title: Generation of isogenic D4Z4 contracted and noncontracted immortal muscle cell clones from a mosaic patient: a cellular model for FSHD.
abstract: In most cases facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of the D4Z4 repeat in the 4q subtelomere. This contraction is associated with local chromatin decondensation and derepression of the DUX4 retrogene. Its complex genetic and epigenetic cause and high clinical variability in disease severity complicate investigations on the pathogenic mechanism underlying FSHD. A validated cellular model bypassing the considerable heterogeneity would facilitate mechanistic and therapeutic studies of FSHD. Taking advantage of the high incidence of somatic mosaicism for D4Z4 repeat contraction in de novo FSHD, we have established a clonal myogenic cell model from a mosaic patient. Individual clones are genetically identical except for the size of the D4Z4 repeat array, being either normal or FSHD sized. These clones retain their myogenic characteristics, and D4Z4 contracted clones differ from the noncontracted clones by the bursts of expression of DUX4 in sporadic nuclei, showing that this burst-like phenomenon is a locus-intrinsic feature. Consequently, downstream effects of DUX4 expression can be observed in D4Z4 contracted clones, like differential expression of DUX4 target genes. We also show their participation to in vivo regeneration with immunodeficient mice, further expanding the potential of these clones for mechanistic and therapeutic studies. These cell lines will facilitate pairwise comparisons to identify FSHD-specific differences and are expected to create new opportunities for high-throughput drug screens.
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Yvonne D
authors.initials: YD
authors.lastname: Krom
authors.forename: Julie
authors.initials: J
authors.lastname: Dumonceaux
authors.forename: Kamel
authors.initials: K
authors.lastname: Mamchaoui
authors.forename: Bianca
authors.initials: B
authors.lastname: den Hamer
authors.forename: Virginie
authors.initials: V
authors.lastname: Mariot
authors.forename: Elisa
authors.initials: E
authors.lastname: Negroni
authors.forename: Linda N
authors.initials: LN
authors.lastname: Geng
authors.forename: Nicolas
authors.initials: N
authors.lastname: Martin
authors.forename: Rabi
authors.initials: R
authors.lastname: Tawil
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
authors.forename: Baziel G M
authors.initials: BG
authors.lastname: van Engelen
authors.forename: Vincent
authors.initials: V
authors.lastname: Mouly
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Butler-Browne
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002999:Clone Cells; D016521:Electrophoresis, Gel, Pulsed-Field; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D009030:Mosaicism; D032342:Muscle Cells / Q000378:metabolism / Q000473:pathology*; D009119:Muscle Contraction / Q000235:genetics*; D024510:Muscle Development / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D032446:Myoblasts / Q000378:metabolism; D012038:Regeneration / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D016615:Telomere / Q000235:genetics
chemical_list: D015415:Biomarkers