Associate editor: P. Madeddu NO sparks off chromatin: Tales of a multifaceted epigenetic regulator Barbara Illi a , Claudia Colussi a , Annalisa Grasselli b,c , Antonella Farsetti c , Maurizio C. Capogrossi d , Carlo Gaetano d, ⁎ a Laboratorio di Biologia Vascolare e Medicina Rigenerativa, Centro Cardiologico Monzino-IRCCS, Milan, Italy b Istituto Nazionale Riposo e Cura Anziani, IRCCS, Ancona, Italy c Istituto di Neurobiologia e Medicina Molecolare, CNR, Rome, Italy d Laboratorio di Patologia Vascolare, IDI-IRCCS, Rome, Italy abstract article info Keywords: Chromatin remodeling Gene expression Nitric oxide S-nitrosylation Tyr-nitration The discovery of nitric oxide (NO) revealed its ambiguous nature, which is related to its pleiotropic activities that control the homeostasis of every organism from bacteria to mammals in several physiological and pathological situations. The wide range of action of NO basically depends on two features: 1) the variety of chemical reactions depending on NO, and 2) the differential cellular responses elicited by distinct NO concentrations. Despite the increasing body of knowledge regarding its chemistry, biology and NO- dependent signaling pathways, little information is available on the nuclear actions of NO in terms of gene expression regulation. Indeed, studies of a putative role for this diatomic compound in regulating chromatin remodeling are still in their infancy. Only recently has the role of NO in epigenetics emerged, and some of its putative epigenetic properties are still only hypothetical. In the present review, we discuss the current evidence for NO-related mechanisms of epigenetic gene expression regulation. We link some of the well known NO chemical reactions and metabolic processes (e.g., S-nitrosylation of thiols, tyrosine nitration, cGMP production) to chromatin modification and address the most recent, striking hypothesis about NO and the control of chromosomes structure. © 2009 Elsevier Inc. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344 2. Epigenetic regulation of gene expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 3. Epigenetics of nitric oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 4. Nuclear nitric oxide synthases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 5. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346 1. Introduction Nitric oxide (NO) is a reactive gaseous molecule that influences the physiology and pathophysiology of every living organism, including invertebrates and plants (Jacklet, 1997; Wilson et al., 2008). Initially discovered as the active component of the endothelium-derived relaxing factor (EDRF; Furchgott & Zawadzki, 1980), NO is synthesized in every cell type by nitric oxide synthases (NOS), namely NOS1 (or nNOS, discovered in neurons), NOS2 (or iNOS, the inducible isoform typical of macrophages) and NOS3 (or the endothelial NOS, eNOS). All of these isozymes share a common catalytic scheme in which the Pharmacology & Therapeutics 123 (2009) 344–352 Abbreviations: GNAT, Gcn5/ScKAT2; MYST, MOZ/Ybf2/Sas3/Sas2/Tip60; CBP, CREB binding protein; MLL, Mixed-lineage leukemia; Su(Var), Suppression of variegation; PRMT, Protein arginine (R) methyltransferase; CARM-1, Coactivator arginine methyl- transferase-1; Sin3, SWI independent 3; NuRD, Nucleosome remodeling deacetylase; CoREST, coRepressor of repressor element 1 silencing transcription factor; MBD, Methyl CpG binding domain containing protein; LSD1, Lysine specific demethylase 1; NcoR, Nuclear corepressor; SMRT, Silencing mediator of retinoic and thyroid receptors; NF-κB, Nuclear factor-kappaB; ICAM, Intracellular adhesion molecule-1; VCAM, Vascular cell adhesion molecule; AP-1, Activator protein-1; HNF4α, Hepatocyte nuclear factor 4α; VDR, 1α,25-dihydroxivitamin D 3 receptor; RXR, retinoid X receptor; HIF1α, Hypoxia inducible factor 1α; VHL, von Hippel Lindau; VEGF, Vascular endothelial growth factor; iκB, Inhibitor of NF-κB; LPS, Lipopolysaccharide; PPARγ, Peroxisome proliferator- activated receptor γ; MEF-2C, Myocyte enhancer factor 2C. ⁎ Corresponding author. E-mail address: c.gaetano@idi.it (C. Gaetano). 347 349 350 350 350 0163-7258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2009.05.003 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera