Profiling of DNA methylation patterns in response to inorganic arsenic exposure and reversal of exposure

Abstract

Epigenetic modifications are heritable changes in gene expression not encoded in the DNA sequence. One such epigenetic mark that has been extensively studied is DNA methylation as it is most stable and also reversible. Recent studies suggest that epigenetic regulation through DNA methylation could be responsible for cellular transformation instigated by environmental toxins, such as inorganic arsenic. Research has been done to investigate DNA methylation and gene expression patterns at specific genes during this process; but so far, a comprehensive understanding of the impact of DNA methylation changes on gene expression patterns is missing. This study presents a comprehensive genome‐wide DNA methylation analysis in response to chronic, low‐dose inorganic arsenic exposure and the removal of this toxin. We aim to determine how inorganic arsenic exposure leads to the epithelial‐to‐mesenchymal transition in cellular transformation and to understand mechanistically the importance of DNA methylation in driving this process. We show that several key genes are differentially expressed during this process and that some of these expression states revert when inorganic arsenic is removed. To understand the functional role of DNA methylation in this process, we profiled DNA methylation changes at individual CpG loci using the Infinium Methylation EPIC Bead Chip Methylation array. We found that chronically inorganic arsenic‐exposed cells showed changes in DNA methylation corresponding with changes in their expression profiles. Many of the methylation changes were concentrated at upstream promoter regions and gene regulatory regions, suggesting a functional relevance in inorganic arsenic‐mediated cellular transformation. Our studies indicate that inorganic arsenic‐mediated transformation is instigated, in part, by DNA methylation pattern changes that cause alterations in gene expression and reversal of inorganic arsenic treatment moderately reverses the methylation and gene expression changes.Support or Funding InformationNSF (MCB 1517986‐YFM), NIEHS (R01‐ES024478‐YFM)