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

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。 人体健康砷是一种普遍存在的环境有毒类金属，可导致致癌作用。世界 世界卫生组织估计，全世界有1亿多人面临饮用砷的风险。 被污染的水。最近的研究表明，砷改变基因表达，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以染色质的形式储存，其基本重复单位是核小体，在细胞内起着不可或缺的作用。 基因调控以前，我们（和其他人）表明启动子内的核小体位置起着关键作用， 在染色质可及性中起作用，从而控制基因活性。因此，染色质可及性是一个 基因调控的重要组成部分尚未完全了解。染色质可及性受以下因素调节： 几个关键的表观遗传因素：组蛋白翻译后修饰（PTM），DNA甲基化，核小体 位置/占用、转录因子和染色质结构蛋白（CAP）。我们最近发现， 除此之外，组蛋白变体（难以捉摸的H2B）掺入染色质中， 在砷介导的疾病病理学中的作用，但其影响的机械理解是未知的。 这些组蛋白变体与典型的H2B组蛋白仅相差一个至最多三个氨基酸， 在癌症中高度表达，表明它们可以作为"癌组蛋白"。因此， 了解这些组蛋白变体如何以及为什么表达（aim 1）;它们的染色质整合 影响染色质结构动力学（aim 2）和整合调节染色质状态和基因 砷暴露过程中的表达，以驱动致癌作用（AIM3）。我们的跨学科，广泛的方法将 建立了对组蛋白H2B变体表达独特的全面的功能和机制见解， 染色质整合和疾病病理学。此外，它将提供一个详细的了解的相互作用 砷诱导的表观遗传变化和哺乳动物细胞中的染色质之间的关系。我们开发了新颖的 系统，将提供一个前所未有的和独特的机会，发现功能和机制 表观基因组在毒物引起的疾病中的作用。

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.