Probing the Activity of DUX4 in FSHD

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): 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. However mechanistically, DUX4 is 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, and a pathological mechanism still eludes the field. The research proposed in this application addresses these issues by (1) probing the activity of cofactors of DUX4 in transcription, (2) investigating the ste cell compartment of skeletal muscle of FSHD patients, and (3) modeling DUX4 expression and D4Z4 regulation in mouse. 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 both an improved animal model and new therapeutic directions.