D4Z4 macrosatellite repeat array (D4Z4)

The D4Z4 macrosatellite repeat array is a polymorphic genomic locus located on the subtelomere of chromosome 4q35, consisting of multiple 3.3-kilobase repeat units (Lemmers et al., 2010, Science). Each unit contains an open reading frame for the Double Homeobox 4 (DUX4) gene, a transcription factor that is normally expressed during early embryonic development but epigenetically silenced in adult somatic tissues (Gabellini et al., 2002, Cell). In healthy individuals, the array typically contains 11 to 100 units and is maintained in a hypermethylated, heterochromatic state. However, in Facioscapulohumeral Muscular Dystrophy (FSHD), the array undergoes epigenetic relaxation—either due to a contraction to 1-10 units (FSHD1) or mutations in chromatin modifiers like SMCHD1 (FSHD2)—leading to the toxic expression of DUX4 in skeletal muscle (van der Maarel et al., 2012, Nature Genetics). This aberrant DUX4 expression triggers a pro-apoptotic and pro-inflammatory gene program that results in progressive muscle wasting. Therapeutic development targeting the D4Z4 array focuses on restoring epigenetic silencing or inhibiting the signaling pathways, such as p38 MAPK, that facilitate DUX4 expression (Fulcrum Therapeutics, 2023; Avidity Biosciences, 2023).

Other names

4q35 repeatD4Z4 repeatDUX4 locusD4Z4 macrosatelliteD4Z4 repeat unit

Epigenetic silencing of the DUX4 gene within the D4Z4 array or inhibition of signaling pathways (e.g., p38 MAPK) that promote DUX4 expression from the array.