Abstract
Facioscapulohumeral dystrophy (FSHD) is caused by the mis-expression of DUX4 in skeletal muscle cells. DUX4 is a transcription factor that activates genes normally associated with stem cell biology and its mis-expression in FSHD cells results in apoptosis. To identify genes and pathways necessary for DUX4-mediated apoptosis, we performed an siRNA screen in an RD rhabdomyosarcoma cell line with an inducible DUX4 transgene. Our screen identified components of the MYC-mediated apoptotic pathway and the double-stranded RNA (dsRNA) innate immune response pathway as mediators of DUX4-induced apoptosis. Further investigation revealed that DUX4 expression led to increased MYC mRNA, accumulation of nuclear dsRNA foci, and activation of the dsRNA response pathway in both RD cells and human myoblasts. Nuclear dsRNA foci were associated with aggregation of the exon junction complex component EIF4A3. The elevation of MYC mRNA, dsRNA accumulation, and EIF4A3 nuclear aggregates in FSHD muscle cells suggest that these processes might contribute to FSHD pathophysiology.
Highlights
Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused by misexpression of the double-homeobox transcription factor DUX4 in skeletal muscle [1]
When DUX4 is expressed in cultured human or mouse skeletal muscle cells, it activates a program of cell death
We found that DUX4 expression led to an accumulation of double stranded RNAs that induced a cell death pathway evolved to protect against viral infections
Summary
Facioscapulohumeral dystrophy (FSHD) is a progressive muscular dystrophy caused by misexpression of the double-homeobox transcription factor DUX4 in skeletal muscle [1]. Ectopic expression of DUX4 in human and mouse cell lines as well as in vivo injection of DUX4 adenovirus into mouse muscle leads to rapid cellular apoptosis [4,5]. This cell death is dependent on the transcriptional activity of DUX4 because expression of DUX4 with mutations in the DNA binding domain or trans-activation domain do not exhibit toxicity [5,6]. It is possible that expression of DUX4 in skeletal muscle inappropriately activates a program of apoptosis that might otherwise be a ’normal’ consequence of DUX4 expression during developmental processes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
