We show that the DUX4 target gene and E3 ubiquitin ligase TRIM21 is necessary for DUX4-mediated downregulation of FAIM2, making the DUX4-TRIM21-FAIM2 axis a potentially attractive target for drug discovery and development in FSHD. This evidence concerns the gene DUX4 and facioscapulohumeral muscular dystrophy.