Investigators: Danielle C Hamm PhD, Stephen Tapscott MD PhD
Category: Research - Basic
Fellowship project: Analysis of histone demethylases as candidate targets for FSHD therapeutics
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 Facioscapulaohumeral muscular dystrophy (FSHD)—DUX4—is found embedded within the D4Z4 macrosatellite repeat array. Failure to maintain repression of the D4Z4 array in skeletal muscle results in toxic DUX4 expression. DUX4 is repressed, in part, through chemical modifications to histone proteins that aid in compacting DNA to silence the underlying genes. We discovered that DUX4 activates several histone modifying enzymes, resulting in a global loss of repressive histone signatures. Repressive histone modifications are reduced in FSHD specifically at the D4Z4 region. Inhibition of the downstream toxic cellular response elicited by DUX4 in FSHD muscle or repression of DUX4 from the D4Z4 array offer promising avenues of therapeutic intervention. Focusing on these two approaches, I propose to characterize the effect of DUX4-induced expression of histone modifying enzymes, as this may represent a novel mechanism by which DUX4 drives transcriptional competence; and to investigate these enzymes as candidate targets to reestablish repression of DUX4 at the D4Z4 array in FSHD.
In addition to her research project, Dr. Hamm will participate in the ethics training programs required for all postdocs at the FHCRC. In addition, she will attend the many lectures and seminars at the FHCRC and UW in topics related to her work and to muscular dystrophies. She will attend the Wellstone research conferences and present her work to the group as well. She will attend an appropriate national scientific meeting to present a poster of her work or give a platform presentation. Her mentor, Dr. Stephen Tapscott, will provide regular evaluation of her work and feedback on her experimental design and data analysis.