EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma

The relationship between cellular histogenesis and molecular phenotypes for the EWSR1- ATF1 fusion in clear cell sarcoma (CCS) requires further characterization. Here, the authors investigate the EWSR1-ATF1 gene regulation networks in CCS cell lines, primary tumors, and mesenchymal stem cells. Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.

Automated summary

This study investigated the gene regulation networks of the EWSR1-ATF1 fusion gene in Clear Cell Sarcoma, revealing its mechanisms in chromatin activation and establishment of 3D networks. It also suggested precursor cells in the neural crest lineage as potential cells of origin for these tumors.