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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045203-18
Application #
9403153
Study Section
Skeletal Muscle Biology and Exercise Physiology Study Section (SMEP)
Program Officer
Cheever, Thomas
Project Start
1998-09-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
18
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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
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
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
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
Lemmers, Richard J L F; Goeman, Jelle J; van der Vliet, Patrick J et al. (2015) Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2. Hum Mol Genet 24:659-69
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
Young, Janet M; Whiddon, Jennifer L; Yao, Zizhen et al. (2013) DUX4 binding to retroelements creates promoters that are active in FSHD muscle and testis. PLoS Genet 9:e1003947

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