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Dr. Kyba will insert D4Z4 repeats into the mouse genome in ES at a site on the X-chromosome, known to enable tissue-specific expression of transgenes, and to tolerate dominant lethal genes. He will study whether the presence of these repeats affects differentiation of the ES cells, and will produce mice bearing D4Z4 repeats, as a potential animal model for FSHD.
What are the researchers aiming to do?
Dr. Kyba has proposed the “stem cell hypothesis” for FSHD. This postulates that muscle stem cells in FSHD are impaired due to interference with an important stem cell-specific gene, known as Pax7. Dr. Kyba’s team has shown that a gene embedded within the D4Z4 repeats, named DUX4, has the ability to interfere with the ability of Pax7 to control muscle regeneration-specific genes. They propose to create a mouse bearing D4Z4 repeats on the X-chromosome as an animal model for FSHD, and to use this model to test the stem cell hypothesis by evaluating muscle stem cells for frequency and function in these mice.
How will the outcomes of the research benefit patients?
An appropriate animal model is critical before therapeutic interventions can be tested. The success of this research program would enable therapies for FSHD to be tested.
Dr. Kyba’s team has shown that DUX4, the gene encoded by the D4Z4 repeats, encodes a protein which has different effects depending on levels at which it is produced in cells. At high levels, it renders cells hypersensitive to stress pathways, particular oxidative stress. At low levels, it interferes with muscle regeneration-specific gene expression, particularly by repressing an key gene known as MyoD. Dr. Kyba’s team has shown that the muscle stem cell regulator, Pax7, competes with DUX4 for regulation of muscle-specific genes, as well as for toxicity. These results led to the stem cell hypothesis, described above