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Background  Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder associated with the partial deletion of integral numbers of 3.3 kb D4Z4 DNA repeats within the subtelomere of chromosome 4q. A number of candidate FSHD genes, adenine nucleotide translocator 1 gene ( ANT1 ), FSHD-related gene 1 ( FRG1 ),  FRG2  and  DUX4c , upstream of the D4Z4 array (FSHD locus), and double homeobox chromosome 4 ( DUX4 ) within the repeat itself, are upregulated in some patients, thus suggesting an underlying perturbation of the chromatin structure. Furthermore, a mouse model overexpressing  FRG1  has been generated, displaying skeletal muscle defects.    Results  In the context of myogenic differentiation, we compared the chromatin structure and tridimensional interaction of the D4Z4 array and  FRG1  gene promoter, and  FRG1  expression, in control and FSHD cells. The  FRG1  gene was prematurely expressed during FSHD myoblast differentiation, thus suggesting that the number of D4Z4 repeats in the array may affect the correct timing of  FRG1  expression. Using chromosome conformation capture (3C) technology, we revealed that the  FRG1  promoter and D4Z4 array physically interacted. Furthermore, this chromatin structure underwent dynamic changes during myogenic differentiation that led to the loosening of the  FRG1 /4q-D4Z4 array loop in myotubes. The  FRG1  promoter in both normal and FSHD myoblasts was characterized by H3K27 trimethylation and Polycomb repressor complex binding, but these repression signs were replaced by H3K4 trimethylation during differentiation. The D4Z4 sequences behaved similarly, with H3K27 trimethylation and Polycomb binding being lost upon myogenic differentiation.    Conclusion  We propose a model in which the D4Z4 array may play a critical chromatin function as an orchestrator of  in cis  chromatin loops, thus suggesting that this repeat may play a role in coordinating gene expression.

bmc biology

Remodeling of the chromatin structure of the facioscapulohumeral muscular dystrophy (FSHD) locus and upregulation of FSHD-related gene 1 (FRG1) expression during human myogenic differentiation