Epigenetics: The third pillar of nitric oxide signaling

Nitric oxide (NO), the endogenously produced free radical signaling molecule, is generally thought to function via its interactions with heme-containing proteins, such as soluble guanylyl cyclase (sGC), or by the formation of protein adducts containing nitrogen oxide functional groups (such as S-nitrosothiols, 3-nitrotyrosine, and dinitrosyliron complexes). These two types of interactions result in a multitude of down-stream effects that regulate numerous functions in physiology and disease. Of the numerous purported NO signaling mechanisms, epigenetic regulation has gained considerable interest in recent years. There is now abundant experimental evidence to establish NO as an endogenous epigenetic regulator of gene expression and cell phenotype. Nitric oxide has been shown to influence key aspects of epigenetic regulation that include histone posttranslational modifications, DNA methylation, and microRNA levels. Studies across disease states have observed NO-mediated regulation of epigenetic protein expression and enzymatic activity resulting in remodeling of the epigenetic landscape to ultimately influence gene expression. In addition to the well-established pathways of NO signaling, epigenetic mechanisms may provide much-needed explanations for poorly understood context-specific effects of NO. These findings provide more insight into the molecular mechanisms of NO signaling and increase our ability to dissect its functional role(s) in specific micro-environments in health and disease. This review will summarize the current state of NO signaling via epigenetic mechanisms (the “third pillar” of NO signaling).

The three pillars of nitric oxide signaling. The first “pillar” of nitric oxide signaling is the interactions of NO with heme-containing proteins, most notably soluble guanylate cyclase (sGC). The second “pillar” of NO signaling results from the formation of protein adducts containing nitrogen oxide functional groups. Examples of these are S-nitrosothiols (RSNO), 3-nitrotyrosine (3-NT), and dinitrosyliron complexes (DNIC). The third “pillar” of nitric oxide signaling is epigenetic regulation. Nitric oxide is implicated in DNA methylation, which requires DNA methyltransferase enzymes (DNMTs), and DNA demethylation, which requires TET enzymes. NO also plays a major role in mediating histone modifications, such as acetylation and methylation, through dynamic interactions with histone methyltransferase enzymes (KMTs) and histone demethylases (KDMs), among other lysine-modifying proteins. The significance of alterations in histone modification is dynamic changes in chromatin structure to activate or inhibit transcription. Nitric oxide can also influence microRNA levels, which is another major form of epigenetic regulation directly effecting protein expression.151