consequently lead to human diseases such as cancer. The Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is expected to play a key role in this process upon exposure to these toxicants. However, how these epigenomic changes are brought about in response to environmental toxicant exposure is far from being understood. One major toxicant is the prototypical polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (B[a]P) which is found in air pollution generated by incomplete combustion of organic materials. To understand important upstream events for implementing epigenomic status in response to environmental toxicants, we will study the effect of B[a]P on higher-order chromatin structure (such as chromatin looping formed via inter- or intra-chromosomal interactions). Epigenomic status and subsequent gene expression profiles of individual genes are governed at the level of higher-order chromatin structure. We will address the role of the genome organizer protein SATB1 in the process of conformational changes of chromatin induced by B[a]P. SATB1 can establish higher-order chromatin folding, affect the epigenomic status at hundreds of its target genes, and reprogram gene expression genome-wide in response to external signaling. Thus, we propose the hypothesis that SATB1 is a critical driver in executing the effects of environmental toxicants in affected cells at the level of higher-order chromatin structure. If so, the gene regulatory role of the ligand-activated AhR after B[a]P exposure would be greatly altered under the influence of SATB1. We will determine the effect of gene expression patterns in response to B[a]P exposure using our breast epithelial MCF10A tumor progression series, containing SATB1- expressing and non-expressing cells. We will determine genomic binding sites of AhR (and its associating partner, ARNT) and SATB1 by chromatin immunoprecipitation, followed by deep sequencing to find if any SATB1 and AhR-ARNT complex binding sites merge upon B[a]P exposure, and we will examine the biological consequences of B[a]P exposure of the cells expressing varying levels of SATB1. We aim to assess whether B[a]P exposure promotes malignancy to a degree dependent on the SATB1 levels in the exposed cells. The potential role of a genome organizer in controlling ligand-activated AhR after exposure to environmental toxicants has never been addressed to date, and testing this hypothesis will likely provide a valuable new perspective for the field of environmental health science.

描述(申请人提供)：环境毒物可以引起暴露细胞表观基因组状态的变化，导致基因表达改变，从而导致人类疾病，如癌症。芳香烃受体(Ahr)是一种配体激活的转录因子，一旦暴露，有望在这一过程中发挥关键作用。 这些毒物。然而，这些表观基因组变化是如何对环境毒物暴露做出反应的，目前还远未被了解。一种主要的有毒物质是典型的多环芳烃(PAH)苯并[a]芘(B[a]P)，它存在于有机物质不完全燃烧产生的空气污染中。为了了解在响应环境毒物时实现表观基因组状态的重要上游事件，我们将研究B[a]P对高阶染色质结构的影响(例如通过染色体间或染色体内相互作用形成的染色质环)。单个基因的表观基因组状态和随后的基因表达谱在高阶染色质结构水平上受到控制。我们将讨论基因组组织蛋白SATB1在B[a]P诱导的染色质构象变化过程中的作用。SATB1可以建立更高级别的染色质折叠，影响其数百个靶基因的表观基因组状态，并对外部信号做出反应，重新编程全基因组的基因表达。因此，我们提出假设，SATB1是在高阶染色质结构水平上执行环境毒物对受影响细胞的影响的关键驱动因素。如果是这样的话，基因调控作用 在SATB1的影响下，B[a]P暴露后配体激活的AhR会发生很大的变化。我们将使用我们的乳腺上皮MCF10A肿瘤进展系列，包括SATB1表达和非表达细胞，确定基因表达模式对苯[a]P暴露的影响。我们将通过染色质免疫沉淀确定AhR(及其结合伙伴ARNT)和SATB1的基因组结合位点，然后进行深度测序，以确定在B[a]P暴露时是否有SATB1和AhR-Arnt复合结合位点合并，并将检测不同水平SATB1表达的细胞在B[a]P暴露下的生物学后果。我们的目标是评估B[a]P暴露是否会在一定程度上促进恶性肿瘤，这取决于暴露细胞中SATB1的水平。到目前为止，基因组组织者在环境毒物暴露后控制配体激活的AhR中的潜在作用从未被讨论过，验证这一假说可能会为环境健康科学领域提供一个有价值的新视角。