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Nat. Commun., Aug 03 2024, 15 (1) 6569 | https://doi.org/10.1038/s41467-024-51050-0 Prion-like domain mediated phase separation of ARID1A promotes oncogenic potential of Ewing's sarcoma

Yong Ryoul Kim^1,13, Jaegeon Joo^2,13, Hee Jung Lee³, Chaelim Kim³, Ju-Chan Park^4,5, Young Suk Yu¹, Chang Rok Kim¹, Do Hui Lee¹, Joowon Cha¹, Hyemin Kwon¹, Kimberley M. Hanssen^6,7,8, Thomas G. P. Grünewald^6,7,8,9, Murim Choi¹⁰, Ilkyu Han¹¹, Sangsu Bae^4,5, Inkyung Jung², Yongdae Shin^3,12 & SungHee Baek¹

¹Creative Research Initiatives Center for Epigenetic Code and Diseases, School of Biological Sciences, Seoul National University, Seoul, South Korea.

²Department of Biological Sciences, Korea Advanced Institute of Science & Technology, Daejeon, South Korea.

³Interdisciplinary Program inBioengineering, Seoul National University, Seoul, South Korea.

⁴Research Center of Genomic Medicine Institute, Seoul National University College of Medicine, Seoul, South Korea.

⁵Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, South Korea.

⁶Hopp-Children’s Cancer Center (KiTZ), Heidelberg, Germany.

⁷Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.

⁸National Center for Tumor Diseases (NCT), NCT Heidelberg, (A Partnership) Between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.

⁹Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

¹⁰Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.

¹¹Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul, South Korea.

¹²Department of Mechanical Engineering, Seoul National University, Seoul, South Korea.

¹³These authors contributed equally: Yong Ryoul Kim, Jaegeon Joo.

Corresponding authors

Correspondence to Inkyung Jung, Yongdae Shin or Sung Hee Baek.

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.

논문정보

형식Research article
게재일2024년 08월 (BRIC 등록일 2024-08-05)
연구진국내(교신)+국외 연구진
분야 생명과학 > 세포생물학

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