Transcriptional and epigenetic analyses of the DMD locus reveal novel cis‑acting DNA elements that govern muscle dystrophin expression

Samuele Gherardi, Matteo Bovolenta, Chiara Passarelli, Maria Sofia Falzarano, Paolo Pigini, Chiara Scotton, Marcella Neri, Annarita Armaroli, Hana Osman, Rita Selvatici, Francesca Gualandi, Alessandra Recchia, Marina Mora, Pia Bernasconi, Lorenzo Maggi, Lucia Morandi, Alessandra Ferlini, Giovanni Perini

Research output: Contribution to journalArticlepeer-review


The dystrophin gene (DMD) is the largest gene in the human genome, mapping on the Xp21 chromosome locus. It spans 2.2 Mb 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 16 h, 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 2.2 Mb 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.

Original languageEnglish
Pages (from-to)1138-1147
Number of pages10
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Issue number11
Publication statusPublished - Nov 1 2017


  • Becker Muscular Dystrophy (BMD)
  • Chromosome Conformation Capture (3C)
  • Duchenne Muscular Dystrophy (DMD)
  • Dystrophin
  • RNA pol II pausing
  • Transcriptional regulation

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics


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