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。世界卫生组织估计，砷是一种普遍存在的环境毒性类金属，会导致癌症。最近的研究表明，砷会改变基因表达，从而导致肿瘤发生。适当的基因调控对于疾病的正常生长、发展和病因学至关重要。以染色质形式储存的真核 DNA，其基本重复单位是核小体，在基因调控中发挥着不可或缺的作用。 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发挥着关键作用，从而控制基因活性。染色质可及性是基因调控的重要组成部分，但尚未完全了解染色质可及性似乎受到几个关键表观遗传因素的调节：组蛋白翻译后修饰。最近的研究表明，DNA 甲基化和组蛋白 PTM 的变化会影响砷对基因的表达：因此，了解砷如何影响基因表达至关重要。这些关键的表观遗传调节剂整合并相互关联，以调节砷暴露期间的染色质状态和基因表达。该项目将确定基因调节、染色质的功能变化。我们发现，砷诱导的核小体位置和占据、组蛋白 PTM 和 CAP 占据的改变共同动态地重组染色质，导致关键的差异表达。基因导致无法确保适当的基因调控和癌症。我们在本申请中提出以下具体目标：（1）确定 iAs 对体内核小体的影响。 (2) 确定 iAs 引发的 CAP-染色质结构调节对基因表达的影响。 (3) 确定 iAs 引起染色质组成变化和结构动态控制的机制。我们的跨学科、广泛的方法将建立独特的综合功能和机制数据，从而详细了解砷诱导的表观遗传变化和染色质之间的相互作用。我们开发了新的系统，将为发现表观基因组在毒素引起的疾病中的功能和机制作用提供前所未有的独特机会。