Developmental Cell
Volume 56, Issue 7, 5 April 2021, Pages 1014-1029.e7
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Article
Negative elongation factor regulates muscle progenitor expansion for efficient myofiber repair and stem cell pool repopulation

https://doi.org/10.1016/j.devcel.2021.02.025Get rights and content
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Highlights

  • Muscle progenitors are a major source of muscle stem cells on regenerated myofibers

  • Loss of NELF in regeneration causes muscle stem cell pool depletion

  • NELF transduces signals that modulate the expansion of the muscle progenitor population

  • NELF-mediated expansion of progenitors occurs through regulation of p53 activity

Summary

Negative elongation factor (NELF) is a critical transcriptional regulator that stabilizes paused RNA polymerase to permit rapid gene expression changes in response to environmental cues. Although NELF is essential for embryonic development, its role in adult stem cells remains unclear. In this study, through a muscle-stem-cell-specific deletion, we showed that NELF is required for efficient muscle regeneration and stem cell pool replenishment. In mechanistic studies using PRO-seq, single-cell trajectory analyses and myofiber cultures revealed that NELF works at a specific stage of regeneration whereby it modulates p53 signaling to permit massive expansion of muscle progenitors. Strikingly, transplantation experiments indicated that these progenitors are also necessary for stem cell pool repopulation, implying that they are able to return to quiescence. Thus, we identified a critical role for NELF in the expansion of muscle progenitors in response to injury and revealed that progenitors returning to quiescence are major contributors to the stem cell pool repopulation.

Keywords

muscle stem cells
muscle regeneration
stem cell niche
transcriptional regulation
NELF
p53 signaling
promoter proximal pausing
PEDF signaling
stem cell self-renewal
nascent transcript stability

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