Premature termination codons in the DMD gene cause reduced local mRNA synthesis
| العنوان: | Premature termination codons in the DMD gene cause reduced local mRNA synthesis |
|---|---|
| المؤلفون: | Laura Jiménez-Gracia, Judit Balog, Monika Hiller, Zarah van der Pal, Kevin Adamzek, Annemieke Aartsma-Rus, Raquel García-Rodríguez, Pietro Spitali |
| المصدر: | Proceedings of the National Academy of Sciences, 117(28), 16456-16464. NATL ACAD SCIENCES Proc Natl Acad Sci U S A |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | musculoskeletal diseases, Duchenne muscular dystrophy, congenital, hereditary, and neonatal diseases and abnormalities, medicine.drug_class, In situ hybridization, Dystrophin, Mice, RNA degradation, Transcription (biology), medicine, Animals, Humans, RNA, Messenger, nascent RNA, skeletal muscle, Messenger RNA, Multidisciplinary, biology, Myogenesis, Histone deacetylase inhibitor, Biological Sciences, medicine.disease, Nonsense Mediated mRNA Decay, Cell biology, nervous system diseases, Muscular Dystrophy, Duchenne, Disease Models, Animal, Histone, Codon, Nonsense, premature termination codons, Mice, Inbred mdx, biology.protein, Chromatin immunoprecipitation |
| الوصف: | Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene leading to the presence of premature termination codons (PTC). Previous transcriptional studies have shown reduced DMD transcript levels in DMD patient and animal model muscles when PTC are present. Nonsense-mediated decay (NMD) has been suggested to be responsible for the observed reduction, but there is no experimental evidence supporting this claim. In this study, we aimed to investigate the mechanism responsible for the drop in DMD expression levels in the presence of PTC. We observed that the inhibition of NMD does not normalize DMD gene expression in DMD. Additionally, in situ hybridization showed that DMD mes-senger RNA primarily localizes in the nuclear compartment, con-firming that a cytoplasmic mechanism like NMD indeed cannot be responsible for the observed reduction. Sequencing of nascent RNA to explore DMD transcription dynamics revealed a lower rate of DMD transcription in patient-derived myotubes compared to healthy controls, suggesting a transcriptional mechanism involved in reduced DMD transcript levels. Chromatin immunoprecipitation in muscle showed increased levels of the repressive histone mark H3K9me3 in mdx mice compared to wild-type mice, indicating a chromatin conformation less prone to transcription in mdx mice. In line with this finding, treatment with the histone deacetylase in-hibitor givinostat caused a significant increase in DMD transcript expression in mdx mice. Overall, our findings show that transcrip-tion dynamics across the DMD locus are affected by the presence of PTC, hinting at a possible epigenetic mechanism responsible for this process. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::192dacf9bc6feff9f183b2518bcbe6f8 http://hdl.handle.net/1887/3184636 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....192dacf9bc6feff9f183b2518bcbe6f8 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |