Chromatin reorganization during myoblast differentiation involves the caspase-dependent removal of SATB2

Summary Induction of lineage-specific gene programs are strongly influenced by alterations in local chromatin architecture. However, key players that impact this genome reorganization remain largely unknown. Here, we report that removal of special AT-rich binding protein 2 (SATB2), a nuclear protein that binds matrix attachment regions, is a key event in initiating myogenic differentiation. Deletion of SATB2 in muscle cell culture models and in vivo, accelerates differentiation and depletes the muscle progenitor pool, respectively. Genome wide analysis indicates that SATB2 binding is both repressive and inductive, as loss of SATB2 leads to expression of differentiation regulatory factors and inhibition of genes that impair this process. Finally, we noted that the differentiation-specific decline in SATB2 protein is dependent on a caspase 7-mediated cleavage event. Taken together, this study demonstrates that temporal control of SATB2 protein is critical for shaping the chromatin environment and coordinating the myogenic differentiation program. Graphical Abstract