REST/NRSF preserves muscle stem cell identity and survival by repressing alternate cell fates

Abstract

Cell fate and identity require timely activation of lineage-specific and concomitant repression of alternate-lineage genes. How this process is epigenetically encoded remains largely unknown. In skeletal muscle stem cells (MuSCs), the myogenic regulatory factors play key roles in sequential activation of the myogenic program, however, less is known about how suppression of alternate lineage genes contributes to this program. Here, we report that a significant number of non-lineage genes in MuSCs retain permissive chromatin marks yet are repressed transcriptionally. We show that the master epigenetic regulator, Repressor Element 1- Silencing Transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), plays a key role in the repression of these non-muscle lineage genes and developmentally regulated genes. MuSCs lacking functional REST exhibit an altered epigenetic and transcriptional signature and impaired self-renewal. Consequently, MuSCs progressively enter cell death by apoptosis and the stem cell pool undergoes depletion. Skeletal muscle lacking REST shows impaired regeneration and display myofiber atrophy. Collectively, our data suggests that REST plays a key role in safeguarding muscle stem cell identity and survival by repressing multiple non-muscle lineage and developmentally regulated genes in adult mice.