Prion-like domain mediated phase separation of ARID1A promotes oncogenic potential of Ewing’s sarcoma

Yong Ryoul Kim, Jaegeon Joo, Hee Jung Lee, Chaelim Kim, Ju-Chan Park, Young Suk Yu, Chang Rok Kim, Do Hui Lee, Joowon Cha, Hyemin Kwon, Kimberley M. Hanssen, Thomas G. P. Grünewald, Murim Choi, Ilkyu Han, Sangsu Bae, Inkyung Jung (), Yongdae Shin () and Sung Hee Baek ()
Additional contact information
Yong Ryoul Kim: Seoul National University
Jaegeon Joo: Korea Advanced Institute of Science & Technology
Hee Jung Lee: Seoul National University
Chaelim Kim: Seoul National University
Ju-Chan Park: Seoul National University College of Medicine
Young Suk Yu: Seoul National University
Chang Rok Kim: Seoul National University
Do Hui Lee: Seoul National University
Joowon Cha: Seoul National University
Hyemin Kwon: Seoul National University
Kimberley M. Hanssen: Hopp-Children’s Cancer Center (KiTZ)
Thomas G. P. Grünewald: Hopp-Children’s Cancer Center (KiTZ)
Murim Choi: Seoul National University College of Medicine
Ilkyu Han: Seoul National University College of Medicine
Sangsu Bae: Seoul National University College of Medicine
Inkyung Jung: Korea Advanced Institute of Science & Technology
Yongdae Shin: Seoul National University
Sung Hee Baek: Seoul National University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Liquid-liquid phase separation (LLPS) facilitates the formation of membraneless organelles within cells, with implications in various biological processes and disease states. AT-rich interactive domain-containing protein 1A (ARID1A) is a chromatin remodeling factor frequently associated with cancer mutations, yet its functional mechanism remains largely unknown. Here, we find that ARID1A harbors a prion-like domain (PrLD), which facilitates the formation of liquid condensates through PrLD-mediated LLPS. The nuclear condensates formed by ARID1A LLPS are significantly elevated in Ewing’s sarcoma patient specimen. Disruption of ARID1A LLPS results in diminished proliferative and invasive abilities in Ewing’s sarcoma cells. Through genome-wide chromatin structure and transcription profiling, we identify that the ARID1A condensate localizes to EWS/FLI1 target enhancers and induces long-range chromatin architectural changes by forming functional chromatin remodeling hubs at oncogenic target genes. Collectively, our findings demonstrate that ARID1A promotes oncogenic potential through PrLD-mediated LLPS, offering a potential therapeutic approach for treating Ewing’s sarcoma.

Date: 2024
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DOI: 10.1038/s41467-024-51050-0

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