P38a Regulates Expression of DUX4 in Facioscapulohumeral Muscular Dystrophy

Here, we describe the identification and characterization of p38a as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent and specific inhibitors of p38a/ß, we show a robust reduction of DUX4 expression, activity and cell death across FSHD1 and FSHD2 patient-derived lines. RNA-seq profiling reveals that a small number of genes are differentially expressed upon p38a/ß inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38a in the aberrant activation of DUX4 in FSHD and support the potential of p38a/ß inhibitors as effective therapeutics to treat FSHD at its root cause. Overall design: RNA-seq profiles of wt myoblasts and FSHD myotubes treated with pamapimod and losmapimod