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2010-11-25 - Colloque/Présentation - communication orale - Français - 1 page(s)

Belayew Alexandra , "Perturbations de réseaux de gènes dans la FSHD" in VIIIè journées annuelles Société Française de Myologie, 13, Nice, France, 2010

  • Codes CREF : Biologie moléculaire (DI3111), Pathologies particulières (DI3370)
  • Unités de recherche UMONS : Biochimie métabolique et moléculaire (M122)

Abstract(s) :

(Anglais) Facioscapulohumeral muscular dystrophy (FSHD) initially described by Landouzy and Dejerine is an autosomal dominant muscle disorder affecting about 1/17,000 births. It is characterized by progressive weakness and atrophy of the muscles from the face, the upper-arms and shoulder girdle to the lower limbs. FSHD is genetically linked to contractions of the D4Z4 repeat array on the 4q35 subtelomeric region. Non-affected individuals typically have between 11-100 copies of the 3.3-kb D4Z4 element, while FSHD patients only have 1-10 copies. Our group has characterized the double homeobox 4 (DUX4) gene within each unit of the D4Z4 repeat array at the FSHD locus and proposed that its expression caused the pathology (Gabriëls et al, 1999). Subsequent collaborative studies showed that (i) the DUX4 messenger RNAs and protein were expressed in primary myoblasts and biopsies of patients with FSHD but not in non-affected individuals, (ii) DUX4 protein expression caused cell death (Kowaljow et al, 2007), (iii) the DUX4 protein was a transcription factor targeting a large set of genes including inter alia genes encoding further transcription factors, (iii) DUX4 gene activation at the FSHD locus initiated a transcription cascade leading to muscle atrophy, inflammation, decreased differentiation potential and oxidative stress, recapitulating the key features of FSHD (Dixit et al, 2007; Bosnakovski et al, 2008). We found that DUX4 transcription could initiate in any D4Z4 unit, but that stable mRNAs comprising the full coding region only derived from the most distal unit and unexpectedly extended within the flanking pLAM region that provided an intron and a polyadenylation signal (Dixit et al, 2007). The presence of this signal is required to develop FSHD as recently shown by others in a detailed genetic analysis of hundreds of patients and thousands of non-affected individuals (Lemmers et al, 2010). We have also identified the homologous DUX4c gene located 42-kb upstream of the D4Z4 locus. It is expressed in muscles from healthy individuals but is induced in FSHD. DUX4c over-expression in human myoblasts induced MYF5 and proliferation suggesting a role in muscle regeneration (Ansseau et al, 2009). FSHD primary myoblasts in culture differentiate to abnormal myotubes, either atrophic or disorganised (Barro et al, 2008). We have now shown that DUX4 expression induced the atrophic phenotype associated to the expression of E3 ubiquitin ligases Murf1 and atrogine1. In contrast DUX4c expression induced beta-catenin, formation of clusters of nuclei and the disorganized myotube phenotype. We reasoned that inhibition of DUX4 or DUX4c expressions should prevent the transcription deregulation cascade and restore control myotube phenotype. We have used different antisense approaches to either induce mRNA destruction by RNA interference (siRNA) or disturb its splicing by use of specific antisense oligomers (AOs). Decreases in DUX4 or DUX4c protein expression were confirmed by immunodetection on western blot. These strategies seem promising and could contribute to future development of therapeutic approaches for FSHD.