Rapid formation of dinitrosyliron complexes (DNIC) arise from the convergence of nitric oxide (NO), chelatable iron, and cellular thiols.  Upon exposure of cells to physiologic NO concentrations, DNIC constitute the largest quantitative population of NO-derived cellular adducts.  Although DNIC were first detected in mammalian systems over 50 years ago, their physiologic or pathologic functions remain obscure.  Our results demonstrate that formation of DNIC result in sequestration of the chelatable iron pool (CIP), which has distinct downstream signaling effects.  Phenotypic consequences of DNIC assembly arise from either direct inhibition of non-heme iron oxygenases or indirectly via sequestration of iron cofactor availability.  One example, is the ability of NO to act as an epigenetic regulator by altering post-translational histone modifications.  Methylation and acetylation of histone lysine residues are important epigenetic regulators of gene transcription.  Methylation is maintained by the activity of methyltransferases and demethylases, while acetylation is regulated by acetyltransferases and deacetylases.  We demonstrated that DNIC formation resulted in inhibition of JMJC-domain histone demethylases leading to significant increases in global histone methylation.  These changes in methylation in turn altered acetylation levels and together modulated transcriptional responses to NO. Microarray, ChIP-seq, and bioinformatic analysis was used to identify genes differentially expressed due to association with NO-altered histone methyl- and acetyl marks.  This genome wide analysis revealed that a significant proportion of NO-mediated signaling is a result of epigenetic regulation via interactions of NO with non-heme iron.  These results represent a novel, non-classical mechanism of NO signaling.

Dinitrosyliron complexes: A new paradigm in nitric oxide signaling

248th National Meeting (2014)

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