Regulation of the NSL complex by TAF4A is critical for genome stability and quiescence of skeletal muscle stem cells [CnR of NF-YA in WT and Taf4asKO MuSCs]

Acetylation of lamin A/C by the NSL complex, containing MOF and KANSL2, is instrumental for maintaining nuclear architecture and genome stability, but the mechanisms controlling expression of NSL complex components in different cell types are poorly characterized. Here, we describe that TAF4A, primarily known as a subunit of the general transcription factor TFIID, is critical for cell type-specific regulation of Kansl2 in MuSCs. Inactivation of Taf4a in MuSCs reduces expression of Kansl2 and alters post-translational modification of lamin A/C, thereby decreasing the stiffness of MuSC nuclei and disrupting the nuclear architecture. Using CUT&RUN technique, we found that TAF4A together with the heterotrimeric transcription factor NF-Y controls Kansl2 expression. In addition to destabilization of the nuclear architecture, reduced expression of Kansl2 in Taf4a-mutant MuSCs changes expression of numerous genes involved in chromatin regulation. The subsequent loss of heterochromatin and MuSC activation, in combination with pronounced genomic instability, activates MuSCs and impairs MuSC 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 MuSCs via the NSL complex.