SS18 regulates pluripotent-somatic transition through phase separation

Junqi Kuang, Ziwei Zhai, Pengli Li, Ruona Shi, Wenjing Guo, Yuxiang Yao, Jing Guo, Guoqing Zhao, Jiangpin He, Shuyang Xu, Chuman Wu, Shengyong Yu, Chunhua Zhou, Linlin Wu, Yue Qin, Baomei Cai, Wei Li, Zichao Wu, Xiaoxi Li, Shilong Chu, Tingting Yang, Bo Wang, Shangtao Cao, Dongwei Li, Xiaofei Zhang, Jiekai Chen, Jing Liu () and Duanqing Pei ()
Additional contact information
Junqi Kuang: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Ziwei Zhai: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Pengli Li: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Ruona Shi: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Wenjing Guo: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Yuxiang Yao: Lanzhou University
Jing Guo: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Guoqing Zhao: Guangzhou Medical University
Jiangpin He: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Shuyang Xu: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Chuman Wu: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Shengyong Yu: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Chunhua Zhou: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Linlin Wu: University of Science and Technology of China
Yue Qin: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Baomei Cai: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Wei Li: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Zichao Wu: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Xiaoxi Li: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Shilong Chu: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Tingting Yang: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Bo Wang: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Shangtao Cao: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Dongwei Li: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Xiaofei Zhang: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Jiekai Chen: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Jing Liu: Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
Duanqing Pei: Westlake University

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract The transition from pluripotent to somatic states marks a critical event in mammalian development, but remains largely unresolved. Here we report the identification of SS18 as a regulator for pluripotent to somatic transition or PST by CRISPR-based whole genome screens. Mechanistically, SS18 forms microscopic condensates in nuclei through a C-terminal intrinsically disordered region (IDR) rich in tyrosine, which, once mutated, no longer form condensates nor rescue SS18−/− defect in PST. Yet, the IDR alone is not sufficient to rescue the defect even though it can form condensates indistinguishable from the wild type protein. We further show that its N-terminal 70aa is required for PST by interacting with the Brg/Brahma-associated factor (BAF) complex, and remains functional even swapped onto unrelated IDRs or even an artificial 24 tyrosine polypeptide. Finally, we show that SS18 mediates BAF assembly through phase separation to regulate PST. These studies suggest that SS18 plays a role in the pluripotent to somatic interface and undergoes liquid-liquid phase separation through a unique tyrosine-based mechanism.

Date: 2021
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DOI: 10.1038/s41467-021-24373-5

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