Chromatin reorganization during myoblast differentiation involves the caspase-dependent removal of SATB2 [ChIP-seq]

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 known to bind matrix attachment regions, is a key event in initiating myogenic differentiation. Deletion of myoblast SATB2 in vitro initiates chromatin remodeling and accelerates differentiation, while in vivo ablation depletes the muscle progenitor pool. Genome wide analysis indicates that SATB2 binding influences both chromatin loop and sub-TAD domain formation. These chromatin changes are 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 Identification of Genome-wide of Satb2 binding sites in C2C12 cells.