Progress Update: Regulation and activity of the DUX4 transcription factor

Submitted by Dr. Stephen Tapscott

See Grant Regulation and activity of the DUX4 transcription factor

Note that the Chris Carrino Foundation shares in funding this multi-year grant.

This award supports four areas of FSHD research. It supports studies of muscle biopsies from FSHD individuals that identify the gene expression signatures that distinguish FSHD muscle from unaffected muscle. These studies are leading to a better understanding of why the muscles might function relatively normally in early life and then loose strength at later times. Not only will this help to plan clinical trials for FSHD, but it also will inform treatment strategies for preventing the progression of muscle weakness. These studies led to the discovery that the complement system, a primitive component of the immune system, is activated early in FSHD muscle, and complement components in the blood are being investigated as a possible serum biomarker of FSHD disease activity. The award also supports research to determine where DUX4 is normally expressed. This study uses a mouse model with a reporter gene that will mark cells expressing the mouse Dux, the mouse version of DUX4, and newly produced antibodies to mouse Dux. After determining where the mouse version of DUX4 is expressed, we can then look at human tissues for similar expression of the human DUX4. This award also supports studies that will determine how DUX4 is turned off by a set of compounds previously identified in screens for drug-like compounds to treat FSHD. Each compound acts through a different pathway but it is unknown how these separate pathways relate to each other. Understanding whether and where these pathways interact to regulate DUX4 expression might yield new and more effective therapies for FSHD. The final project focuses on a set of proteins that disappear when DUX4 is expressed. These proteins normally regulate how the immune system is activated and we want to know whether the loss of these proteins contributes to the disease progression in FSHD, which would potentially be a new target for developing drugs to treat FSHD.