Molecular Underpinnings in the Establishment of an Oncogenic 3D Genome inResponse to Environmental Arsenic Exposure

建立响应环境砷暴露的致癌 3D 基因组的分子基础

• 批准号: 10594774
• 负责人: Yvonne Nsokika Fondufe-Mittendorf
• 金额: $ 59.27万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-19 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594774
• 关键词: 3-Dimensional; ATAC-seq; Affect; Alternative Splicing; Animal Model; Arsenic; Automobile Driving; Binding; Binding Sites; Biochemical; Biology; CCCTC-binding factor; Cancer Biology; Carcinogens; Cell model; Cells; Cessation of life; ChIP-seq; Chromatin; Chromatin Loop; Chromatin Structure; DNA; DNA Binding; DNA Damage; DNA Methylation; DNA Modification Methylases; Development; Diagnosis; Diagnostic; Dimensions; Disease; Enhancers; Environment; Environmental Exposure; Environmental Pollutants; Epigenetic Process; Etiology; Exposure to; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genome; Genomic Segment; Genomics; Goals; Growth and Development function; Health; Histones; Human; Hybrids; Knowledge; Light; Malignant Neoplasms; Maps; Mediating; Metals; Modeling; Molecular; Mutation; Neoplasm Metastasis; Nucleosomes; Oncogenic; Organism; Pathogenesis; Pathogenicity; Pathology; Pattern; Persons; Pharmaceutical Preparations; Play; Process; Proteins; Reactive Oxygen Species; Risk; Role; Site; Spliced Genes; Techniques; Testing; Therapeutic; Therapeutic Agents; Transcription Initiation; Variant; Work; Writing; arsenic carcinogenesis; base; carcinogenesis; carcinogenicity; chromatin remodeling; disorder prevention; epigenome; epigenomics; epithelial to mesenchymal transition; gene regulatory network; genome-wide; in vivo; metaplastic cell transformation; pollutant; prevent; promoter; targeted treatment; therapeutic development; three dimensional structure; tool

Abstract Establishing the influence of pollutants on genome function is essential in defining their impact on human health. Environmental pollutants such as inorganic arsenic (iAs) are responsible for over thirteen million deaths yearly. Importantly, 24% of the diseases caused by environmental exposures might have been avoided by disease prevention, diagnosis and the development of safer metal-based therapeutic agents. In order to understand how these pollutants cause disease, we need to understand how pollutants change gene expression. Proper gene regulation is essential for normal growth, development and etiology of diseases such as cancer. Eukaryotic DNA stored as chromatin plays an integral role in gene regulation. At the one- dimensional (1D) level, chromatin is found as nucleosomes and at the three dimensional level (3D), chromatin is found in loops and topological domains, both of which regulate gene expression by allowing accessibility to the DNA wrapped up as chromatin. Inorganic arsenic is a ubiquitous metal that impacts gene regulation through modulating the epigenome. We recently provided the epigenetic landscape (DNA methylation, histone PTMs and histone variants) mediated by iAs. This landscape though important, makes it difficult to decipher whether the observed effects on gene activity are due to local changes in epigenetic environments, or effects caused by remote changes several kilobases away, such as the activity of enhancer(s). Additionally, the effect of the 3D chromatin structure supersedes that at the 1D chromatin level. This 3D information is mediated by CTCF, known as a ‘master weaver’ of the genome, and any dysregulation of the CTCF binding alters this 3D structure, resulting in gene dysregulation. We recently showed that iAs selectively inhibits CTCF from binding to some of its target sites and instigating oncogenic expression patterns. Interestingly, carcinogenesis is not a linear process but involves a several hybrid in-between stages till final cancer state. We therefore hypothesize that by inhibiting CTCF binding, iAs reorganizes the genome to maintain specific topologically-activated domains at the 3D chromatin structure to drive specific oncogenic potentials. To test this hypothesis, we will map CTCF binding (Aim 1), chromatin 3D (Aim 2) and ChIP-seq of histone marks (Aim 3) as cells undergo iAs- mediated carcinogenesis. The knowledge derived from the proposed studies will allow us to characterize the resulting gene regulatory network mediated by iAs exposure, and allow us to unambiguously anchor iAs exposure to changes in the CTCF interactome in the process of iAs-mediated cancer. Additionally, these studies will allow us to decipher how iAs initiates, establishes and maintains particular chromatin signatures that ultimately drive gene expression in iAs pathogenesis. Such studies are critically needed for the identification of translational targets and the development of therapeutic drugs needed in iAs-disease pathology.

摘要 确定污染物对基因组功能的影响对于确定其对人类的影响至关重要 健康环境污染物，如无机砷（iAs），造成超过1300万人死亡 每年一次。重要的是，通过以下措施可以避免24%由环境暴露引起的疾病 疾病预防、诊断和开发更安全的金属基治疗剂。为了 了解这些污染物如何导致疾病，我们需要了解污染物如何改变基因 表情适当的基因调控对正常生长、发育和疾病的病因学至关重要， 癌症真核DNA作为染色质储存在基因调控中起着不可或缺的作用。在一个- 在三维（1D）水平上，染色质被发现为核小体，而在三维（3D）水平上，染色质被发现为核小体。 在环和拓扑结构域中发现，这两种结构域都通过允许可接近性来调节基因表达。 DNA包裹成染色质。无机砷是一种普遍存在的影响基因调控的金属 通过调节表观基因组。我们最近提供了表观遗传景观（DNA甲基化，组蛋白 PTM和组蛋白变体）。这一景观虽然重要， 观察到的对基因活性的影响是否是由于表观遗传环境的局部变化， 由几个碱基的远程变化引起，如增强子的活性。此外，效果 3D染色质结构取代了1D染色质水平。这种3D信息是由 CTCF，被称为基因组的“主编织者”，CTCF结合的任何失调都会改变这种3D 结构，导致基因失调。我们最近发现iAs选择性地抑制CTCF结合 它的一些目标网站和煽动致癌的表达模式。有趣的是，致癌作用不是一个 这是一个线性过程，但涉及到几个阶段之间的混合，直到最终的癌症状态。因此我们假设 通过抑制CTCF结合，iAs重组基因组以维持特定的拓扑激活， 结构域的三维染色质结构，以驱动特定的致癌潜力。为了验证这个假设，我们将 当细胞经历iAs时，绘制CTCF结合（Aim 1）、染色质3D（Aim 2）和组蛋白标记的ChIP-seq（Aim 3）。 介导的致癌作用。从拟议的研究中获得的知识将使我们能够描述 由此产生的基因调控网络介导的iAs暴露，并允许我们明确锚iAs 在iAs介导的癌症过程中暴露于CTCF相互作用组的变化。此外，这些 研究将使我们能够破译iAs如何启动，建立和维持特定的染色质签名 最终驱动iAs发病机制中的基因表达。这些研究是迫切需要的， 确定iAs疾病所需的翻译靶点和开发治疗药物 病理