Advance Access publication March 4, 2008 Arsenite alters global histone H3 methylation

Arsenic (As) is a well-characterized human carcinogen but is gen-erally not mutagenic. The evidence that As induces both loss of global DNA methylation and gene promoter DNA hypermethyla-tion has suggested that epigenetic mechanisms may play an im-portant role in As-induced carcinogenesis. In the present study, we examined the change in histone methylation by As exposure. In human lung carcinoma A549 cells, exposure to inorganic trivalent As (arsenite) increased H3K9 dimethylation (H3K9me2) and de-creased H3K27 trimethylation (H3K27me3), both of which rep-resent gene silencing marks, while increasing the global levels of the H3K4 trimethylation (H3K4me3), a gene-activating mark. The increase in H3K9me2 was mediated by an increase in the histone methyltransferase G9a protein and messenger RNA lev-els. We also observed strikingly significant altered histone mod-ifications induced by very low-dose (0.1 mM) arsenite. Taken together, these results suggest a potential mechanism by which As induces carcinogenesis through the alteration of specific his-tone methylations that represent both gene silencing and activat-ing marks. Furthermore, these marks are known to affect DNA methylation, and it is likely that arsenic’s effect is not limited to histone modifications alone, but extends, perhaps by them, to DNA methylations as well. Future studies in our laboratory will address the genomic location of these silencing and activating marks using ChIP-on-chip technology