Molecular Underpinnings in the Establishment of an Oncogenic 3D Genome in Response 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

基本信息

批准号：
10159289
负责人：
Yvonne Nsokika Fondufe-Mittendorf
金额：
$ 49.15万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2020-05-06 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159289
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 Pharmaceutical Preparations Play Process Proteins Reactive Oxygen Species Regulator Genes 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 genome-wide in vivo metaplastic cell transformation pollutant prevent promoter response targeted treatment therapeutic development three dimensional structure tool

项目摘要

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.

抽象的建立污染物对基因组功能的影响对于确定其对人的影响至关重要健康。环境污染物（例如无机砷（IAS））造成1300万人死亡每年。重要的是，可能已经避免了由环境暴露引起的24％的疾病疾病预防，诊断和更安全的基于金属的治疗剂的发展。为了了解这些污染物如何引起疾病，我们需要了解污染物如何改变基因表达。适当的基因调节对于疾病的正常生长，发展和病因至关重要作为癌症。以染色质为基因调节中持续的真核DNA在基因调节中起着不可或缺的作用。在一个尺寸（1D）水平，染色质被发现为核小体，在三维水平（3D），染色质中在循环和拓扑结构域中发现，这两者都可以通过可访问性来调节基因表达 DNA包裹为染色质。无机砷是一种无处不在的金属，影响基因调节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 PTMS和Hisstone变体）由IAS介导。这种景观虽然很重要，但很难破译观察到的对基因活性的影响是由于表观遗传环境中局部变化引起的还是影响由于远程变化而引起的几千碱基，例如增强剂的活性。另外，效果在1D染色质水平上取代的3D染色质结构中。此3D信息由 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3D 结构，导致基因失调。我们最近表明，IAS选择性抑制CTCF的结合到其一些目标位点和煽动致癌表达模式。有趣的是，癌变不是线性过程，但涉及到最终癌症状态之间的一些混合阶段。因此，我们假设通过抑制CTCF结合，IAS重新组织了基因组以维持特定的拓扑激活 3D染色质结构的结构域以驱动特定的致癌潜力。为了检验这一假设，我们将 MAP CTCF结合（AIM 1），染色质3D（AIM 2）和组蛋白标记的ChIP-seq（AIM 3）随着细胞经历IAS- 介导的致癌作用。从拟议的研究中得出的知识将使我们能够表征由IAS暴露介导的基因调节网络，使我们能够明确锚定IAS 在IAS介导的癌症过程中，CTCF相互作用组的变化暴露。另外，这些研究将使我们能够破译IAS的启动，建立和维护特定的染色质特征最终驱动IAS发病机理中的基因表达。这样的研究至关重要识别翻译靶标的和IAS酶中所需的热药的发展病理。