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Cytosine methylation patterns are essential for the proper control of gene expression in higher vertebrates. Although alterations in methylation patterns are frequently observed in human tumors, neither the mechanisms for establishing methylation patterns during normal development nor the mechanisms leading to pathological alterations of methylation patterns are currently known. While epidemiological studies have implicated inflammation in cancer etiology, a mechanistic link has yet to be established. Investigations of inflammation-mediated DNA damage may have provided important new insights. Ourin vitrostudies revealed that the inflammation-mediated DNA damage product, 5-chlorocytosine, could direct fraudulent methylation of previously unmethylated CpG sites. The purpose of this study was to recapitulate ourin vitrofindings by introducing 5-chlorocytosine residues into the DNA of replicating mammalian cells and to examine its impact on gene expression and cytosine methylation patterns. CHO-K1 cells hemizygous for thehprtgene were electroporated with the triphosphates of cytosine [2′-deoxycytidine-5′-triphosphate (dCTP)], 5-methylcytosine [5-methyl-2′-deoxycytidine-5′-triphosphate (MedCTP)] and 5′-chloro-2′-deoxycytidine-5′-triphosphate (CldCTP), and then selected with 6-thioguanine for silencing thehprtgene. Both modified nucleotides, MedCTP and CldCTP, but not unmodified dCTP, silencedhprtgene expression. Subsequent bisulfite pyrosequencing of CpG sites within thehprtpromoter region of the selected cells confirmed hypermethylation, although global methylation levels as measured by gas chromatography–mass spectrometry did not change. Modified nucleotide-induced gene silencing could be reversed with 5-aza-2′-deoxycytidine indicating an epigenetic rather than mutagenic alteration. These results provide further evidence that the inflammation damage product 5-chlorocytosine could be a link between inflammation and cancer development.

Incorporation of 5-chlorocytosine into mammalian DNA results in heritable gene silencing and altered cytosine methylation patterns