Probing the activity of DUX4 in FSHD

PROJECT SUMMARY Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant progressive muscular dystrophy associated with inappropriate expression of the DUX4 gene. FSHD afflicts over 25,000 individuals in the United States, is a very common genetic disease, and is currently without treatment. In the previous cycle of this renewal application, we discovered that DUX4 gene expression is self-limited to short bursts of activity, with the DUX4 target gene DUXA serving as a feedback inhibitor, and a degron in the C-terminus leading to protein instability. We also discovered that transient DUX4 expression in muscle fibers in our iDUX4pA doxycycline-inducible mouse model tips muscle into an injury-sensitive pro-fibrotic state mediated by long-term changes to the FAP compartment, and developed a p300-specific inhibitor, iP300w, for treating DUX4-induced disease, including finding that iP300w inhibits CIC-DUX4, a fusion oncoprotein that causes a very aggressive pediatric sarcoma. The renewal application builds on this work, with a series of studies aimed at continuing to explore the molecular mechanism of DUX4 activity by understanding the function of proteins that interact with DUX4 including those that degrade it, developing p300 inhibition as a therapeutic approach, and investigating pathological mechanisms underlying DUX4-mediated skeletal muscle disease using transient and cell type-restricted expression of DUX4 in the iDUX4pA mouse model.