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Nitric oxide (NO) is an endogenously produced signaling molecule with multiple regulatory functions in physiology and disease. The most studied molecular mechanisms underlying the biological functions of NO include its reaction with heme proteins and regulation of protein activity via modification of thiol residues. A significant number of transcriptional responses and phenotypes observed in NO microenvironments, however, still lack mechanistic understanding. Recent studies shed new light on NO signaling by revealing its influence on epigenetic changes within the cell. Epigenetic alterations are important determinants of transcriptional responses and cell phenotypes, which can relay heritable information during cell division. As transcription across the genome is highly sensitive to these upstream epigenetic changes, this mode of NO signaling provides an alternate explanation for NO-mediated gene expression changes and phenotypes. This review will provide an overview of the interplay between NO and epigenetics as well as emphasize the unprecedented importance of these pathways to explain phenotypic effects associated with biological NO synthesis.

Nitric oxide (•NO) is a biologically important short-lived free radical signaling molecule. Both the enzymatic synthesis and the predominant forms of cellular metabolism of •NO are oxygen-dependent. For these reasons, changes in local oxygen concentrations can have a profound influence on steady-state •NO concentrations. Many proteins are regulated by •NO in a concentration-dependent manner, but their responses are elicited at different thresholds. Using soluble guanylyl cyclase (sGC) and p53 as model •NO-sensitive proteins, we demonstrate that their concentration-dependent responses to •NO are a function of the O2 concentration. p53 requires relatively high steady-state •NO concentrations (>600 nM) to induce its phosphorylation (P-ser-15), whereas sGC responds to low •NO concentrations (, Graphical Abstract Highlights ►► O2 regulates •NO signaling by modulating •NO synthesis and metabolism. ► O2 affects •NO synthesis by regulating NOS expression and substrate availability. ► The rate of enzymatic •NO production increases linearly from 1–8% O2. ► The rate of cellular •NO metabolism increases with increasing [O2]. ► •NO-mediated sGC activation is maximal between 5% and 8% O2.