Fig. 6

Overview of DUX4 signalling. Antagonists of DUX4 are depicted on the left; Signalling pathways for DUX4 gene activation have been associated with MAPK, especially p38α/β, bottom); DUX4 is located within the D4Z4 macrosatellite, which interacts with subtelomeric regions and the nuclear lamina via long distance-interactions, influencing (1) methylation levels and (2) gene expression. Interactions found in control cells and in FSHD are depicted at the top of the graphic. (For reasons of clarity, interactions of FSHD2 cells are not illustrated here, but are mentioned in the text.) FAT1 gene is shown to aggravate FSHD, when expressed at low levels. Muscles are more sensitive to gene deregulations and become affected earlier [83]; DUX4 generally requires help of p300/CBP and H3.X/H3.Y for target gene expression; Depicted on the right: DUX4 expression affects multiple genes, which are either upregulated or downregulated by DUX4 protein. ROS seem to have a prominent role in disease mechanism and are probably activated directly by DUX4 itself and indirectly through further targets of DUX4