Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant progressive muscular dystrophy affecting approximately 1/20,000 individuals. Although the disease is caused by a deletion of repeated sequence on chromosome 4, which is thought to inappropriately activate nearby genes, the identity of the key causative gene is unknown and mechanisms relating genes in the area to muscle pathology are unknown. There is currently no effective treatment for FSHD. We have screened candidate genes from the FSHD region of chromosome 4 in a cell culture system, and identified a gene (the double-homeodomain transcription factor, DUX4, which is embedded within the D4Z4 repeats on chromosome 4) with extreme toxicity to myoblasts. Using an inducible gene expression system, we show that expression of DUX4 causes changes in expression of a set of genes previously identified in microarray and proteomic studies as specifically misregulated in FHSD, including elements of stress response pathways, and the transcription factor MyoD. We further show that these responses involve competition with Pax7, a transcription factor at the apex of the myogenic hierarchy with a highly related homeodomain. We propose to investigate the molecular pathways downstream of DUX4 and identify genes relevant to muscle regeneration that are oppositely regulated by DUX4 and Pax7 (Aim 1), to generate novel cell and mouse models for FSHD based on expression of patient-derived D4Z4/DUX4 sequences (Aim 2), and to test the hypothesis that the stem or progenitor cell compartments of muscle are specifically affected by DUX4 in FSHD (Aim 3).
Facioscapulohumeral muscular dystrophy (FSHD) a genetically dominant progressive muscular dystrophy associated with a deletion of repetitive sequences on chromosome 4. This deletion is thought to deregulate nearby genes and we have shown that one of the genes associated with this deletion, DUX4, causes myoblasts to become sensitive to oxidative stress, and interferes with myogenic pathways by competing with the muscle stem cell master regulator, Pax7. We propose to investigate the molecular pathways downstream of DUX4 and identify genes relevant to muscle regeneration that are oppositely regulated by DUX4 and Pax7 (Aim 1), to generate a mouse model for FSHD based on expression of patient-derived D4Z4/DUX4 sequences (Aim 2), and to test the hypothesis that the stem or progenitor cell compartments of muscle are specifically affected by DUX4 in FSHD (Aim 3).
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|Bosnakovski, Darko; Gearhart, Micah D; Toso, Erik A et al. (2017) p53-independent DUX4 pathology in cell and animal models of facioscapulohumeral muscular dystrophy. Dis Model Mech 10:1211-1216|
|Arpke, Robert W; Kyba, Michael (2016) Flow Cytometry and Transplantation-Based Quantitative Assays for Satellite Cell Self-Renewal and Differentiation. Methods Mol Biol 1460:163-79|
|Choi, Si Ho; Gearhart, Micah D; Cui, Ziyou et al. (2016) DUX4 recruits p300/CBP through its C-terminus and induces global H3K27 acetylation changes. Nucleic Acids Res 44:5161-73|
|Choi, Si Ho; Bosnakovski, Darko; Strasser, Jessica M et al. (2016) Transcriptional Inhibitors Identified in a 160,000-Compound Small-Molecule DUX4 Viability Screen. J Biomol Screen 21:680-8|
|Zhang, Yu; Lee, John K; Toso, Erik A et al. (2016) DNA-binding sequence specificity of DUX4. Skelet Muscle 6:8|
|Le, Gengyun; Lowe, Dawn A; Kyba, Michael (2016) Freeze Injury of the Tibialis Anterior Muscle. Methods Mol Biol 1460:33-41|
|Dandapat, Abhijit; Perrin, Benjamin J; Cabelka, Christine et al. (2016) High Frequency Hearing Loss and Hyperactivity in DUX4 Transgenic Mice. PLoS One 11:e0151467|
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|Filareto, Antonio; Rinaldi, Fabrizio; Arpke, Robert W et al. (2015) Pax3-induced expansion enables the genetic correction of dystrophic satellite cells. Skelet Muscle 5:36|
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