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Updated: Sep 1, 2025
Author Spotlight: Investigating mRNA Spatial Distribution in Drosophila Muscle Tissue
Published on: September 8, 2023
Prolonged FOS activity disrupts a global myogenic transcriptional program by altering 3D chromatin architecture in
A Rasim Barutcu1,2, Gabriel Elizalde3,4, Alfredo E Gonzalez1
1Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Background:
The AP-1 transcription factor, FBJ osteosarcoma oncogene (FOS), is induced in adult muscle satellite cells (SCs) within hours following muscle damage and is required for effective stem cell activation and muscle repair. However, why FOS is rapidly downregulated before SCs enter cell cycle as progenitor cells (i.e., transiently expressed) remains unclear. Further, whether boosting FOS levels in the proliferating progeny of SCs can enhance their myogenic properties needs further evaluation.
Methods:
We established an inducible, FOS expression system to evaluate the impact of persistent FOS activity in muscle progenitor cells ex vivo. We performed various assays to measure cellular proliferation and differentiation, as well as uncover changes in RNA levels and three-dimensional (3D) chromatin interactions.
Results:
Persistent FOS activity in primary muscle progenitor cells severely antagonizes their ability to differentiate and form myotubes within the first 2 weeks in culture. RNA-seq analysis revealed that ectopic FOS activity in muscle progenitor cells suppressed a global pro-myogenic transcriptional program, while activating a stress-induced, mitogen-activated protein kinase (MAPK) transcriptional signature. Additionally, we observed various FOS-dependent, chromosomal re-organization events in A/B compartments, topologically associated domains (TADs), and genomic loops near FOS-regulated genes.
Conclusions:
Our results suggest that elevated FOS activity in recently activated muscle progenitor cells perturbs cellular differentiation by altering the 3D chromosome organization near critical pro-myogenic genes. This work highlights the crucial importance of tightly controlling FOS expression in the muscle lineage and suggests that in states of chronic stress or disease, persistent FOS activity in muscle precursor cells may disrupt the muscle-forming process.
Insights
Transient FOS expression is crucial for muscle stem cell activation and repair. Persistent FOS activity in muscle progenitor cells impairs differentiation and disrupts 3D chromatin organization, hindering muscle formation.
Area of Science:
- Muscle stem cell biology
- Transcriptional regulation
- Epigenetics and chromatin dynamics
Background:
- The AP-1 transcription factor, FBJ osteosarcoma oncogene (FOS), is rapidly induced in adult muscle satellite cells (SCs) after injury, essential for stem cell activation and muscle repair.
- The precise reasons for FOS's transient expression and downregulation before SCs enter the cell cycle remain unclear.
- The potential benefits of sustained FOS levels in SC progeny for enhancing muscle-forming capacity require investigation.
Purpose of the Study:
- To investigate the impact of persistent FOS activity on muscle progenitor cell differentiation and myogenic properties.
- To elucidate the molecular mechanisms underlying FOS's role in muscle repair, including transcriptional and epigenetic alterations.
Main Methods:
- Establishment of an inducible FOS expression system for evaluating sustained FOS activity in muscle progenitor cells ex vivo.
- Comprehensive analysis of cellular proliferation and differentiation.
- RNA sequencing (RNA-seq) to assess global gene expression changes.
- Three-dimensional (3D) chromatin interaction assays to map chromosomal organization.
Main Results:
- Sustained FOS activity in muscle progenitor cells significantly inhibited their differentiation and myotube formation capacity.
- RNA-seq revealed suppression of pro-myogenic gene programs and activation of stress-induced MAPK signaling pathways.
- Observed FOS-dependent alterations in 3D chromatin organization, including changes in A/B compartments, TADs, and genomic loops near key genes.
Conclusions:
- Elevated FOS activity in muscle progenitor cells disrupts differentiation by altering 3D chromatin organization near pro-myogenic genes.
- Tight regulation of FOS expression is critical for maintaining the muscle lineage.
- Chronic FOS activity in muscle precursor cells during stress or disease may impair muscle regeneration.
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