Methylation at cytosine (5mC) is a fundamental epigenetic DNA modification recently associated with iAs-mediated carcinogenesis. In contrast, the role of 5-hydroxymethylcytosine (5hmC), the oxidation product of 5mC in iAs-mediated carcinogenesis is unknown. Here we assess the hydroxymethylome in iAs-transformed cells, showing that dynamic modulation of hydroxymethylated DNA is associated with specific transcriptional networks. Moreover, this pathologic iAs-mediated carcinogenesis is characterized by a shift toward a higher hydroxymethylation pattern genome-wide. At specific promoters, hydroxymethylation correlated with increased gene expression. Furthermore, this increase in hydroxymethylation occurs concurrently with an upregulation of ten-eleven translocation (TET) enzymes that oxidize 5-methylcytosine (5mC) in DNA. To gain an understanding into how iAs might impact TET expression, we found that iAs inhibits the binding of CTCF at the proximal, weak CTCF binding sites of the TET1 and TET2 gene promoters and enhances CTCF binding at the stronger distal binding site. Further analyses suggest that this distal site acts as an enhancer, thus high CTCF occupancy at the enhancer region of TET1 and TET2 possibly drives their high expression in iAs-transformed cells. These results have major implications in understanding the impact of differential CTCF binding, genome architecture and its consequences in iAs-mediated pathogenesis.

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Published in Toxicology and Applied Pharmacology, v. 338, p. 124-133.

© 2017 Published by Elsevier Inc.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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This work was supported by NSF grant MCB 1517986 to YFN-M, NIEHS grant R01-ES024478, TG was supported by NIEHSR25ES027864 to the SURES program at UK, and NIH T32 grant 165990 to MR, through Markey Cancer Center at University of Kentucky.

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GEO accession numbers for Methyl-MiniSeq data is GSE85012 and RRHP data is GSE103626.

Supplementary data to this article can be found online at https://doi.org/10.1016/j.taap.2017.11.015.

1-s2.0-S0041008X1730460X-mmc1.docx (747 kB)
Supplementary Material