The impact of TRF2 deletion on gene expression profile of muscle stem cells

Telomeric proteins are present in all mammalian cells protecting chromosomal ends and ensuring organismal homeostasis. However, it was also suggested that they have additional roles in certain tissues. Muscle stem cells (MuSCs), expressing a pivotal transcription factor Pax7, are fundamental to preserve regenerative capacity of muscle tissue. Yet, the cell autonomous mechanism that regulates Pax7 expression to maintain MuSC identity is unclear. Here, we uncover that the telomeric protein TRF2 is critical to sustain stem cell identity in adult muscles and is dynamically regulated upon injury. MuSC-specific TRF2 ablation in mice aggravates muscular dystrophy, mimicking closely the severity of the human disease. Mechanistically, TRF2 directly binds to the regulatory regions of Pax7 gene and affects its expression. These findings identify a unique non-telomeric TRF2 function essential for transcribing Pax7 gene, a master stem cell regulator of the myogenic lineage, to modulate cellular properties indispensable for stem cell maintenance.