Nitric oxide deficiency determines global chromatin changes in Duchenne muscular dystrophy.
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.
Colussi
Claudia
C
Laboratorio di Terapia Genica e Biologia Vascolare, Istituto Cardiologico Monzino, Milan, Italy.
Gurtner
Aymone
A
Rosati
Jessica
J
Illi
Barbara
B
Ragone
Gianluca
G
Piaggio
Giulia
G
Moggio
Maurizio
M
Lamperti
Costanza
C
D'Angelo
Grazia
G
Clementi
Emilio
E
Minetti
Giulia
G
Mozzetta
Chiara
C
Antonini
Annalisa
A
Capogrossi
Maurizio C
MC
Puri
Pier Lorenzo
PL
Gaetano
Carlo
C
D000818:Animals; D002467:Cell Nucleus; D002843:Chromatin / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D018482:Muscle, Skeletal / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000473:pathology*; D009569:Nitric Oxide / Q000172:deficiency*; D011499:Protein Processing, Post-Translational
D002843:Chromatin; D006657:Histones; D009569:Nitric Oxide