REST/NRSF Preserves muscle stem cell identity by repressing alternate cell fate

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.

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Publication Details

Journal
Nature Communications
Published
2025-08-12
DOI
https://doi.org/10.1038/s41467-025-62758-y
Citations
3
Primary Topic
Muscle Physiology and Disorders
Type
article
Field-Weighted Citation Impact
2.42

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article

REST/NRSF Preserves muscle stem cell identity by repressing alternate cell fate

Julia von Maltzahn, David H. Wilson, Maryam Vahidyeganeh, Vahab D. Soleimani et al.
3 citations
Nature Communications
Muscle Physiology and Disorders
2.42
article

REST/NRSF Preserves muscle stem cell identity by repressing alternate cell fate

Julia von Maltzahn, David H. Wilson, Maryam Vahidyeganeh, Vahab D. Soleimani, Felicia Lazure, Tony Kwan, Guillaume Bourque, Michael A. Rudnicki, Arezu Jahani‐Asl, Darren M. Blackburn, Yasuhiro Yamada, Korin Sahinyan, Nawal Alsadi, Marie-Michelle Simon
article en
3 citations

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, 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.

Nature CommunicationsVol. 16(1)
University of Ottawa (CA), Ottawa Hospital (CA), Jewish General Hospital (CA), Ontario Genomics (CA), MIND Research Institute (US), MRC Centre for Regenerative Medicine (GB), McGill Genome Centre (CA), Ottawa Hospital Research Institute (CA), McGill University (CA), Brandenburg University of Technology Cottbus-Senftenberg (DE), The University of Tokyo (JP), Ottawa University (US)
University of Ottawa, McGill University, Stem Cell Network, National Institutes of Health, Canadian Institutes of Health Research, Lady Davis Institute for Medical Research
Openalex Percentile: Top 11%
Muscle Physiology and Disorders
2.42
DOIOpen Access PDFOpenAlex
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