Diversity Supplement: The Role of Chromatin Structural and Epigenetic Changes in Arsenic-Induced Gene Expression Supplement

多样性补充：染色质结构和表观遗传变化在砷诱导的基因表达补充中的作用

• 批准号: 9278387
• 负责人: Yvonne Nsokika Fondufe-Mittendorf
• 金额: $ 0.85万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9278387
• 关键词: Adhesions; Affect; Architecture; Arsenic; Binding; Biochemical; Bioinformatics; Biophysics; 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; Transcriptional Regulation; World Health Organization; Zinc Fingers; base; carcinogenesis; carcinogenicity; cell transformation; chromatin protein; chromatin remodeling; clinical biomarkers; clinical development; contaminated water; 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; targeted treatment; 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(由申请人提供)：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。砷是一种普遍存在的环境有毒金属，具有致癌作用。世界卫生组织估计，全球有超过1亿人面临饮用被砷污染的水的风险。最近的研究表明，砷改变了导致肿瘤发生的基因表达。适当的基因调控对癌症等疾病的正常生长、发展和病因学至关重要。真核DNA以染色质的形式储存，其基本重复单位是核小体，在基因调控中起着不可或缺的作用。此前，我们(和其他人)表明，启动子内的核小体位置在染色质可及性中起着关键作用，从而控制基因的活性。因此，染色质的可及性是基因调控中的一个重要组成部分，但尚不完全清楚。染色质的可及性似乎受几个关键的表观遗传因素的调节：组蛋白翻译后修饰(PTM)、DNA甲基化、核小体位置/占位、转录因子和染色质结构蛋白(CAPs)。最近的研究表明，DNA甲基化和组蛋白PTM的改变影响了砷的反应基因的表达：因此，了解这些关键的表观遗传调节因子如何整合和相互作用来调节染色质状态和砷暴露过程中的基因表达是至关重要的。该项目将确定正常细胞和IAS转化细胞中砷对全基因组的基因调控、染色质组成、结构和动力学的功能变化。我们假设IAS诱导的核小体位置和占位、组蛋白PTM和CAP占位的改变都结合在一起动态地重组染色质，导致关键基因的差异表达，从而无法确保适当的基因调控和癌症。在这一应用中，我们提出了以下具体目标：(1)确定IAS在体内对IAS诱导转化过程中核小体定位和/或占据的影响。(2)确定IAS触发的CAPS-染色质结构调控对基因表达的影响。(3)确定IAS引起染色质组成、结构和动力学变化控制Tf占位的机制。我们的跨学科、广泛的方法将建立独特的全面的功能和机制数据，这些数据将提供对砷诱导的表观遗传变化和哺乳动物细胞染色质之间的相互作用的详细了解。我们已经开发了新的系统，将提供一个前所未有的和独特的机会来发现表观基因组在毒素诱导的疾病中的功能和机制作用。