Developmental regulators drive DUX4 expression in facioscapulohumeral muscular dystrophy

Abstract

AbstractFacioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle wasting disease caused by misexpression of the Double Homeobox 4 (DUX4) transcription factor in skeletal muscle. While epigenetic derepression of D4Z4 macrosatellite repeats is recognized to cause DUX4 misexpression in FSHD, the factors promotingDUX4transcription are unknown. Here, we show that SIX (sine oculis) transcription factors, critical during embryonic development, muscle differentiation, regeneration and homeostasis, are key regulators ofDUX4expression in FSHD muscle cells. In this study, we demonstrate SIX1, SIX2, and SIX4 to be necessary for induction ofDUX4transcription in differentiating FSHD myotubesin vitro, with SIX1 and SIX2 being the most critical in drivingDUX4expression. Interestingly, DUX4 downregulatesSIXRNA levels, suggesting negative feedback regulation. Our findings highlight the involvement of SIX transcription factors in driving the pathogenesis of FSHD by promotingDUX4and DUX4 target gene expression.TeaserWe identified a family of developmental regulators that promote aberrantDUX4expression in FSHD differentiating muscle cells.