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A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy
| Content Provider | Paperity |
|---|---|
| Author | Feng, Qing Stephen, J. Tapscott Maarel, Silvère M. Van Der Tawil, Rabi Snider, Lauren Jagannathan, Sujatha Robert, K. Bradley |
| Abstract | Facioscapulohumeral muscular dystrophy (FSHD) is a muscular dystrophy caused by inefficient epigenetic repression of the D4Z4 macrosatellite array and somatic expression of the DUX4 retrogene. DUX4 is a double homeobox transcription factor that is normally expressed in the testis and causes apoptosis and FSHD when misexpressed in skeletal muscle. The mechanism(s) of DUX4 toxicity in muscle is incompletely understood. We report that DUX4-triggered proteolytic degradation of UPF1, a central component of the nonsense-mediated decay (NMD) machinery, is associated with profound NMD inhibition, resulting in global accumulation of RNAs normally degraded as NMD substrates. DUX4 mRNA is itself degraded by NMD, such that inhibition of NMD by DUX4 protein stabilizes DUX4 mRNA through a double-negative feedback loop in FSHD muscle cells. This feedback loop illustrates an unexpected mode of autoregulatory behavior of a transcription factor, is consistent with ‘bursts’ of DUX4 expression in FSHD muscle, and has implications for FSHD pathogenesis. |
| File Format | HTM / HTML |
| ISSN | 2050084X |
| DOI | 10.7554/eLife.04996 |
| Journal | eLife |
| e-ISSN | 2050084X |
| Language | English |
| Publisher | eLife Sciences Publications Ltd |
| Publisher Date | 2015-01-07 |
| Access Restriction | Open |
| Subject Keyword | Facioscapulohumeral muscular dystrophy Human Rna surveillance Nonsense-mediated decay Dux4 |
| Content Type | Text |
| Resource Type | Article |
| Subject | Neuroscience Immunology and Microbiology Medicine Biochemistry, Genetics and Molecular Biology |
