The broad and long-term goal of this application is to identify the molecular mechanisms that cause facioscapulofaciohumeral dystrophy (FSHD). The broad hypothesis is that deletion of a subset of the D4Z4 units on 4qA161 results in increased or aberrant transcription from the remaining D4Z4 units on the deleted allele. Our preliminary studies have identified multiple sense and anti-sense transcripts from the D4Z4 unit. We have characterized one of the polyadenylated D4Z4 sense transcripts and developed assays to demonstrate its biological function. The specific goal of this application is to determine whether the protein product of a D4Z4 transcript causes FSHD.
Aim 1 will characterize sense and anti-sense transcripts from pathogenic and non-pathogenic D4Z4 alleles, their potential protein products, and their expression relative to FSHD.
Aim 2 will test the hypothesis that the polyadenylated RNA transcripts from the D4Z4 locus encode several distinct proteins, including the full-length DUX4 and splice-isoforms of DUX4, each with specific developmental biological functions in myogenesis, and that these functions contribute to FSHD pathology.
Aim 3 will characterize the IRES element of the DUX4 RNA and test a new hypothesis regarding transitions between RNA translational programs during myogenic differentiation. Together, these studies will advance our knowledge regarding the pathophysiology of FSHD and muscle cell biology.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Nuckolls, Glen H
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Fred Hutchinson Cancer Research Center
United States
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Balog, Judit; Goossens, Remko; Lemmers, Richard J L F et al. (2018) Monosomy 18p is a risk factor for facioscapulohumeral dystrophy. J Med Genet 55:469-478
Campbell, Amy E; Shadle, Sean C; Jagannathan, Sujatha et al. (2018) NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins. Elife 7:
Campbell, Amy E; Belleville, Andrea E; Resnick, Rebecca et al. (2018) Facioscapulohumeral dystrophy: activating an early embryonic transcriptional program in human skeletal muscle. Hum Mol Genet 27:R153-R162
Hendrickson, Peter G; Doráis, Jessie A; Grow, Edward J et al. (2017) Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nat Genet 49:925-934
Whiddon, Jennifer L; Langford, Ashlee T; Wong, Chao-Jen et al. (2017) Conservation and innovation in the DUX4-family gene network. Nat Genet 49:935-940
Campbell, Amy E; Oliva, Jonathan; Yates, Matthew P et al. (2017) BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells. Skelet Muscle 7:16
Shadle, Sean C; Zhong, Jun Wen; Campbell, Amy E et al. (2017) DUX4-induced dsRNA and MYC mRNA stabilization activate apoptotic pathways in human cell models of facioscapulohumeral dystrophy. PLoS Genet 13:e1006658
van den Boogaard, Marlinde L; Lemmers, Richard J F L; Camaño, Pilar et al. (2016) Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2. Eur J Hum Genet 24:78-85
Feng, Qing; Snider, Lauren; Jagannathan, Sujatha et al. (2015) A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy. Elife 4:
Balog, Judit; Thijssen, Peter E; Shadle, Sean et al. (2015) Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4. Epigenetics 10:1133-42

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