The evolution of DUX4 gene regulation and its implication for facioscapulohumeral muscular dystrophy

Double homeobox 4 (DUX4) is an early embryonic transcription factor whose expression in the skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). Despite decades of research, our knowledge of FSHD and DUX4 biology is incomplete, and the disease has currently no cures or targeted therapies. The unusual evolutionary origin of DUX4, its extensive epigenetic and post-transcriptional gene regulation, and various feedback regulatory loops that control its expression and function all contribute to the highly complex nature of FSHD pathogenesis. In this minireview, I synthesize the current state of knowledge in DUX4 and FSHD biology to highlight key areas where further research is needed to better understand DUX4 regulation. I also emphasize post-transcriptional regulation of and by DUX4 via changes in RNA and protein stability that might underlie key features of FSHD pathophysiology. Finally, I discuss the various feedback loops involved in DUX4 regulation and the context-specific consequences of its expression, which could be key to developing novel therapeutic approaches to combat FSHD.