Document Detail

DUX4 expression in FSHD muscle cells: how could such a rare protein cause a myopathy?
MedLine Citation:
PMID:  23206257     Owner:  NLM     Status:  MEDLINE    
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.
Alexandra Tassin; Dalila Laoudj-Chenivesse; Céline Vanderplanck; Marietta Barro; Sébastien Charron; Eugénie Ansseau; Yi-Wen Chen; Jacques Mercier; Frédérique Coppée; Alexandra Belayew
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-12-04
Journal Detail:
Title:  Journal of cellular and molecular medicine     Volume:  17     ISSN:  1582-4934     ISO Abbreviation:  J. Cell. Mol. Med.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-30     Completed Date:  2013-11-13     Revised Date:  2014-08-08    
Medline Journal Info:
Nlm Unique ID:  101083777     Medline TA:  J Cell Mol Med     Country:  England    
Other Details:
Languages:  eng     Pagination:  76-89     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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MeSH Terms
Cell Differentiation
Cell Nucleus / genetics,  metabolism,  pathology
Cytoplasm / genetics,  metabolism
Gene Expression Regulation
Homeodomain Proteins / genetics,  metabolism*
Muscle Fibers, Skeletal / metabolism*,  pathology
Muscle Proteins / genetics,  metabolism*
Muscular Dystrophy, Facioscapulohumeral / genetics,  metabolism*,  pathology
Myoblasts, Skeletal / metabolism*,  pathology
Paired Box Transcription Factors / genetics,  metabolism*
Primary Cell Culture
Proteasome Endopeptidase Complex / metabolism
Protein Binding
RNA, Messenger / genetics,  metabolism*
Signal Transduction
Grant Support
Reg. No./Substance:
0/DUX4 protein, human; 0/Homeodomain Proteins; 0/Muscle Proteins; 0/Paired Box Transcription Factors; 0/RNA, Messenger; 0/homeobox protein PITX1; EC Endopeptidase Complex

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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