P38α Regulates Expression of DUX4 in Facioscapulohumeral Muscular Dystrophy

FSHD is caused by the loss of repression at the D4Z4 locus leading to DUX4 expression in skeletal muscle, activation of its early embryonic transcriptional program and muscle fiber death. While progress toward understanding the signals driving DUX4 expression has been made, the factors and pathways involved in the transcriptional activation of this gene remain largely unknown. Here, we describe the identification and characterization of p38 as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent and specific inhibitors of p38/{beta}, 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 p38/{beta} inhibition, the vast majority of which are DUX4 target genes. Our results reveal a novel and apparently critical role for p38 in the aberrant activation of DUX4 in FSHD and support the potential of p38/{beta} inhibitors as effective therapeutics to treat FSHD at its root cause. VISUAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=160 SRC="FIGDIR/small/700195v2_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@d2d55corg.highwire.dtl.DTLVardef@1b5c8fcorg.highwire.dtl.DTLVardef@19e4667org.highwire.dtl.DTLVardef@202b96_HPS_FORMAT_FIGEXP M_FIG C_FIG