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.
Proper regulation of gene expression is essential to the development and health of all organisms. The DNA in each eukaryotic cell, found as chromatin plays an integral part in this gene regulation. Indeed where nucleosomes are located is important in our understanding of gene regulation. Furthermore knowing how chromatin structure responds to particular stimuli to control the on and off state of genes would be helpful in the development of new diagnostic and therapeutic tools.
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