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2013-10-21 - Colloque/Présentation - communication orale - Anglais - 1 page(s)

Ansseau Eugénie , Charron Sébastien , Laoudj-Chenivesse Dalila, Coppée Frédérique , Belayew Alexandra , "Interplay between Sp1, YY1 and MYOD in transcription regulation of the DUX4 gene that causes facioscapulohumeral muscular dystrophy (FSHD)." in FSH Society (FacioScapuloHumeral Muscular Dystrophy) International Reasearch Consortium & Reasearch Planning Meeting, Boston, USA, 2013

  • Codes CREF : Pathologies particulières (DI3370)
  • Unités de recherche UMONS : Biologie moléculaire (M122)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)

Abstract(s) :

(Anglais) FSHD is linked to DNA hypomethylation of the D4Z4 repeat array in 4q35 resulting in a gain of function of the DUX4 gene we have identified within the D4Z4 unit. The DUX4 gene functionality was questioned for a decade because of its location in repeated DNA elements and the characterization by Gabellini et al (2002) of a transcription inhibitory element (DBE) that precisely mapped on its promoter. The DBE bound a multiprotein complex including the YY1 transcription factor. The Sp1-binding GC box that mediates basal DUX4 promoter activity maps close to the DBE suggesting a steric hindrance upon YY1 binding. We confirmed YY1 could bind to the DBE. However co-transfection of a human rhabdomyosarcoma cell line with a YY1 expression vector activated a reporter gene fused to the proximal DUX4 promoter (DUX4-Luc). This lack of repression was confirmed by the observed co-localisation of the endogenous YY1 and DUX4 proteins in nuclei of FSHD myoblasts/myotubes. We characterized an E-box on the major DUX4 transcription start site, and showed its interaction with MYOD repressed DUX4-Luc expression. During FSHD myoblast differentiation endogenous DUX4 expression was increased when MYOD levels were the lowest i.e. during fast proliferation or in myotubes, but not at myoblast fusion time. In another experiment, we tranfected mouse myoblast C2C12 cells with the DUX4-Luc reporter gene and measured luciferase activity after 0, 1, 3, 4 or 6 days of differentiation. The luciferase activity was decreased at day 1 and reactivated at days 3, 4 and 6. Those data are in keeping with what we have observed here in primary myoblast cultures. In conclusion the interplay between Sp1, YY1 and MYOD could explain why DUX4 expression is observed in proliferating FSHD myoblasts and differentiated myotubes.