Facioscapulohumeral dystrophy (FSHD) is the third most common muscular dystrophy and is caused by the mis-expression in skeletal muscle of DUX4, a double homeobox transcription factor normally expressed in the germline. DUX4 activates the expression of many genes; however, the mechanisms by which DUX4 induces toxicity remain largely unknown. The broad and long-term goal of this proposal is to determine the mechanisms of DUX4-induced cellular toxicity in FSHD and develop animal models that can be used to accurately measure DUX4 expression and biological activity. The major hypothesis is that human DUX4 activates a conserved transcriptional pathway in humans and mice that includes induction of apoptosis, whereas a major portion of its transcriptional targets are not conserved across species and will require development of human-derived preclinical models. The significance is that these studies will determine the portion of DUX4-induced pathophysiology conserved in mice and establish a human-derived preclinical model for studying the primate-specific aspects of DUX4-induced pathophysiology.
The specific aims of the application are to:
(Aim 1) Determine the genes in human cells necessary for DUX4 to induce apoptosis and their mechanisms.
(Aim 2) Determine the conservation of the human DUX4 and mouse Dux transcriptional programs with special attention to the apoptotic pathway.
(Aim 3) Determine whether different methods of human muscle progenitor cell expansion improve the efficiency of xenotransplantation of FSHD muscle into mice, and the relative levels of DUX4, DUX4 targets, and apoptosis. Together these aims will determine the cause of DUX4 toxicity in human cells and the opportunities and limitations of studying these pathways in mouse cells, and develop a preclinical model of FSHD by improving the xenotransplantation of human muscle progenitor cells into mice. These advances will provide the basis for future therapeutic development and preclinical testing.

Public Health Relevance

The proposed research will determine the mechanisms of DUX4-induced toxicity and the portion of DUX4- induced toxicity conserved in mice. It will also establish a human-derived preclinical model for studying the primate-specific aspects of DUX4-induced pathophysiology. The health relevance of this research is that these studies provide the basis for developing therapeutic agents to treat FSHD.

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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Cheever, Thomas
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Fred Hutchinson Cancer Research Center
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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
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