title: A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy.
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.
authors.affiliation: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Lauren
authors.initials: L
authors.lastname: Snider
authors.affiliation: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Jagannathan
authors.affiliation: Department of Neurology, University of Rochester, Rochester, United States.
authors.forename: Rabi
authors.initials: R
authors.lastname: Tawil
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
authors.affiliation: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Bradley
mesh_terms: D025461:Feedback, Physiological; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics*; D059365:Nonsense Mediated mRNA Decay; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D020365:RNA Helicases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018626:Retroelements / Q000235:genetics*; D013379:Substrate Specificity; D015534:Trans-Activators / Q000378:metabolism
chemical_list: C121257:DUX4L1 protein, human; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D018626:Retroelements; D015534:Trans-Activators; D046988:Proteasome Endopeptidase Complex; D020365:RNA Helicases; C101828:UPF1 protein, human
keywords: DUX4; RNA surveillance; evolutionary biology; facioscapulohumeral muscular dystrophy; genomics; human; human biology; medicine; nonsense-mediated decay