Progress Update: DUX4-induced mechanisms contributing to FSHD pathogenesis

Posted by Friends of FSH Research on May 28, 2021

Report from Dr. Danielle C Hamm
Mentor: Stephen J. Tapscott, MD, PhD
See grant DUX4-induced mechanisms contributing to FSHD pathogenesis

FSHD is caused by the aberrant production of the double homeobox protein 4 (DUX4) transcription factor in skeletal muscle. However, DUX4 is difficult to find in FSHD muscle biopsy and myoblast cell cultures as it exists at extremely low levels and appears sporadically. The DUX4 gene is classically expressed in the human embryo, where it activates many cellular programs necessary for early development. A major question in the FSHD research field is how brief expression of the embryonic gene DUX4 in FSHD muscle – turned on in the wrong place at the wrong time – result in cellular toxicity and eventually muscle cell death. My research has identified multiple cellular functions that are altered by DUX4, and I find that this dysfunction persists in the cell long after DUX4 itself disappears. During the current funding period, I have worked to identify exactly how a short burst of DUX4 rearranges the DNA structure, induces unique RNA molecules, and changes the protein repertoire of the cell on a genome-wide level. These data support our view that transient DUX4 expression promotes a more naïve cellular state, characteristic of the early embryo, that is detrimental to muscle cells. Understanding what happens to cells after they express DUX4, what toxic cellular pathways are set into motion, and identifying how we might turn these pathways off, is instrumental in helping us understand the basic biology of FSHD.