New Insights into MYOD: The Dual Role of a Muscle Regulator as a Gene Silencer

August 11, 2025 – Researchers at Sanford-Burnham Prebys have uncovered a surprising new role for MYOD, a well-known protein critical for muscle development and regeneration. Traditionally recognized as a master activator that binds to DNA at E-box motifs to promote muscle gene expression, MYOD has now been discovered to possess a versatile, dual function. Recent studies show that MYOD can also act as a gene silencer, binding to non-E-box DNA regions to suppress the expression of genes related to cell growth, proliferation, and lineage identity.

For over three decades, scientists have examined how MYOD reprograms muscle stem cells, effectively turning them into muscle fibers by remodeling gene expression patterns. While its role as a activator activating muscle-specific genes is well established, this new research reveals that MYOD can simultaneously bind to regions of DNA associated with the cell's original lineage, removing prior gene expression programs to reset cellular identity. This process of gene repression is essential for cellular reprogramming and differentiation.

The team’s experiments, involving human fibroblasts during reprogramming into skeletal muscle cells, demonstrated that approximately one-third of MYOD's binding events occurred at traditional activation sites, while over half targeted DNA regions that downregulate previous gene activity. These findings challenge the conventional understanding that MYOD's DNA binding is restricted to E-box motifs, suggesting a more complex and promiscuous DNA-binding behavior.

"Our findings indicate that MYOD has a much broader role in gene regulation than previously thought," says Pier Lorenzo Puri, MD, senior author of the study. "It can act like a molecular eraser, removing outdated gene expression patterns before establishing new muscle-specific programs."

Furthermore, the research shows that MYOD’s ability to repress non-lineage genes plays a vital role in cell reprogramming, contributing to muscle regeneration and potentially informing regenerative medicine therapies. The team observed this behavior not only in cell culture but also validated it in mouse models of muscle injury, emphasizing its relevance in physiological conditions.

Understanding MYOD’s dual function opens new avenues for therapeutic interventions. For instance, better grasping how MYOD regulates gene silencing could lead to more effective strategies for treating muscle degenerative diseases like muscular dystrophy and age-related sarcopenia. Researchers are also exploring how incomplete repression by MYOD may contribute to the variable recovery capacity seen in aging athletes and patients.

Overall, this study broadens the perception of transcription factors, highlighting their versatility in gene regulation. The insights gained could accelerate regenerative medicine approaches, aiming to convert one cell type into another or to correct pathological cell states by manipulating gene expression programs.

Source: https://medicalxpress.com/news/2025-08-muscle-master-moonlights-gene-silencer.html