Consequences of epigenetic derepression in facioscapulohumeral muscular dystrophy

Abstract

Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is caused either by the contraction of the D4Z4 macrosatellite repeat at the distal end of chromosome 4q to a size of 1 to 10 repeat units (FSHD1) or by mutations in D4Z4 chromatin modifiers such as Structural Maintenance of Chromosomes Hinge Domain Containing 1 (FSHD2). These two genotypes share a phenotype characterized by progressive and often asymmetric muscle weakening and atrophy, and common epigenetic alterations of the D4Z4 repeat. All together, these epigenetic changes converge the two genetic forms into one disease and explain the derepression of the DUX4 gene, which is otherwise kept epigenetically silent in skeletal muscle. DUX4 is consistently transcriptionally upregulated in FSHD1 and FSHD2 skeletal muscle cells where it is believed to exercise a toxic effect. Here we provide a review of the recent literature describing the progress in understanding the complex genetic and epigenetic architecture of FSHD, with a focus on one of the consequences that these epigenetic changes inflict, the DUX4-induced immune deregulation cascade. Moreover, we review the latest therapeutic strategies, with particular attention to the potential of epigenetic correction of the FSHD locus. K E Y W O R D S

Skeletal muscle regeneration in facioscapulohumeral muscular dystrophy is correlated with pathological severity

“…FSHD1 and FSHD2 manifest as a coherent clinical condition through ectopic expression of DUX4 ( 7 , 8 , 10 ), which could also affect the regenerative response to dystrophy since DUX4 is toxic to many cell types across numerous species ( 63 , 64 ). Two myogenic enhancers proximal to D4Z4 ( 65 ) likely explain DUX4 expression in skeletal muscle, hence FSHD manifesting as a muscular dystrophy ( 7 ).…”

“…FSHD1 is characterized by the presence of 1–10 D4Z4 repeats on at least one 4q chromosome, while the unaffected population normally have between 11 and ~100 D4Z4 units ( 4–6 ). So few D4Z4 units in FSHD1 patients leads to epigenetic derepression at the locus, including DNA hypomethylation and chromatin relaxation ( 7 , 8 ). Crucially, at least one D4Z4 unit is required for FSHD ( 9 ).…”

“…Restricted to old world primates, DUX4 is a pioneer transcription factor ( 14 ) that drives transcription of genes and retroelements during the cleavage stage of early development to control zygotic genome activation ( 15 , 16 ). DUX4 is then repressed in somatic cells via epigenetic modification at D4Z4 ( 7 , 8 ). In FSHD, however, epigenetic derepression at D4Z4 causes transcription of DUX4 from the normally somatically repressed distal-most D4Z4 unit ( 17 ).…”

Cellular and animal models for facioscapulohumeral muscular dystrophy

“…The risk of developing FSHD1 increases with decreasing numbers of repeat units, with individuals carrying seven or fewer having a high probability of disease, individuals carrying eight to ten units having moderate probability, and individuals with a larger number of units having lower probability ( Lunt et al, 1995 ; Orrell et al, 1999 ; Ricci et al, 1999 ; Rossi et al, 2007 ; Sacconi et al, 2019 ; Schaap et al, 2013 ; Scionti et al, 2012 ; van Deutekom et al, 1993 ; Wijmenga et al, 1992 ). Allele contraction results in a host of epigenetic changes that relax the chromatin and allow expression of the genes in the region (reviewed in Greco et al, 2020 ; Salsi et al, 2020 ). Additionally, to become pathogenic, the shortened array must be present on a ‘permissive’ chromosome ( Box 1 ) that carries a 4qA allele adjacent to the D4Z4 array, as well as particular simple sequence length polymorphisms ( Box 1 ) ( Lemmers et al, 2002 , 2004 , 2007 , 2010a , b ; Spurlock et al, 2010 ; van Geel et al, 2002 ).…”

DUX4 Expression in FSHD Muscles: Focus on Its mRNA Regulation

“…Double homeobox 4 ( DUX4 ) is a transcription factor that is normally expressed during embryonic development and in the human testes but suppressed in somatic tissue (for review see [ 1 ]). The recent finding of DUX4 in an early cleavage-stage embryo raised the hypothesis that DUX4 might act as a functional transcriptional programmer to activate the cleavage-stage transcriptional platform and might be a key regulator of zygotic genome activation [ 2 , 3 , 4 ].…”