Abstract
The dystrophin gene (DMD) is the largest gene in the human genome, mapping on the Xp21 chromosome locus. It spans 2.2Mb and accounts for approximately 0,1% of the entire human genome. Mutations in this gene cause Duchenne and Becker Muscular Dystrophy, X-linked Dilated Cardiomyopathy, and other milder muscle phenotypes. Beside the remarkable number of reports describing dystrophin gene expression and the pathogenic consequences of the gene mutations in dystrophinopathies, the full scenario of the DMD transcription dynamics remains however, poorly understood. Considering that the full transcription of the DMD gene requires about 16h, we have investigated the activity of RNA Polymerase II along the entire DMD locus within the context of specific chromatin modifications using a variety of chromatin-based techniques.Our results unveil a surprisingly powerful processivity of the RNA polymerase II along the entire 2.2Mb of the DMD locus with just one site of pausing around intron 52. We also discovered epigenetic marks highlighting the existence of four novel cis‑DNA elements, two of which, located within intron 34 and exon 45, appear to govern the architecture of the DMD chromatin with implications on the expression levels of the muscle dystrophin mRNA.Overall, our findings provide a global view on how the entire DMD locus is dynamically transcribed by the RNA pol II and shed light on the mechanisms involved in dystrophin gene expression control, which can positively impact on the optimization of the novel ongoing therapeutic strategies for dystrophinopathies.
Highlights
Mutations in the dystrophin gene (DMD) cause Duchenne Muscular Dystrophy (OMIM *310200), an X-linked muscle disorder, characterized by the complete absence of the dystrophin protein
Our findings provide a global view on how the entire DMD locus is dynamically transcribed by the RNA pol II and shed light on the mechanisms involved in dystrophin gene expression control, which can positively impact on the optimization of the novel ongoing therapeutic strategies for dystrophinopathies
The RNA Pol II binding to DNA along its functional modifications in the Carboxyl-Terminal Domain (CTD) were correlated with histone marks such as Ac-H3, H3K4me2, which characterize the open chromatin of genes actively transcribed
Summary
Mutations in the dystrophin gene (DMD) cause Duchenne Muscular Dystrophy (OMIM *310200), an X-linked muscle disorder, characterized by the complete absence of the dystrophin protein. Milder allelic forms are both the Becker Muscular Dystrophy (BMD, OMIM *300376), presenting a disease course mitigated by the presence of a residual Dystrophin expression, and the X-linked dilated cardiomyopathy (XLDC, OMIM *302405) characterized by predominant heart involvement. The DMD gene consists of 79 exons and 78 introns encoding for at least seven distinct isoforms, whom transcription is driven by seven different promoters. Such promoters have a tissue- and timespecific regulation [1]. Three of them drive the transcription of fulllength isoforms that share 78 exons, but with one first exon that is
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