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

Korin Sahinyan, Darren M. Blackburn, Marie-Michelle Simon, Felicia Lazure, Tony Kwan, David H. Wilson, Maryam Vahidyeganeh, Nawal Alsadi, Julia Maltzahn, Yasuhiro Yamada, Arezu Jahani-Asl, Guillaume Bourque, Michael A. Rudnicki and Vahab D. Soleimani ()
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Korin Sahinyan: 3640 rue University
Darren M. Blackburn: 451 Smyth Rd
Marie-Michelle Simon: 3640 rue University
Felicia Lazure: 3640 rue University
Tony Kwan: 3640 rue University
David H. Wilson: Edinburgh EH16 4UU
Maryam Vahidyeganeh: 451 Smyth Rd
Nawal Alsadi: 451 Smyth Rd
Julia Maltzahn: Universitätsplatz 1
Yasuhiro Yamada: 7-3-1 Hongo
Arezu Jahani-Asl: University of Ottawa
Guillaume Bourque: 3640 rue University
Michael A. Rudnicki: University of Ottawa
Vahab D. Soleimani: 3640 rue University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62758-y

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