Duchenne muscular dystrophy (DMD) is a genetic disease characterized by progressive skeletal and cardiac muscle dysfunction. In the absence of dystrophin, nitric oxide (NO) production is compromised determining increase in oxidative stress, alteration of intracellular signalling and gene expression. Despite its relevance as therapeutic approach for cardiovascular diseases, no information is available about the epigenetic mechanism of NO in the heart neither how it affect nuclear matrix and chromatin organization. Here we have identified a component of the nuclear pore complex, the nucleoporin 153 (nup153), as a new mediator of NO signaling involved in chromatin remodeling associated to dystrophic cardiomyopathy. In mdx heart, mouse model of DMD, Nup153 showed a nucleoplasmic localization, a higher protein level and an increased acetylation level. Interestingly, mdx treatment with the HAT inhibitor anacardic acid counteracted nup153 acetylation, whereas cardiomyocyte HL-1 cells treated with HDAC inhibitors (TSA or MC1568) or HAT activator (SPV106), exhibited a higher level of Nup153 acetylation, suggesting for this post-transduction modification an important regulatory function. To address the role of Nup153 in NO-dependent gene transcription we analyzed how NO deprivation or Nup153 knockdown, alone or in combination, could affect in HL-1 cells chromatin structure and transcription. We found that Nup153 is required in NO signalling for 1) changes of histone modifications (increased H3K9ac, decreased H3K27m3); 2) upregulation of genes involved in cardiac fibrosis and hyperthrophy; 3) silencing of long non-coding-RNA involved in chromatin repression and cardiac remodelling. This data support the hypothesis of Nup153 is a new player in dystrophic cardiomyopathy.
Nup153 mediates nitric oxide nuclear signaling leading to chromatin structure modification in dystrophic cardiomyopathy
Claudia Colussi
2013
Abstract
Duchenne muscular dystrophy (DMD) is a genetic disease characterized by progressive skeletal and cardiac muscle dysfunction. In the absence of dystrophin, nitric oxide (NO) production is compromised determining increase in oxidative stress, alteration of intracellular signalling and gene expression. Despite its relevance as therapeutic approach for cardiovascular diseases, no information is available about the epigenetic mechanism of NO in the heart neither how it affect nuclear matrix and chromatin organization. Here we have identified a component of the nuclear pore complex, the nucleoporin 153 (nup153), as a new mediator of NO signaling involved in chromatin remodeling associated to dystrophic cardiomyopathy. In mdx heart, mouse model of DMD, Nup153 showed a nucleoplasmic localization, a higher protein level and an increased acetylation level. Interestingly, mdx treatment with the HAT inhibitor anacardic acid counteracted nup153 acetylation, whereas cardiomyocyte HL-1 cells treated with HDAC inhibitors (TSA or MC1568) or HAT activator (SPV106), exhibited a higher level of Nup153 acetylation, suggesting for this post-transduction modification an important regulatory function. To address the role of Nup153 in NO-dependent gene transcription we analyzed how NO deprivation or Nup153 knockdown, alone or in combination, could affect in HL-1 cells chromatin structure and transcription. We found that Nup153 is required in NO signalling for 1) changes of histone modifications (increased H3K9ac, decreased H3K27m3); 2) upregulation of genes involved in cardiac fibrosis and hyperthrophy; 3) silencing of long non-coding-RNA involved in chromatin repression and cardiac remodelling. This data support the hypothesis of Nup153 is a new player in dystrophic cardiomyopathy.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
