Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7

Facioscapulohumeral muscular dystrophy (FSHD) is characterised by progressive skeletal muscle weakness and wasting. FSHD is linked to epigenetic derepression of the subtelomeric D4Z4 macrosatellite at chromosome 4q35. Epigenetic derepression permits the distal-most D4Z4 unit to transcribe DUX4, with transcripts stabilised by splicing to a poly(A) signal on permissive 4qA haplotypes. The pioneer transcription factor DUX4 activates target genes that are proposed to drive FSHD pathology. While this toxic gain-of-function model is a satisfying bottom-up genotype-to-phenotype link, DUX4 is rarely detectable in muscle and DUX4 target gene expression is inconsistent in patients. A reliable biomarker for FSHD is suppression of a target gene score of PAX7, a master regulator of myogenesis. However, it is unclear how this top-down finding links to genomic changes that characterise FSHD and to DUX4. Here, we explore the roles and interactions of DUX4 and PAX7 in FSHD pathology and how the relationship between these two transcription factors deepens understanding via the immune system and muscle regeneration. Considering how FSHD pathomechanisms are represented by DUX4opathy models has implications for developing therapies and current clinical trials.

Automated summary

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by skeletal muscle weakness and wasting due to epigenetic derepression of the D4Z4 macrosatellite, leading to transcription of DUX4 which activates target genes. PAX7 suppression serves as a reliable biomarker for FSHD, but its link to genomic changes and DUX4 remains unclear. Understanding the roles of DUX4 and PAX7 in FSHD pathology can deepen knowledge of the disease through interactions with the immune system and muscle regeneration.