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).
|Iacovino, Michelina; Roth, Megan E; Kyba, Michael (2014) Rapid genetic modification of mouse embryonic stem cells by Inducible Cassette Exchange recombination. Methods Mol Biol 1101:339-51|
|Bosnakovski, Darko; Choi, Si Ho; Strasser, Jessica M et al. (2014) High-throughput screening identifies inhibitors of DUX4-induced myoblast toxicity. Skelet Muscle 4:4|
|Dandapat, Abhijit; Bosnakovski, Darko; Hartweck, Lynn M et al. (2014) Dominant lethal pathologies in male mice engineered to contain an X-linked DUX4 transgene. Cell Rep 8:1484-96|
|Chan, Sunny Sun-Kin; Shi, Xiaozhong; Toyama, Akira et al. (2013) Mesp1 patterns mesoderm into cardiac, hematopoietic, or skeletal myogenic progenitors in a context-dependent manner. Cell Stem Cell 12:587-601|
|Arpke, Robert W; Darabi, Radbod; Mader, Tara L et al. (2013) A new immuno-, dystrophin-deficient model, the NSG-mdx(4Cv) mouse, provides evidence for functional improvement following allogeneic satellite cell transplantation. Stem Cells 31:1611-20|
|Dandapat, Abhijit; Hartweck, Lynn M; Bosnakovski, Darko et al. (2013) Expression of the human FSHD-linked DUX4 gene induces neurogenesis during differentiation of murine embryonic stem cells. Stem Cells Dev 22:2440-8|
|Hartweck, Lynn M; Anderson, Lindsey J; Lemmers, Richard J et al. (2013) A focal domain of extreme demethylation within D4Z4 in FSHD2. Neurology 80:392-9|