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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Yao, Zizhen; Snider, Lauren; Balog, Judit et al. (2014) DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle. Hum Mol Genet 23:5342-52
Krom, Yvonne D; Thijssen, Peter E; Young, Janet M et al. (2013) Intrinsic epigenetic regulation of the D4Z4 macrosatellite repeat in a transgenic mouse model for FSHD. PLoS Genet 9:e1003415
Sacconi, Sabrina; Lemmers, Richard J L F; Balog, Judit et al. (2013) The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet 93:744-51
Geng, Linda N; Yao, Zizhen; Snider, Lauren et al. (2012) DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell 22:38-51
van der Maarel, Silvere M; Tawil, Rabi; Tapscott, Stephen J (2011) Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends Mol Med 17:252-8
Geng, Linda N; Tyler, Ashlee E; Tapscott, Stephen J (2011) Immunodetection of human double homeobox 4. Hybridoma (Larchmt) 30:125-30
Cao, Yi; Yao, Zizhen; Sarkar, Deepayan et al. (2010) Genome-wide MyoD binding in skeletal muscle cells: a potential for broad cellular reprogramming. Dev Cell 18:662-74
Diede, Scott J; Guenthoer, Jamie; Geng, Linda N et al. (2010) DNA methylation of developmental genes in pediatric medulloblastomas identified by denaturation analysis of methylation differences. Proc Natl Acad Sci U S A 107:234-9
Snider, Lauren; Geng, Linda N; Lemmers, Richard J L F et al. (2010) Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet 6:e1001181
Snider, Lauren; Asawachaicharn, Amy; Tyler, Ashlee E et al. (2009) RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy. Hum Mol Genet 18:2414-30

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