FSHD affects over 25,000 individuals in the United States. It is the third most common muscular dystrophy by incidence but may be the most common by prevalence (Orphanet, 2008). The DNA lesion associated with this disease is a contraction within a series of 3.3 kb repeats (D4Z4 repeats) near the telomere of 4q. The contraction modifies the chromatin configuration of 4q35.2 which results in misexpression of a gene encoded within each D4Z4 repeat, DUX4. We have shown that DUX4 is cytotoxic when expressed at high levels in various cellular model systems, and interferes with myogenic gene expression when expressed at low levels in satellite cells and myoblasts, and have generated an animal model that recapitulates one key aspect of the human disease: muscle deterioration in the presence of barely-detectable DUX4 protein. However mechanistically, DUX4 is still not well understood, we do not have a clear picture of which cell types in muscle express DUX4 and what the consequence of that expression is, a pathological mechanism explaining muscle loss still eludes the field, and we suffer from a dearth of specific therapies for FSHD. The research proposed in this application addresses these issues by (1) probing the mechanism of DUX4-mediated transcription, including studying inhibitors of that transcription (2) investigating the effects of inhibiting the p300 pathway genetically and pharmacologically in the mouse model, and (3) studying DUX4 expression in primary cells from FSHD patients. This research will address key outstanding questions in FSHD, will advance a mechanistic understanding of DUX4 in FSHD at the molecular, cellular, and tissue levels, and may lead to new therapeutic directions.
Summary Facioscapulohumeral muscular dystrophy (FSHD) a genetically dominant progressive muscular dystrophy associated with inappropriate expression of the DUX4 gene. This application focuses on understanding how DUX4 functions and how it perturbs cells, on investigating mechanisms of disease in human cells, and on testing a new therapeutic intervention in a new DUX4-based animal model. This work thus helps us understand the disease and also has the potential to lead to therapies for FSHD based in inhibiting DUX4 activity.
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