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2016-03-14 - Colloque/Présentation - poster - Anglais - 1 page(s)

Ansseau Eugénie , O Jocelyn, Lancelot Céline , Tassin Alexandra , Matteoti Christel, Yip Cassandre, Liu Jian, Leroy Baptiste , Hubeau Céline, Gerbaux Cécile, Cloet Samuel, Wauters Armelle, Zorbo Sabrina, Meyer Pierre, Pirson Isabelle, Laoudj Chevinesse Dalila, Wattiez Ruddy , Harper Scott, Belayew Alexandra , Coppée Frédérique , "The translocation of DUX4 and DUX4c during myoblast differentiation allows their association with nucleo-cytoplasmic proteins associated with mRNP granules." in International Congress Of Myology, Lyon, France, 2016

  • Codes CREF : Biologie moléculaire (DI3111), Pathologies particulières (DI3370), Biologie cellulaire (DI311D)
  • Unités de recherche UMONS : Biologie moléculaire (M122)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)
Texte intégral :

Abstract(s) :

(Anglais) Eugénie Ansseau1, Jocelyn O. Eidahl2¶, Céline Lancelot1¶, Alexandra Tassin1¶, Christel Matteotti1, Cassandre Yip1, Jian Liu2, Baptiste Leroy3, Céline Hubeau1, Cécile Gerbaux1, Samuel Cloet1, Armelle Wauters1, Sabrina Zorbo1, Pierre Meyer4, Isabelle Pirson5, Dalila Laoudj-Chenivesse6, Ruddy Wattiez3, Scott Q. Harper2,7, Alexandra Belayew1& and Frédérique Coppée1&*. 1Laboratory of Molecular Biology, Research Institute for Health Sciences and Technology, University of Mons, Mons, Belgium 2 Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, OH, USA 3Laboratory of Proteomic and Microbiology, Research Institute for Biosciences, University of Mons, Mons, Belgium 4Pediatric Department, CHRU Montpellier, Montpellier, France 5I.R.I.B.H.M., Free University of Brussels, Belgium 6Laboratory of Physiology and Experimental Medicine, INSERM U1046, Montpellier, France 7Department of Pediatrics, Ohio State University College of Medicine, Columbus, OH, USA ¶ These authors contributed equally as second authors. & These authors contributed equally as senior authors. Hundreds of double homeobox (DUX) genes map within 3.3-kb repeated elements dispersed in the human genome and encode DNA-binding proteins. Among these, we identified DUX4, a potent transcription factor that causes facioscapulohumeral muscular dystrophy (FSHD). In the present study, we performed yeast two-hybrid screens and protein co-purifications to identify protein partners of DUX4, DUX4c (identical to DUX4 except for the end of the carboxyl terminal domain) and DUX1 (limited to the double homeodomain). Unexpectedly, we identified and validated (by co-immunoprecipitation, GST pull-down, co-immunofluorescence and in situ Proximal Ligation Assay) the interaction of DUX4, DUX4c and DUX1 with type III intermediate filament protein desmin in the cytoplasm and at the nuclear periphery. Desmin filaments link adjacent sarcomeres at the Z-discs, interact with mitochondria and contribute to positioning of the nuclei. All these functions are altered in FSHD muscles. Another Z-disc protein, LMCD1 was also validated as a DUX4 partner. The functionality of DUX4 or DUX4c interactions with cytoplasmic proteins is underscored by the observation of DUX4 and DUX4c nucleo-cytoplasmic translocation upon myoblast fusion. In addition, we also validated (by co-immunoprecipitation, co-immunofluorescence or in situ PLA) several RNA-binding proteins involved in mRNA splicing and translation. Among these, the nuclear FUS and SFPQ are reported to translocate to the cytoplasm of neuronal cells where they associated with ribonucleoparticles (RNPs). These complexes contain untranslated mRNAs, bring mRNAs to subcellular areas where their translation is required at specific times. Several other validated or identified DUX4/4c partners are also contained in mRNP-granules, and the co-localization with cytoplasmic DAPI-positive spots is in keeping with such an association. Large muscle RNPs were recently shown to exit the nucleus via a novel mechanism of nuclear envelope budding. Following DUX4 or DUX4c overexpression in muscle cell cultures, we observed their association with similar nuclear buds. In conclusion, in addition to their transcriptional activities, DUX4 and DUX4c induction in FSHD muscle cells might disturb cytoskeletal dynamics and mRNA splicing, location and translation by their association with proteins regulating these processes. Further investigations are on-going to confirm such function that might be common to proteins encoded by hundreds of DUX genes.