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Chemical-induced phase transition and global conformational reorganization of chromatin

Author

Listed:
  • Tengfei Wang

    (ShanghaiTech University)

  • Shuxiang Shi

    (ShanghaiTech University
    Lingang Laboratory)

  • Yuanyuan Shi

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Peipei Jiang

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Ganlu Hu

    (ShanghaiTech University)

  • Qinying Ye

    (ShanghaiTech University)

  • Zhan Shi

    (ShanghaiTech University)

  • Kexin Yu

    (ShanghaiTech University
    ShanghaiTech University)

  • Chenguang Wang

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine
    Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine)

  • Guoping Fan

    (ShanghaiTech University)

  • Suwen Zhao

    (ShanghaiTech University
    ShanghaiTech University)

  • Hanhui Ma

    (ShanghaiTech University)

  • Alex C. Y. Chang

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine
    Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine)

  • Zhi Li

    (ShanghaiTech University)

  • Qian Bian

    (Shanghai Jiao Tong University School of Medicine
    Shanghai Jiao Tong University School of Medicine)

  • Chao-Po Lin

    (ShanghaiTech University)

Abstract

Chemicals or drugs can accumulate within biomolecular condensates formed through phase separation in cells. Here, we use super-resolution imaging to search for chemicals that induce phase transition within chromatin at the microscale. This microscopic screening approach reveals that adriamycin (doxorubicin) — a widely used anticancer drug that is known to interact with chromatin — specifically induces visible local condensation and global conformational change of chromatin in cancer and primary cells. Hi-C and ATAC-seq experiments systematically and quantitatively demonstrate that adriamycin-induced chromatin condensation is accompanied by weakened chromatin interaction within topologically associated domains, compartment A/B switching, lower chromatin accessibility, and corresponding transcriptomic changes. Mechanistically, adriamycin complexes with histone H1 and induces phase transition of H1, forming fibrous aggregates in vitro. These results reveal a phase separation-driven mechanism for a chemotherapeutic drug.

Suggested Citation

  • Tengfei Wang & Shuxiang Shi & Yuanyuan Shi & Peipei Jiang & Ganlu Hu & Qinying Ye & Zhan Shi & Kexin Yu & Chenguang Wang & Guoping Fan & Suwen Zhao & Hanhui Ma & Alex C. Y. Chang & Zhi Li & Qian Bian , 2023. "Chemical-induced phase transition and global conformational reorganization of chromatin," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41340-4
    DOI: 10.1038/s41467-023-41340-4
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