The oxidative histone demethylases remove a number of transcriptional activating and inhibitory marks on the histone tails. These enzymes are members of the dioxygenase superfamily of enzymes which have Fe in their active site and decarboxylate oxogluterate releasing C02 and formaldehyde as a result of the oxidative demethylation of their substrates.  They also use ascorbate to reduce the oxidized Fe. The dependence of these enzymes on oxygen results in their inhibition by hypoxia, and there is an accumulation of transcriptional activating marks such as H3K4 trimethylation and  silencing marks such as H3K9 dimethylation. Thus, there is extensive activation and repression of genes beyond what is attributable to the transcription factor HIF-1 alpha.   Exposure to metals such as Ni inhibits the dioxygenase enzymes by displacing the Fe from the active site.  We have shown this using the dioxygenase DNA demethylase ABH2 as well as for truncated JMJD2A and JMJD2C which could be expressed in bacteria. Nickel displacement of ABH2 was studied by XAS and 63Ni binding. We have mapped the changes in H3K4 trimethylation in the whole genome using ChIP-Seq and correlated this with changes in gene expression using RNA-Seq following hypoxia and Nickel exposure in BEAS2B cells.  With nickel exposure for example, H3K4 trimethylation increases in the promoter of the most induced genes. Since the dioxygenase superfamily of enzymes also require reduced ascrobate, the depletion  by oxidative stress leads to inhibition of the oxidative histone demethylases. Chromate, for example, increases H3K4 trimethylation and H3K9 dimethylation by reacting with and decreasing cellular reduced ascrobate levels and this results in the inhibition of the respective oxidative histone demethylases. Thus, metals, hypoxia and oxidative stress all impact the epigenetic program and result in changes in gene expression, which is likely responsible for their toxic and carcinogenic effects.

Control of histone methylation and gene expression by oxidative stress, hypoxia, and metals

246th National Meeting (2013)

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