Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Abstract

Significance: Aberrant epigenetic regulation is an integral aspect of many diseases and complex disorders. Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, is caused by disrupted genetic and epigenetic regulation of a macrosatellite repeat. FSHD provides a powerful model to investigate disease-relevant epigenetic modifiers and general mechanisms of epigenetic regulation that govern gene expression. Recent Advances: In the context of a genetically permissive allele, the one aspect of FSHD that is consistent across all known cases is the aberrant epigenetic state of the disease locus. In addition, certain mutations in the chromatin regulator SMCHD1 (structural maintenance of chromosomes hinge-domain protein 1) are sufficient to cause FSHD2 and enhance disease severity in FSHD1. Thus, there are multiple pathways to generate the epigenetic dysregulation required for FSHD. Critical Issues: Why do some individuals with the genetic requirements for FSHD develop disease pathology, while others remain asymptomatic? Similarly, disease progression is highly variable among individuals. What are the relative contributions of genetic background and environmental factors in determining disease manifestation, progression, and severity in FSHD? What is the interplay between epigenetic factors regulating the disease locus and which, if any, are viable therapeutic targets? Future Directions: Epigenetic regulation represents a potentially powerful therapeutic target for FSHD. Determining the epigenetic signatures that are predictive of disease severity and identifying the spectrum of disease modifiers in FSHD are vital to the development of effective therapies.

Large family cohorts of lymphoblastoid cells provide a new cellular model for investigating facioscapulohumeral muscular dystrophy

“…A.2) and found that the 3 healthy LCLs with contracted 4qB alleles displayed FSHD1-like levels of DNA hypomethylation (GM16349, Q1=7.1%; GM16350, Q1=0.0%; GM16352, Q1=0.0%) as compared with the non-contracted 4qB alleles with healthy levels of DNA methylation. This data supports the hypothesis that the physical removal of heterochromatin at D4Z4 arrays causes the epigenetic disruption in FSHD1 [15, 26, 28, 57]. In addition, this data provides further support for the unifying model for FSHD [23], again confirming that a 4q35 D4Z4 contraction alone is not causal for FSHD, but requires a permissive 4qA subtelomere in cis to cause disease [39].…”

“…FSHD is ultimately caused by the disruption of epigenetic regulation governing the chromosome 4q35 D4Z4 macrosatellite array, combined with an FSHD-permissive 4q35 PAS, resulting in the pathogenic expression of the DUX4 gene [15, 26, 35, 57]. In FSHD1, the epigenetic disruption is caused by the loss of large regions of regulatory heterochromatin.…”

“…All forms of FSHD are genetically and epigenetically linked to the chromosome 4q35 D4Z4 macrosatellite array, with the interplay between these factors accounting for much of the high variability in disease penetrance and severity characteristic of the disease [1, 6–15]. The predominant form of the disease, FSHD1 (OMIM 158900), represents >95% of reported cases and results from large DNA deletions within the 4q35 D4Z4 repeat array [16, 17].…”

“…In both forms of FSHD, chromatin de-repression at the 4q35 D4Z4 macrosatellite has similar downstream molecular consequences, resulting in the aberrant expression of a pathogenic isoform of the DUX4 ( d o u ble homeobo x 4) gene, DUX4-fl , in skeletal muscle [33] [34, 35] [15, 23, 26, 35–38]. Each D4Z4 RU encodes a copy of DUX4 [33]; however, only DUX4-fl produced from the distal-most 4q35 D4Z4 RU is stably expressed in FSHD.…”

Scalpel or Straitjacket: CRISPR/Cas9 Approaches for Muscular Dystrophies

“…Consider Facioscapulohumeral Muscular Dystrophy (FSHD), the most prevalent myopathy affecting males and females of all ages (reviewed in [6]). In contrast to DMD, which is caused by the loss of a functional protein, FSHD is caused by the aberrant expression of a protein that is normally silent due to its extreme toxicity.…”