Epigenetic regulation by nitrosative stress

Protein S-nitrosylation (SNO) of DNMT, a predominant enzyme in epigenetic gene regulation by catalyzing the methylation of cytosine residues, attenuates DNMT enzymatic activity and consequent demethylation in genomic DNA. However, little is known about the mechanism of epigenetic gene regulation through SNO-DNMT formation. Here, we demonstrated that SNO-DNMT drives demethylation of the specific transcription factor binding regions by elucidating whole-genome methylation profiles, and these alterations enhance hypoxia-inducible factor binding to DNA. Among candidate genes upregulated by this mechanism, we identified 12 genes, whose upregulation were abrogated by DBIC, a specific inhibitor of DNMT3 S-nitrosylation, and aberrant upregulation of DBIC sensitive genes via SNO-DNMT was sufficient to perturb cellular function. Finally, we provided evidence of pathophysiological link between SNO-DNMT and human disorders using clinical samples. Collectively, our findings provide mechanistic insight into redox-dependent epigenetic gene regulation mediated by S-nitrosylation of DNMT, and highlight its unrecognized pathophysiological relevance.