The Role of Chromatin Structural and Epigenetic Changes in Arsenic-induced Gene Expression

Establishing the influence of pollutants on genome function is essential in defining their impact on human health. Environmental pollutants are responsible for over thirteen million deaths yearly. Importantly, 24% of the diseases caused by environmental exposures might have been avoided by disease prevention, diagnostics and the development of safer metal-based therapeutic agents. 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 4 o 5. Consequently, chromatin accessibility is an essential component in gene regulation yet is not fully understood. For example, chromatin accessibility could 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 environmental pollutants "2, including arsenic: a ubiquitous environmental toxic metalloid that leads to carcinogenesis. 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, differentiating and diseased cells. We hypothesize that arsenic induced alterations in histone PTMs, CAP occupancy, nucleosome position and occupancy combine to restructure the transcriptional state of key genes, resulting in a failure to ensure proper gene regulation and cancer.