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).

Nitric oxide, the new architect of epigenetic landscapes.

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 Regulates Gene Expression in Cancers by Controlling Histone Posttranslational Modifications.

Altered nitric oxide (•NO) metabolism underlies cancer pathology, but mechanisms explaining many •NO-associated phenotypes remain unclear. We have found that cellular exposure to •NO changes histone posttranslational modifications (PTM) by directly inhibiting the catalytic activity of JmjC-domain containing histone demethylases. Herein, we describe how •NO exposure links modulation of histone PTMs to gene expression changes that promote oncogenesis. Through high-resolution mass spectrometry, we generated an extensive map of •NO-mediated histone PTM changes at 15 critical lysine residues on the core histones H3 and H4. Concomitant microarray analysis demonstrated that exposure to physiologic •NO resulted in the differential expression of over 6,500 genes in breast cancer cells. Measurements of the association of H3K9me2 and H3K9ac across genomic loci revealed that differential distribution of these particular PTMs correlated with changes in the level of expression of numerous oncogenes, consistent with epigenetic code. Our results establish that •NO functions as an epigenetic regulator of gene expression mediated by changes in histone PTMs.