Posted by Amanda Rickard on Jul 26, 2019
Dr. Danielle Hamm is a Postdoctoral Fellow studying FSHD in Dr. Stephen Tapscott’s lab (https://research.fhcrc.org/tapscott/en.html) at the Fred Hutchison Cancer Research Center, and the recipient of the FSH Fellowship award co-sponsored by Friends of FSH Research and the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center (http://depts.washington.edu/mdcrc/). Her project is titled “Analysis of histone demethylases as candidate targets for FSHD therapeutics.” We interviewed Dr. Hamm to learn more about her exciting work and plans for her Fellowship.
Why did you decide to study FSHD during your postdoctoral fellowship?
While earning my PhD, I studied the biology of how genes are first turned on in the very earliest stages of embryo development. Many genes that are critical for the growth and development of a living thing are active in the embryo, then go silent for the remainder of life. Through my research, I became interested in one such gene: DUX4. When the human embryo exists early on as just 4 cells, DUX4 turns on and activates hundreds of other genes necessary for development. However, long before its role in the embryo was discovered, DUX4 was identified to be the gene that causes FSHD. As I learned about the role of DUX4 in FSHD, I was interested in studying the biology of the disease, and particularly asking: Why is this important factor—DUX4—that is normally needed in the early embryo, so toxic when present in muscle?
What about the Tapscott Lab do you find most interesting/exciting?
I chose to do a postdoc in the Tapscott lab to broaden my training and research experience. I am most excited about Stephen’s focus on interdisciplinary research in both development and disease. In his lab, I aim to investigate the cause and consequence of developmental programs being switched back on in FSHD muscle. By approaching mechanisms underlying disease as aspects of embryo development gone awry, we can gain insight into disease.
What will be the focus of your project?
I am interested in how the disease-causing gene DUX4 itself is only turned on in a very low number of FSHD cells, roughly 1 in 1000, yet it is so toxic to the muscle. The focus of my project is to identify how brief DUX4 activity induces lasting cellular responses. DUX4 turns on hundreds of genes, some of which make proteins that change how the DNA is packaged within a cell.
Why is it important to study changes in DNA structure in FSHD cells?
A single cell contains two meters of DNA that forms a complex with protein partners to help package it tightly into such a tiny space. This DNA-protein complex is referred to as chromatin. Cells package their DNA into chromatin not only to compact it, but also to control its use. In FSHD muscle, DUX4 turns on proteins that change DNA compaction. We believe these enzymes open up the chromatin, allowing for genes that are normally closed and off to now be used. Therefore, it is important to study how the DNA structure is changing in response to DUX4 in order to understand how other genes are mis-regulated in FSHD.
What are the most significant challenges that you anticipate?
A significant challenge lies in prioritizing the many exciting research avenues and opportunities facing us. The biology of FSHD is very complex, making it difficult to distill which of the many activities of DUX4 are the most important to focus on to best treat the disease. Many unknowns still remain about the fundamental mechanisms causing FSHD, underscoring the need for further biochemical and molecular investigation of DUX4 function.
How could your work support FSHD therapy development?
If our hypothesis implicating chromatin changes in FSHD is correct, it will inform future work to find potential therapies that affect these proteins and test their effectiveness in FSHD muscle. Understanding the mechanisms downstream of DUX4 that induce changes in the DNA structure and result in gene mis-regulation may provide new strategies for effective FSHD therapeutics.
You can read more about Dr. Hamm in her researcher bio (https://research.fhcrc.org/tapscott/en.html)and in the summary of her Fellowship Grant (http://www.fshfriends.org/research/grant-history/wellstone-fshd-fellowship). Keep an eye on our site for updates!