EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma
Emely Möller, Viviane Praz, Sanalkumar Rajendran, Rui Dong, Alexandra Cauderay, Yu‐Hang Xing, Lukuo Lee, Carlo Fusco, Liliane C. Broye, Luisa Cironi, Sowmya Iyer, Shruthi Rengarajan, Mary E. Awad, Beverly Naigles, Igor Letovanec, Nicola Ormas, Giovanna Finzi, Stefano La Rosa, Fausto Sessa, Ivan Chebib, G. Petur Nielsen, Antonia Digklia, Dimitrios Spentzos, Gregory M. Coté, Edwin Choy, Martin J. Aryee, Ivan Stamenkovic, Gaylor Boulay, Miguel N. Rivera, Nicolò Riggi
Abstract
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.