'Overexpression of the double homeodomain protein DUX4c interferes with myofibrillogenesis and induces clustering of myonuclei'

Vanderplanck, Céline; Tassin, Alexandra; Ansseau, Eugénie; Charron, Sébastien; Wauters, Armelle; Lancelot, Céline; Vancutsem, Kelly; Laoudj Chevinesse, Dalila; Belayew, Alexandra; Coppée, Frédérique

doi:10.1186/s13395-017-0148-4

Article (Scientific journals)

'Overexpression of the double homeodomain protein DUX4c interferes with myofibrillogenesis and induces clustering of myonuclei'

Vanderplanck, Céline; Tassin, Alexandra; Ansseau, Eugénie et al.

2018 • In Skeletal Muscle, 8 (2)

Peer reviewed

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https://hdl.handle.net/20.500.12907/32904

DOI
10.1186/s13395-017-0148-4

PubMed
29329560

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Abstract :

[en] Background: Facioscapulohumeral muscular dystrophy (FSHD) is associated with DNA hypomethylation at the 4q35 D4Z4 repeat array. Both the causal gene DUX4 and its homolog DUX4c are induced. DUX4c is immunodetected in every myonucleus of proliferative cells, while DUX4 is present in only 1/1000 of myonuclei where it initiates a gene deregulation cascade. FSHD primary myoblasts differentiate into either atrophic or disorganized myotubes. DUX4 expression induces atrophic myotubes and associated FSHD markers. Although DUX4 silencing normalizes the FSHD atrophic myotube phenotype, this is not the case for the disorganized phenotype. DUX4c overexpression increases the proliferation rate of human TE671 rhabdomyosarcoma cells and inhibits their differentiation, suggesting a normal role during muscle differentiation. Methods: By gain- and loss-of-function experiments in primary human muscle cells, we studied the DUX4c impact on proliferation, differentiation, myotube morphology, and FSHD markers. Results: In primary myoblasts, DUX4c overexpression increased the staining intensity of KI67 (a proliferation marker) in adjacent cells and delayed differentiation. In differentiating cells, DUX4c overexpression led to the expression of some FSHD markers including β-catenin and to the formation of disorganized myotubes presenting large clusters of nuclei and cytoskeletal defects. These were more severe when DUX4c was expressed before the cytoskeleton reorganized and myofibrils assembled. In addition, endogenous DUX4c was detected at a higher level in FSHD myotubes presenting abnormal clusters of nuclei and cytoskeletal disorganization. We found that the disorganized FSHD myotube phenotype could be rescued by silencing of DUX4c, not DUX4. Conclusion: Excess DUX4c could disturb cytoskeletal organization and nuclear distribution in FSHD myotubes. We suggest that DUX4c up-regulation could contribute to DUX4 toxicity in the muscle fibers by favoring the clustering of myonuclei and therefore facilitating DUX4 diffusion among them. Defining DUX4c functions in the healthy skeletal muscle should help to design new targeted FSHD therapy by DUX4 or DUX4c inhibition without suppressing DUX4c normal functio

Disciplines :

General & internal medicine
Biotechnology
Zoology

Author, co-author :

Vanderplanck, Céline

Tassin, Alexandra ; Université de Mons > Faculté de Médecine et de Pharmacie > Physiologie et réadaptation respiratoire

Ansseau, Eugénie ; Université de Mons > Faculté de Médecine et de Pharmacie > Biochimie métabolique et moléculaire

Charron, Sébastien

Wauters, Armelle

Lancelot, Céline

Vancutsem, Kelly

Laoudj Chevinesse, Dalila

Belayew, Alexandra ; Université de Mons > Faculté de Médecine et de Pharmacie > FMP - Service du Doyen

Coppée, Frédérique ; Université de Mons > Faculté de Médecine et de Pharmacie > Service de Biochimie métabolique et moléculaire

Language :

English

Title :

'Overexpression of the double homeodomain protein DUX4c interferes with myofibrillogenesis and induces clustering of myonuclei'

Publication date :

12 January 2018

Journal title :

Skeletal Muscle

Publisher :

BioMed Central, London, United Kingdom

Volume :

Issue :

Peer reviewed :

Peer reviewed

Research unit :

M122 - Biochimie métabolique et moléculaire

Research institute :

R550 - Institut des Sciences et Technologies de la Santé

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