Chronic low dose inorganic arsenic exposure causes cells to take on an epithelial-to-mesenchymal phenotype, which is a crucial process in carcinogenesis. Inorganic arsenic is not a mutagen and thus epigenetic alterations have been implicated in this process. Indeed, during the epithelial-to-mesenchymal transition, morphologic changes to cells correlate with changes in chromatin structure and gene expression, ultimately driving this process. However, studies on the effects of inorganic arsenic exposure/withdrawal on the epithelial-to-mesenchymal transition and the impact of epigenetic alterations in this process are limited. In this study we used high-resolution microarray analysis to measure the changes in DNA methylation in cells undergoing inorganic arsenic-induced epithelial-to-mesenchymal transition, and on the reversal of this process, after removal of the inorganic arsenic exposure. We found that cells exposed to chronic, low-dose inorganic arsenic exposure showed 30,530 sites were differentially methylated, and with inorganic arsenic withdrawal several differential methylated sites were reversed, albeit not completely. Furthermore, these changes in DNA methylation mainly correlated with changes in gene expression at most sites tested but not at all. This study suggests that DNA methylation changes on gene expression are not clear-cut and provide a platform to begin to uncover the relationship between DNA methylation and gene expression, specifically within the context of inorganic arsenic treatment.
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This work was supported by NSF grant MCB 1517986 to YFN-M, NIEHS grant R01-ES024478 with diversity supplement 02S1 to YNF-M and NIH T32 grant 165990 to MR, through Markey Cancer Center at University of Kentucky.
The Transparency document associated with this article can be found in online version.
The GEO accession number for methylation data is GSE60760.
Supplementary data to this article can be found online at https://doi.org/10.1016/j.taap.2017.03.017.
Eckstein, Meredith; Rea, Matthew; and Fondufe-Mittendorf, Yvonne N., "Transient and Permanent Changes in DNA Methylation Patterns in Inorganic Arsenic-Mediated Epithelial-to-Mesenchymal Transition" (2017). Molecular and Cellular Biochemistry Faculty Publications. 157.