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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

基本信息

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
项目类别：
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

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.

摘要