DUX4-induced mechanisms contributing to FSHD pathogenesis

Investigators: Danielle C Hamm PhD, Stephen Tapscott MD PhD

Category: Research - Basic

Mentor: Stephen J Tapscott, MD, PhD

In coordination with the Wellstone Muscular Dystrophy Cooperative Research Center for research in Seattle, Friends is providing co-funding for a one-year fellowship.

The causal gene of facioscapulohumeral muscular dystrophy (FSHD) is DUX4, found embedded within the D4Z4 repeat array. DUX4 is active during early development and is epigenetically silenced in healthy somatic tissues. Failure to maintain repression of the D4Z4 array in skeletal muscle results in toxic DUX4 expression, which turns on genes associated with early embryonic development in the wrong place at the wrong time.

It took nearly two decades from mapping the FSHD locus to identifying DUX4 as the causative gene for FSHD, and only recently has DUX4 been recognized to have a role in development. This begs the question as to why the identification of DUX4 was so elusive. DUX4 is difficult to detect and exists at very low levels in both development and disease. Given the nature of DUX4 expression, the robustness and longevity of cellular responses triggered by DUX4 are quite remarkable. I hypothesize that brief expression of DUX4 initiates long lived regulatory factors that contribute to FSHD pathogenicity.

We recently discovered multiple avenues by which DUX4 acts to alter gene expression and normal cellular function when mis-expressed in muscle, including changes to the chromatin landscape and the localization of RNAs and proteins within the cell. However, the intermediate regulators downstream of DUX4 remain unknown. I plan to identify the factors activated by DUX4 that are responsible for these events and how they contribute to cell toxicity. My approach uses experiments in cell models of DUX4 expression and patient derived FSHD cells. Through a better understanding of the role DUX4 plays in disrupting cellular function in FSHD, we may reveal novel diagnostic and therapeutic targets.

Note: Grant recipient's support was transferred to an NRSA Individual Postdoctoral Fellowship (F32 grant) near the end of the grant term, so original grant for $60,830 was reduced by $7850.84.