Fig. 2

Roles of KAP1/TRIM28 and SETDB1 in muscle physiology and regeneration. Top: In myogenic cells KAP1 associates with KRAB-ZFPs and SETDB1 to silence TEs through H3K9me3, but also forms a distinct repressive complex at the Myog promoter, a gene essential for differentiation. Phosphorylation of KAP1 leads to dissociation of specific corepressors, allowing Myogenin transcription and differentiation. However, it is possible that a KAP1-KZFP complex and myogenic transcription factors bind to nearby sequences in the promoter, without directly interacting. Phosphorylation of KAP1 is also associated with exercise-induced hypertrophy. Bottom: Consequences of KAP1 or SETDB1 loss in muscle stem cells on muscle regeneration. Normally, satellite cells activate 3–4 days after injury, myotubes fuse between 7 and 10 days post-injury, and regeneration is complete between 21 and 28 days post-injury. When KAP1 is absent from the satellite cells, myotubes do not fuse and excessive fibrosis persists during regeneration. When Setdb1 is knocked out in satellite cells, the CGAS-STING pathway is activated, leading to elimination of satellite cells by the immune system. The early loss of the critical satellite cells abrogates muscle regeneration