Posted by Friends of FSH Research on Nov 25, 2019
Investigator: Danielle C Hamm PhD
Mentor: Stephen J Tapscott MD PhD
The causal gene of FSHD is DUX4, found embedded within the D4Z4 repeat array. Failure to maintain chromatin-mediated repression of the D4Z4 array in skeletal muscle results in toxic DUX4 expression. The objective of this proposed research is to identify how DUX4 mis-expression in skeletal muscle alters the chromatin landscape and gene expression, and how these changes contribute to FSHD pathology.
In the first six months of our funding period, we have published data showing that DUX4-induced histone protein variants, H3.X and H3.Y, are incorporated into regions of the genome activated by DUX4 and promote the DUX4 network in FSHD muscle (Resnick, R. et al. Cell Rep. 29, 1812-1820.e5 (2019)). We have also characterized the downstream effects of DUX4-induced expression of a histone demethylase enzyme. We find that DUX4 activation of this enzyme in muscle cells catalyzes the removal of repressive histone modifications and results in modest changes in gene expression. Future work will focus on identifying where in the genome DUX4-induced histone demethylases act and investigating their role in regulating the D4Z4 array in FSHD cells.
Note that the Wellstone co-funds this grant.