Consequences of epigenetic derepression in facioscapulohumeral muscular dystrophy

Figures

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  Figure 1. D4Z4 structure and genetic elements. A, The D4Z4 macrosatellite repeat on chromosomes 4 and 10 are highly homologous and consist of repeating 3.3 kb D4Z4 units (one large triangle represents one D4Z4 repeat unit). In healthy individuals, the length of the repeat is larger than 8 units and the D4Z4 repeat is heavily methylated (black popsicles). When the repeat is contracted to a short to intermediate size of 8 to 20 units, additional alteration of D4Z4 chromatin modifiers can lead to methylation loss (white popsicles) and development of Facioscapulohumeral muscular dystrophy (FSHD) (FSHD2). However, methylation status of the repeat can also be greatly influenced by the nature of the mutations in, for example, SMCHD1, DNMT3B, or LRIF1. Mutations in these factors act on methylation status of D4Z4 repeats on chromosome 4q and 10q simultaneously (not visualized). Upon a severe contraction of the repeat below 10 units, chromatin relaxation becomes less dependent on modifiers, and methylation status of the repeat is further reduced (FSHD1). Contractions below 8 units together with an SMCHD1 mutations are known as FSHD1/2 and are generally severe cases of FSHD. Relative locations of the…

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  Figure 2. D4Z4 chromatin components and the facioscapulohumeral muscular dystrophy (FSHD) disease continuum. A,D4Z4 is host to a plethora of repressor complexes which keep the repeat silenced in healthy controls by direct binding or deposition of repressive chromatin marks (top of (A)). In FSHD, these protein complexes and the chromatin state are altered (bottom of (A)). See main body of text for further information of illustrated complexes. The listed alterations in FSHD do not have to occur simultaneously in a single patient, although some combinations can increase disease severity. (B) Simplified representation of the FSHD disease spectrum. As the D4Z4 repeat size changes from 100 (asymptomatic) to 1 unit, chromatin modifiers (eg, SMCHD1) have less additional effect on the repression of DUX4 expression, therefore mutations are seldom seen together with shorter repeats. Rare cases of patients with relatively long repeats, or carriers with short alleles are not accounted for

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  Figure 3. Schematic representation of the DUX4‐induced transcriptional cascade in skeletal muscle cells. DUX4‐induced misexpression of Cancer testis antigens (CTAg) and germline antigens (GLAg) in facioscapulohumeral muscular dystrophy (FSHD) skeletal muscle cells would induce an immune response which could explain the inflammatory infiltrates associated with FSHD histology. PITX1, another DUX4 target gene, is a transcription factor able to activate p53 (cell cycle arrest mediator), Atrogin 1 and Murf1 (proteasome family members) eventually leading to muscle atrophy. DUX4‐induced upregulation of caspase 3/7 activity (CASP3/7) would lead to muscle cell death which is a further stimulus for interleukin 1α (IL‐1α) secretion, a potent inflammatory cytokine; DUX4 also upregulates a group of genes belonging to the innate immunity defense like DEFB103B, IFRD1, CXADR, CBARA1 and CXCR4. These findings could be responsible for the presence of muscle inflammation. Genes belonging to the glutathione‐redox pathway appear to be downregulated resulting in an elevated reactive oxygen species (ROS) production and therefore in an increased susceptibility to oxidative stress. Finally, DUX4 could also…