PAX3-FOXO1 establishes myogenic super enhancers and recruits BRD4 de novo [7250 ChIP-seq]

The fusion transcription factor PAX3-FOXO1 drives oncogenesis in a subset of rhabdomyosarcomas, however the mechanisms by which it remodels chromatin are unknown. We find PAX3-FOXO1 reprograms the cis-regulatory landscape by inducing super enhancers (SEs), in collaboration with master transcription factors MYOG, MYOD and MYCN. This myogenic SE circuitry is consistent across cell lines and primary tumors. Deregulation of PAX3-FOXO1 itself occurs by translocation-induced chromatin loops bringing the PAX3 promoter under the control of FOXO1 enhancers. Protein targets induced by, or bound to, PAX3-FOXO1 occupied SEs, were selectively sensitive to small molecule inhibition. PAX3-FOXO1 co-binds BRD4 at SEs, and BET bromodomains are required for PAX3-FOXO1-dependent transcription and cancer cell growth. Genome-wide profiles for histone mark H3K27ac, DNase hypersensitivity, PAX3-FOXO1 and coactivator BRD4 in fibroblast cells stably transduced with either empty vector or PAX3-FOXO1 vector.