Thomas Braun

Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany

Skeletal  muscle  contraction  is  mediated  by syncytial  myofibers  that contain specialized contractile machinery supported by numerous post-mitotic myonuclei. Because adult myofibers are terminally differentiated, tissue maintenance and repair rely on muscle stem cells (MuSCs) located beneath the basal lamina. We investigated the transcriptional and epigenetic networks that generate muscle cells during embryogenesis and govern MuSC-mediated regeneration. We found that   the    H4K20    methyltransferase    Kmt5b    is    essential    for    preserving heterochromatin in quiescent MuSCs; its loss drives premature activation, causes aberrant S-phase transcription, induces transcription–replication conflicts, and

ultimately   leads   to   genome    instability   and   rhabdomyosarcoma  formation.   These   findings  establish chromatin-modifier regulation as a key determinant of MuSC quiescence and nuclear architecture.To identify upstream  regulators  of  these  chromatin  modifiers,  we  examined  transcriptional  factors  controlling  MuSC homeostasis. Unexpectedly, we identified TAF4A, a TFIID subunit, as critical for MuSC quiescence and genome stability. TAF4A maintains expression of Kansl2, a component of the NSL complex that acetylates lamin A/C. Reduced  lamin A/C  acetylation  compromises  nuclear  stiffness,  disrupts  heterochromatin  organization,  and impairs MuSC proliferation. We propose that diminished lamin A/C acetylation and nuclear instability contribute to aging-associated MuSC dysfunction.