Chemical-induced phase transition and global conformational reorganization of chromatin

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 () and Chao-Po Lin ()
Additional contact information
Tengfei Wang: ShanghaiTech University
Shuxiang Shi: ShanghaiTech University
Yuanyuan Shi: Shanghai Jiao Tong University School of Medicine
Peipei Jiang: Shanghai Jiao Tong University School of Medicine
Ganlu Hu: ShanghaiTech University
Qinying Ye: ShanghaiTech University
Zhan Shi: ShanghaiTech University
Kexin Yu: ShanghaiTech University
Chenguang Wang: Shanghai Jiao Tong University School of Medicine
Guoping Fan: ShanghaiTech University
Suwen Zhao: ShanghaiTech University
Hanhui Ma: ShanghaiTech University
Alex C. Y. Chang: Shanghai Jiao Tong University School of Medicine
Zhi Li: ShanghaiTech University
Qian Bian: Shanghai Jiao Tong University School of Medicine
Chao-Po Lin: ShanghaiTech University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41340-4

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