RT Journal Article
SR Electronic
T1 P38α Regulates Expression of DUX4 in Facioscapulohumeral Muscular Dystrophy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 700195
DO 10.1101/700195
A1 L. Alejandro Rojas
A1 Erin Valentine
A1 Anthony Accorsi
A1 Joseph Maglio
A1 Ning Shen
A1 Alan Robertson
A1 Steven Kazmirski
A1 Peter Rahl
A1 Rabi Tawil
A1 Diego Cadavid
A1 Lorin A. Thompson
A1 Lucienne Ronco
A1 Aaron N. Chang
A1 Angela M. Cacace
A1 Owen Wallace
YR 2019
UL http://biorxiv.org/content/early/2019/07/12/700195.abstract
AB 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 p38α as a novel regulator of DUX4 expression in FSHD myotubes. By using multiple highly characterized, potent and specific inhibitors of p38α/β, 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 p38α/β 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 p38α/β inhibitors as effective therapeutics to treat FSHD at its root cause.