Facioscapulohumeral muscular dystrophy (Facio-face; scapulo-scapula or shoulder blade; humeral-arm muscles around the humerus) or FSHD is an inherited muscle disorder characterized by the progressive weakening of specific muscle groups. It often has a subtle onset – a smile becomes harder to hold, reaching up to a high shelf takes more effort than expected. But over time, it can rob patients of muscle strength, mobility, and independence. There is currently no cure.
It took nearly two decades of incremental discoveries to establish DUX4 as the causative gene in FSHD. For many genetic diseases, the path from mutated protein to cellular dysfunction is clear and relatively direct, but the link between DUX4 expression and muscle degeneration was far from obvious.
DUX4 is a transcription factor, a protein that interacts with DNA to turn specific genes on or off, that acts in early embryonic development. During the critical four-cell to eight-cell stage in human embryos, DUX4 activates hundreds of genes to help establish early developmental programs. After this brief window, DUX4 expression is silenced in virtually all healthy tissues.
In FSHD this silence is broken and DUX4 protein is expressed in a small fraction of muscle cells, in sporadic bursts. This rare and short-lived presence of DUX4 is enough to cause progressive muscle loss and functional decline. The effects of DUX4 expression extend far beyond simply activating embryonic genes, disrupting fundamental processes like protein synthesis and DNA damage repair. The story of FSHD is layered and complex, and researchers are actively piecing together a more comprehensive understanding of how DUX4 causes widespread muscle damage.
A growing body of work points to an unexpected player in this story – RNA.
Cells contain vast amounts of RNA molecules that don’t code for proteins. These noncoding RNA molecules can fold into complex structures, interact with proteins, and form molecular machines that participate in or regulate essential cellular processes. But when noncoding RNA molecules accumulate in the wrong place or at the wrong time, they can become actively harmful.
Researchers from the Tapscott Lab in the Human Biology Division have extensively investigated DUX4 to better understand its roles in development and disease. They previously demonstrated that DUX4 expression causes the acccumulation of noncoding RNA in muscle nuclei, contributing to the cellular toxicity observed in FSHD. Specifically, DUX4 induces transcription of satellite RNA HSATII, a normally dormant noncoding genomic sequence. Satellite RNA molecules act as scaffolds that can bind and trap proteins and drive toxic protein aggregation if they accumulate inappropriately.
A recent study led by postdoctoral researcher Dr. Tessa Arends took a closer look at this RNA-driven protein aggregation to gain insight into the molecular mechanisms underlying FSHD. The team used a muscle cell line in which DUX4 expression could be precisely controlled to model FSHD in the lab then carefully isolated and identified the proteins that get tangled up with HSATII RNA.
They found that HSATII RNA accumulates in the nucleus and sequesters several proteins involved with RNA processing. One notable example is YBX-1, a protein that normally resides in the cytoplasm where it binds and stabilizes mRNA molecules required for muscle cell differentiation. Given its critical role in muscle development and regeneration, the sequestration of YBX-1 likely contributes to the progressive muscle loss observed in FSHD.
This work fundamentally reframes how DUX4 causes muscle toxicity in FSHD. Rather than treating protein aggregation as a passive byproduct of cellular stress, this research establishes satellite RNA as an active regulatory element in the cell. More broadly, this research draws a direct line from satellite RNA expression to the widespread disruption of RNA processing, affecting genes involved with the immune response, DNA damage repair, cell cycle regulation, and beyond. While prior studies had shown that satellite RNAs interact with regulatory proteins in cancer cell lines, Dr. Arends’ work is the first to comprehensively map endogenous HSATII RNA-protein interactions within a disease context. These findings suggest that satellite RNA can trigger oncogenic changes in cells, independent of the typical DNA mutations we usually associate with cancer.
By uncovering how satellite RNA actively disrupts essential cellular processes, these findings chart new paths for studying RNA biology and raises the possibility of therapeutically targeting satellite RNA to open new avenues for treating FSHD and even other diseases like cancer.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Member Dr. Stephen Tapscott contributed to this research.
The spotlighted research was funded by the National Institutes of Health and Friends of FSH Research.
Arends T, Bennett SR, Tapscott SJ. 2026. DUX4-induced HSATII RNA accumulation drives protein aggregation, impacting RNA processing pathways. Journal of Cell Biology. DOI: 10.1083/jcb.202501129
Science Spotlight writer Thamiya Vasanthakumar is a postdoctoral research fellow in the Campbell Lab at Fred Hutch. As a structural biologist, she uses cryogenic electron microscopy (cryoEM) to visualize the molecular structures of receptors found on the surface of immune cells.
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