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Nitric oxide deficiency determines global chromatin changes in Duchenne muscular dystrophy

Claudia Colussi^*, Aymone Gurtner, Jessica Rosati, Barbara Illi^*, Gianluca Ragone, Giulia Piaggio, Maurizio Moggio^||, Costanza Lamperti^||, Grazia D'Angelo^#, Emilio Clementi^#,¶, Giulia Minetti^**, Chiara Mozzetta^**, Annalisa Antonini, Maurizio C. Capogrossi, Pier Lorenzo Puri^**, and Carlo Gaetano^,1

^* Laboratorio di Terapia Genica e Biologia Vascolare, Istituto Cardiologico Monzino, Milan, Italy;

Laboratorio di Oncogenesi Molecolare and Rome Oncogenomic Center, Istituto Regina Elena, Rome, Italy;

Laboratorio di Patologia Vascolare and

Laboratorio di Oncologia Molecolare, Istituto Dermopatico dell’ Immacolata, Rome, Italy;

^|| Fondazione Ospedale Maggiore Mangiagalli e Regina Elena Centro Dino Ferrari and

^¶ Dipartimento di Scienze Precliniche, Università di Milano, Milan, Italy;

^# Istituto Scientifico E. Medea, Bosisio Parini, Italy;

^** Istituto Dulbecco Telethon at Istituto Di Ricovero e Cura a Carattere Scientifico, Santa Lucia Fondazione and European Brain Research Institute, Rome, Italy; and

Burnham Institute for Medical Research, San Diego, California, USA

¹ Correspondence: Laboratorio di Patologia Vascolare, Istituto Dermopatico dell’ Immacolata, Via Monti di Creta 104, 00167, Roma, Italy. E-mail: gaetano{at}idi.it

The present study provides evidence that abnormal patterns of global histone modification are present in the skeletal muscle nuclei of mdx mice and Duchenne muscular dystrophy (DMD) patients. A combination of specific histone H3 modifications, including Ser-10 phosphorylation, acetylation of Lys 9 and 14, and Lys 79 methylation, were found enriched in muscle biopsies from human patients affected by DMD and in late-term fetuses, early postnatal pups, or adult mdx mice. In this context, chromatin immunoprecipitation experiments showed an enrichment of these modifications at the loci of genes involved in proliferation or inflammation, suggesting a regulatory effect on gene expression. Remarkably, the reexpression of dystrophin induced by gentamicin treatment or the administration of nitric oxide (NO) donors reversed the abnormal pattern of H3 histone modifications. These findings suggest an unanticipated link between the dystrophin-activated NO signaling and the remodeling of chromatin. In this context, the regulation of class IIa histone deacetylases (HDACs) 4 and 5 was found altered as a consequence of the reduced NO-dependent protein phosphatase 2A activity, indicating that both NO and class IIa HDACs are important for satellite cell differentiation and gene expression in mdx mice. In conclusion, this work provides the first evidence of a role for NO as an epigenetic regulator in DMD.

Key Words: histone deacetylase • protein phosphatase • differentiation • myoblast • histone