TRF2 couples muscle stem cell identity to regenerative repair.

Abstract

Stem cell-mediated regeneration is essential for tissue integrity. In skeletal muscle, tissue repair largely depends on muscle stem cells (MuSCs), which undergo dynamic cell-state transitions through making precise fate decisions during regeneration. However, the molecular regulators of cell-state conversion in MuSCs remain unclear. Here, we identify a previously unrecognized, noncanonical role for TRF2 in MuSC biology. TRF2 is dynamically regulated upon injury and required to preserve stem cell identity, support reparative myogenesis, and sustain self-renewal. MuSC-specific TRF2 disruption exacerbates muscular dystrophy pathology in mice, recapitulating key features of human disease. Mechanistically, TRF2 associates with regulatory regions enriched for DNA G-quadruplex-forming sequences at lineage-specific genes, sustaining their expression. These findings establish TRF2 as a pivotal regulator of adult stem cell function and tissue-specific regenerative responses.