Sahinyan Korin, Blackburn Darren M, Simon Marie-Michelle, Lazure Felicia, Kwan Tony, Wilson David H, Vahidyeganeh Maryam, Alsadi Nawal, von Maltzahn Julia, Yamada Yasuhiro, Jahani-Asl Arezu, Bourque Guillaume, Rudnicki Michael A, Soleimani Vahab D
Department of Human Genetics, McGill University, 3640 rue University, Montréal, QC, Canada.
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chem. de la Côte-Sainte-Catherine, Montréal, QC, Canada.
Nat Commun. 2025 Aug 12;16(1):7487. doi: 10.1038/s41467-025-62758-y.
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, the myogenic regulatory factors are well-established drivers of muscle gene activation but less is known about how non-muscle gene repression is achieved. Here, we show that the master epigenetic regulator, Repressor Element 1-Silencing Transcription factor (REST), also known as Neuron-Restrictive Silencer Factor (NRSF), is a key regulator of this process. We show that many non-lineage genes retain permissive chromatin state but are actively repressed by REST. Loss of functional REST in muscle stem cells and progenitors disrupts muscle specific epigenetic and transcriptional signatures, impairs differentiation, and triggers apoptosis in progenitor cells, leading to depletion of the stem cell pool. Consequently, REST-deficient skeletal muscle exhibits impaired regeneration and reduced myofiber growth postnatally. Collectively, our data suggests that REST plays a key role in safeguarding muscle stem cell identity by repressing multiple non-muscle lineage and developmentally regulated genes in adult mice.
细胞命运和特性需要谱系特异性基因的及时激活以及对其他谱系基因的同步抑制。这个过程如何通过表观遗传学编码在很大程度上仍然未知。在骨骼肌干细胞中，成肌调节因子是肌肉基因激活的公认驱动因素，但对于如何实现非肌肉基因的抑制了解较少。在这里，我们表明主要的表观遗传调节因子，即抑制元件1沉默转录因子（REST），也称为神经元限制性沉默因子（NRSF），是这一过程的关键调节因子。我们发现许多非谱系基因保持着允许的染色质状态，但被REST积极抑制。肌肉干细胞和祖细胞中功能性REST的缺失会破坏肌肉特异性表观遗传和转录特征，损害分化，并触发祖细胞凋亡，导致干细胞池的耗竭。因此，缺乏REST的骨骼肌在出生后表现出再生受损和肌纤维生长减少。总的来说，我们的数据表明，REST通过抑制成年小鼠中的多个非肌肉谱系和发育调控基因，在维护肌肉干细胞特性方面发挥关键作用。
