Molecular mechanisms of iAs-mediated carcinogenesis through the lens of histone H2B variants

通过组蛋白 H2B 变异观察 iAs 介导的致癌作用的分子机制

• 批准号: 10616739
• 负责人: Yvonne Nsokika Fondufe-Mittendorf
• 金额: $ 66.71万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-02 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10616739
• 关键词: Affect; Amino Acids; Architecture; Arsenic; Automobile Driving; Binding Proteins; Biochemical; Bioinformatics; Biology; Biophysics; Cell Culture Techniques; Cell Proliferation; Cells; ChIP-seq; Chromatin; Chromatin Structure; Compensation; DNA; DNA Methylation; Deposition; Development; Disease; Epigenetic Process; Epithelium; Etiology; Eukaryotic Cell; Exposure to; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genome; Genomic DNA; Genomics; Growth; Health; Histone H2B; Histones; Human; In Vitro; Location; Malignant Neoplasms; Mammalian Cell; Maps; Mass Spectrum Analysis; Mediating; Mesenchymal; Messenger RNA; Methylation; Modification; Molecular; Mutation; Neoplastic Cell Transformation; Normal Cell; Nucleosomes; Oncogenic; Organism; Pathology; Persons; Play; Poly(A) Tail; Positioning Attribute; Post-Translational Protein Processing; Process; Protein Isoforms; Proteins; Recurrence; Risk; Role; Series; Site; Spliced Genes; Structure; System; Testing; Therapeutic; Tissue-Specific Gene Expression; Toxicology; Transcript; Transcription Initiation; Tumor Biology; Variant; Work; World Health Organization; Xenograft Model; arsenic-induced carcinogenesis; biophysical analysis; cancer type; carcinogenesis; cell transformation; cell type; contaminated water; differential expression; drinking; epigenome; experimental study; functional genomics; gene function; gene repression; genome-wide; genomic locus; in vivo; insight; knock-down; lens; metaplastic cell transformation; mutant; novel; novel diagnostics; novel therapeutics; oncohistone; overexpression; pollutant; promoter; response; stem; tool; toxicant; transcription factor; tumor progression; tumorigenesis

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 is modulated by several key epigenetic factors: histone post-translational modifications (PTMs), DNA methylation, nucleosome position/occupancy, transcription factors and chromatin architectural proteins (CAPs). We showed recently that in addition to the above, incorporation of histone variants (the elusive H2B), into chromatin play a significant role in arsenic-mediated diseases pathology, yet a mechanistic understanding of their impact is unknown. These histone variants differ by just one to maximally three amino acids from the canonical H2B histone and are highly expressed in cancers, suggesting that they could act as `oncohistones'. Thus it is critically important to understand how and why these histone variants get expressed (aim 1); how their chromatin integration impacts chromatin structural dynamics (aim 2) and integration regulate the chromatin state and gene expression during arsenic exposure to drive carcinogenesis (aim3). Our interdisciplinary, broad approach will establish unique comprehensive functional and mechanistic insight into histone H2B variant expression, chromatin integration and disease pathology. Further it 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 toxicant-induced diseases.

确定污染物对基因组功能的影响对于确定它们对 人类健康。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，全世界有超过1亿人面临饮用砷的风险 被污染的水。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。以前，我们(和其他人)证明了启动子中的核小体位置起着至关重要的作用 在染色质可及性中发挥作用，从而控制基因活性。因此，染色质的可及性是一种 基因调控中的重要组成部分还不完全清楚。染色质的可及性受 几个关键的表观遗传因素：组蛋白翻译后修饰(PTMS)、DNA甲基化、核小体 位置/占用、转录因子和染色质结构蛋白(CAPS)。我们最近展示了 除了上述，将组蛋白变体(难以捉摸的H_2B)掺入染色质中也起到了重要的作用 在砷介导的疾病病理中的作用，但对其影响的机制了解尚不清楚。 这些组蛋白变体与典型的组蛋白H_2B和H_2B仅相差一到三个氨基酸。 在癌症中高度表达，这表明它们可能起到‘癌组织蛋白’的作用。因此，它是至关重要的 了解这些组蛋白变体的表达方式和原因(目标1)；它们的染色质整合如何 影响染色质结构动力学(目标2)和整合调节染色质状态和基因 在砷暴露导致癌症发生过程中的表达(AIM3)。我们的跨学科、广泛的方法将 对组蛋白H2 B变体表达建立独特的全面的功能和机制洞察力， 染色质整合与疾病病理学。此外，它还将提供对相互作用的详细了解 砷诱导的表观遗传学变化与哺乳动物细胞染色质之间的关系。我们已经开发出了小说 系统将提供前所未有的独特机会来发现功能性和机械性 表观基因组在毒物性疾病中的作用。