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Nitric oxide deficiency determines global chromatin changes in Duchenne muscular dystrophy
Author(s) -
Colussi Claudia,
Gurtner Aymone,
Rosati Jessica,
Illi Barbara,
Ragone Gianluca,
Piaggio Giulia,
Moggio Maurizio,
Lamperti Costanza,
D'Angelo Grazia,
Clementi Emilio,
Minetti Giulia,
Mozzetta Chiara,
Antonini Annalisa,
Capogrossi Maurizio C.,
Puri Pier Lorenzo,
Gaetano Carlo
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-115618
Subject(s) - duchenne muscular dystrophy , histone , dystrophin , chromatin remodeling , epigenetics , biology , chromatin immunoprecipitation , muscular dystrophy , microbiology and biotechnology , chromatin , histone methyltransferase , epigenome , endocrinology , medicine , gene expression , dna methylation , genetics , gene , promoter
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 lateterm 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 Ila histone deacetylases (HDACs) 4 and 5 was found altered as a consequence of the reduced NOdependent 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.—Colussi, C.,Gurtner, A., Rosati, J., Illi, B., Ragone, G., Piaggio, G., Moggio, M., Lamperti, C., D'Angelo, G.,Clementi, E., Minetti, G., Mozzetta, C., Antonini, A., Capogrossi, M. C., Puri, P. L., Gaetano, C. Nitric oxide deficiency determines global chromatin changes in Duchenne muscular dystrophy. FASEBJ. 23, 2131–2141 (2009)