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

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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.