The role of chromatin structural and epigenetic changes in arsenic-induced gene expression

染色质结构和表观遗传变化在砷诱导的基因表达中的作用

• 批准号: 8887884
• 负责人: Yvonne Nsokika Fondufe-Mittendorf
• 金额: $ 32.98万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-07 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887884
• 关键词: Adhesions; Affect; Arsenic; Binding; Biochemical; Bioinformatics; Biological Markers; Cell Adhesion; ChIP-seq; Chromatin; Chromatin Structure; Cues; DNA; DNA Binding; DNA Methylation; DNA Sequence; Data; Development; Diagnostic; Disease; Ensure; Epigenetic Process; Etiology; Eukaryotic Cell; Exposure to; Failure; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Structure; Generations; Genes; Genetic Transcription; Genome; Goals; Growth and Development function; Health; Heavy Metals; Histones; Human; ITGB4 gene; In Vitro; Integrins; Lead; Location; Malignant Neoplasms; Malignant neoplasm of lung; Mammalian Cell; Mediating; Modification; Molecular Profiling; Molecular Target; NCAM1 gene; Neoplasm Metastasis; Nucleosomes; Organism; Outcome; Pathogenesis; Play; Positioning Attribute; Post-Translational Protein Processing; Prevention; Process; Proteins; Reactive Oxygen Species; Research; Risk; Role; Site; Specific qualifier value; Stimulus; Structure; System; To specify; Toxin; Water; World Health Organization; Zinc Fingers; base; carcinogenesis; cell transformation; chromatin protein; chromatin remodeling; differential expression; drinking; epigenome; epigenomics; epithelial to mesenchymal transition; genome-wide; in vivo; insight; metaplastic cell transformation; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; pollutant; promoter; public health relevance; response; single-molecule FRET; therapeutic target; tool; transcription factor; tumorigenesis

 DESCRIPTION (provided by applicant): Establishing the influence of pollutants on genome function is essential in defining their impact on human health. Arsenic is a ubiquitous environmental toxic metalloid that leads to carcinogenesis. The World Health Organization estimates that over 100 million people worldwide are at risk to drinking arsenic contaminated water. Recent studies indicate that arsenic alters gene expression leading to tumorigenesis. Proper gene regulation is essential for normal growth, development and etiology of diseases such as cancer. Eukaryotic DNA stored as chromatin whose basic repeating unit is the nucleosome, plays an integral role in gene regulation. Previously, we (and others) showed that nucleosome locations within promoters play critical roles in chromatin accessibility, thus controlling gene activity. Consequently, chromatin accessibility is an essential component in gene regulation yet is not fully understood. Chromatin accessibility appears to be modulated by several key epigenetic factors: histone post-translational modifications (PTMs), DNA methylation, nucleosome position/occupancy, transcription factors and chromatin architectural proteins (CAPs). Recent studies now indicate that changes in DNA methylation and histone PTMs influence gene expression in response to arsenic: Thus it is critically important to understand how these key epigenetic modulators integrate and interrelate to regulate the chromatin state and gene expression during arsenic exposure. This project will determine the functional changes in gene regulation, chromatin composition, structure and dynamics genome-wide due to arsenic in normal and iAs- transformed cells. We hypothesize that iAs-induced alterations in nucleosome position and occupancy, histone PTMs, and CAP occupancy all combine to dynamically restructure chromatin resulting in differential expression of key genes resulting in a failure to ensure proper gene regulation and cancer. We propose in this application the following Specific Aims: (1) determine the effect of iAs on in vivo nucleosome positioning and/occupancy during iAs-induced transformation. (2) Determine the impact of iAs- triggered modulation of CAPs-chromatin structure to impact gene expression. (3) Determine the mechanisms whereby iAs-provoked changes in chromatin composition, structure and dynamics control TF occupancy. Our interdisciplinary, broad approach will establish unique comprehensive functional and mechanistic data that will provide a detailed understanding of the interplay between arsenic-induced epigenetic changes and chromatin in the mammalian cell. We have developed novel systems that will provide an unprecedented and unique opportunity to discover the functional and mechanistic roles of the epigenome in toxin-induced diseases.

 描述（由适用提供）：确定污染物对基因组功能的影响对于确定其对人类健康的影响至关重要。砷是一种无处不在的环境有毒金属，可导致癌变。世界卫生组织估计，全世界有超过1亿人有饮用砷污染的水的风险。最近的研究表明，砷会改变基因表达导致肿瘤发生。适当的基因调节对于癌症等疾病的正常生长，发育和病因至关重要。真核DNA存储为染色质，其基本重复单位是核小体，在基因调节中起着不可或缺的作用。以前，我们（和其他）表明，启动子中的核小体位置在染色质访问性中起关键作用，从而控制基因活性。因此，染色质的可及性是基因调节中必不可少的组成部分，但尚未完全了解。染色质的可及性似乎是由几个关键的表观遗传因素调节的：组蛋白翻译后修饰（PTMS），DNA甲基化，核小体位置/占用率，转录因子和染色质结构蛋白（CAPS）。最近的研究现在表明，DNA甲基化和组蛋白PTM的变化会影响基因表达对砷的反应：了解这些关键表观遗传调节剂如何整合和相互关联以调节砷暴露期间的染色质状态和基因表达非常重要。该项目将确定基因调节，染色质组成，结构和动态基因组在正常和IAS转化细胞中的功能变化。我们假设IAS诱导的核小体位置和占用率，组蛋白PTM和CAP占用率的变化均组合为动态重组染色质，从而导致关键基因的差异表达，从而导致无法确保适当的基因调节和癌症。我们在本应用中提出以下具体目的：（1）确定IAS在IAS诱导的转化过程中体内核粘液量定位和/占用率的影响。 （2）确定caps-染色质结构的IAS触发调节对影响基因表达的影响。 （3）确定IAS发动机染色质组成，结构和动力学控制TF占用率的机制。我们的跨学科，广泛的方法将建立独特的综合功能和机械数据，这些数据将对哺乳动物细胞中砷诱导的表观遗传变化和染色质之间的相互作用提供详细的了解。我们已经开发了新型系统，这些系统将提供前所未有的独特机会，以发现表观基因组在毒素诱导的疾病中的功能和机械作用。