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Abstract
Chronic low dose inorganic arsenic (iAs) exposure leads to changes in gene expression and epithelial-to-mesenchymal transformation. During this transformation, cells adopt a fibroblast-like phenotype accompanied by profound gene expression changes. While many mechanisms have been implicated in this transformation, studies that focus on the role of epigenetic alterations in this process are just emerging. DNA methylation controls gene expression in physiologic and pathologic states. Several studies show alterations in DNA methylation patterns in iAs-mediated pathogenesis, but these studies focused on single genes. We present a comprehensive genome-wide DNA methylation analysis using methyl-sequencing to measure changes between normal and iAs-transformed cells. Additionally, these differential methylation changes correlated positively with changes in gene expression and alternative splicing. Interestingly, most of these differentially methylated genes function in cell adhesion and communication pathways. To gain insight into how genomic DNA methylation patterns are regulated during iAs-mediated carcinogenesis, we show that iAs probably targets CTCF binding at the promoter of DNA methyltransferases, regulating their expression. These findings reveal how CTCF binding regulates DNA methyltransferase to reprogram the methylome in response to an environmental toxin.
Highlights
Inorganic arsenic, is an environmental carcinogen with worldwide exposure to millions of people through water, and with health effects ranging from acute toxicities to malignant transformation[1,2,3,4]
BEAS-2B cells were transformed with inorganic arsenic (iAs) as previously described[14,38] and global DNA methylation in normal cells (NT) and iAs-transformed cells was assessed using the 5-methylcytosine (5-mC) DNA ELISA kit
We present genome-wide DNA methylation profiles of iAs-induced EMT in BEAS-2B cells, allowing a characterization of the extensive reprogramming of the methylome that occurs during this transition
Summary
Inorganic arsenic (iAs), is an environmental carcinogen with worldwide exposure to millions of people through water, and with health effects ranging from acute toxicities to malignant transformation[1,2,3,4]. Several studied have shown that iAs exposure alters epigenetic marks, such as histone post-translational modifications (PTMs), histone variants and DNA methylation, resulting in changes of gene expression patterns for both transcription initiation and gene splicing[4,14]. One study showed that 17 tumor suppressor genes, including p53, are hypermethylated in iAs-exposed cells, which leads to a reduced gene expression[28,33] Such changes would have a great impact on the progression of the carcinogenic pathology. We investigated a potential epigenetic mechanism of chronic low dose arsenic exposure, DNA methylation, and examined target genes genome-wide in iAs-mediated EMT. We observed methylation and expression changes at key genes, suggesting a potential mechanism through which epigenetic methylation can drive differential gene expression of oncogenes and tumor suppressors Such analyses are key to identifying possible target genes that propel the carcinogenic potential of iAs
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