title: DUX4 expression in FSHD muscle cells: how could such a rare protein cause a myopathy?
abstract: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most frequent hereditary muscle disorders. It is linked to contractions of the D4Z4 repeat array in 4q35. We have characterized the double homeobox 4 (DUX4) gene in D4Z4 and its mRNA transcribed from the distal D4Z4 unit to a polyadenylation signal in the flanking pLAM region. It encodes a transcription factor expressed in FSHD but not healthy muscle cells which initiates a gene deregulation cascade causing differentiation defects, muscle atrophy and oxidative stress. PITX1 was the first identified DUX4 target and encodes a transcription factor involved in muscle atrophy. DUX4 was found expressed in only 1/1000 FSHD myoblasts. We have now shown it was induced upon differentiation and detected in about 1/200 myotube nuclei. The DUX4 and PITX1 proteins presented staining gradients in consecutive myonuclei which suggested a diffusion as known for other muscle nuclear proteins. Both protein half-lifes were regulated by the ubiquitin-proteasome pathway. In addition, we could immunodetect the DUX4 protein in FSHD muscle extracts. As a model, we propose the DUX4 gene is stochastically activated in a small number of FSHD myonuclei. The resulting mRNAs are translated in the cytoplasm around an activated nucleus and the DUX4 proteins diffuse to adjacent nuclei where they activate target genes such as PITX1. The PITX1 protein can further diffuse to additional myonuclei and expand the transcriptional deregulation cascade initiated by DUX4. Together the diffusion and the deregulation cascade would explain how a rare protein could cause the muscle defects observed in FSHD.
authors.affiliation: Laboratory of Molecular Biology, Research Institute for Health Sciences and Technology, University of Mons, Mons, Belgium.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Tassin
authors.forename: Dalila
authors.initials: D
authors.lastname: Laoudj-Chenivesse
authors.forename: Céline
authors.initials: C
authors.lastname: Vanderplanck
authors.forename: Marietta
authors.initials: M
authors.lastname: Barro
authors.forename: Sébastien
authors.initials: S
authors.lastname: Charron
authors.forename: Eugénie
authors.initials: E
authors.lastname: Ansseau
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Jacques
authors.initials: J
authors.lastname: Mercier
authors.forename: Frédérique
authors.initials: F
authors.lastname: Coppée
authors.forename: Alexandra
authors.initials: A
authors.lastname: Belayew
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006207:Half-Life; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D032448:Myoblasts, Skeletal / Q000378:metabolism* / Q000473:pathology; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D009124:Muscle Proteins; D051761:Paired Box Transcription Factors; D012333:RNA, Messenger; C101485:homeobox protein PITX1; D046988:Proteasome Endopeptidase Complex