Regulation of NSL by TAF4A is critical for genome stability and quiescence of muscle stem cells

Angelina M. Georgieva, Krishna Sreenivasan, Dong Ding, Clementine Villeneuve, Sara A. Wickström, Stefan Günther, Carsten Kuenne, Ulrich Gärtner, Xinyue Guo, Yonggang Zhou, Xuejun Yuan () and Thomas Braun ()
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Angelina M. Georgieva: Max Planck Institute for Heart and Lung Research
Krishna Sreenivasan: Max Planck Institute for Heart and Lung Research
Dong Ding: Max Planck Institute for Heart and Lung Research
Clementine Villeneuve: Max Planck Institute for Molecular Biomedicine
Sara A. Wickström: Max Planck Institute for Molecular Biomedicine
Stefan Günther: Max Planck Institute for Heart and Lung Research
Carsten Kuenne: Max Planck Institute for Heart and Lung Research
Ulrich Gärtner: University of Giessen
Xinyue Guo: Max Planck Institute for Heart and Lung Research
Yonggang Zhou: Max Planck Institute for Heart and Lung Research
Xuejun Yuan: Max Planck Institute for Heart and Lung Research
Thomas Braun: Max Planck Institute for Heart and Lung Research

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

Abstract: Abstract Acetylation of lamin A/C by the non-specific lethal complex, containing MOF and KANSL2, is instrumental for maintaining nuclear architecture and genome stability, but the mechanisms controlling expression of its components in different cell types are poorly characterized. Here, we show that TAF4A, primarily known as a subunit of TFIID, forms a complex with the heterotrimeric transcription factor NF-Y and is critical for cell type-specific regulation of Kansl2 in muscle stem cells. Inactivation of Taf4a reduces expression of Kansl2 and alters post-translational modification of lamin A/C, thereby decreasing nuclear stiffness, which disrupts the nuclear architecture and results in severe genomic instability. Reduced expression of Kansl2 in Taf4a-mutant muscle stem cells changes expression of numerous genes involved in chromatin regulation. The subsequent loss of heterochromatin, in combination with pronounced genomic instability, activates muscle stem cells but impairs their proliferation, which depletes the stem cell pool and abolishes skeletal muscle regeneration. We conclude that TAF4A-NF-Y-dependent transcription regulation safeguards heterochromatin and genome stability of muscle stem cells via the non-specific lethal complex.

Date: 2025
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DOI: 10.1038/s41467-025-64402-1

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