Super-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis

Jianquan Xu, Hongqiang Ma, Hongbin Ma, Wei Jiang, Christopher A. Mela, Meihan Duan, Shimei Zhao, Chenxi Gao, Eun-Ryeong Hahm, Santana M. Lardo, Kris Troy, Ming Sun, Reet Pai, Donna B. Stolz, Lin Zhang, Shivendra Singh, Randall E. Brand, Douglas J. Hartman, Jing Hu, Sarah J. Hainer () and Yang Liu ()
Additional contact information
Jianquan Xu: University of Pittsburgh
Hongqiang Ma: University of Pittsburgh
Hongbin Ma: University of Pittsburgh
Wei Jiang: University of Pittsburgh
Christopher A. Mela: University of Pittsburgh
Meihan Duan: University of Pittsburgh
Shimei Zhao: University of Pittsburgh
Chenxi Gao: University of Pittsburgh
Eun-Ryeong Hahm: University of Pittsburgh
Santana M. Lardo: University of Pittsburgh
Kris Troy: University of Pittsburgh
Ming Sun: University of Pittsburgh
Reet Pai: University of Pittsburgh School of Medicine
Donna B. Stolz: University of Pittsburgh
Lin Zhang: University of Pittsburgh
Shivendra Singh: University of Pittsburgh
Randall E. Brand: University of Pittsburgh Hillman Cancer Center
Douglas J. Hartman: University of Pittsburgh School of Medicine
Jing Hu: University of Pittsburgh Hillman Cancer Center
Sarah J. Hainer: University of Pittsburgh
Yang Liu: University of Pittsburgh

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Genomic DNA is folded into a higher-order structure that regulates transcription and maintains genomic stability. Although progress has been made on understanding biochemical characteristics of epigenetic modifications in cancer, the in-situ higher-order folding of chromatin structure during malignant transformation remains largely unknown. Here, using optimized stochastic optical reconstruction microscopy (STORM) for pathological tissue (PathSTORM), we uncover a gradual decompaction and fragmentation of higher-order chromatin folding throughout all stages of carcinogenesis in multiple tumor types, and prior to tumor formation. Our integrated imaging, genomic, and transcriptomic analyses reveal functional consequences in enhanced transcription activities and impaired genomic stability. We also demonstrate the potential of imaging higher-order chromatin disruption to detect high-risk precursors that cannot be distinguished by conventional pathology. Taken together, our findings reveal gradual decompaction and fragmentation of higher-order chromatin structure as an enabling characteristic in early carcinogenesis to facilitate malignant transformation, which may improve cancer diagnosis, risk stratification, and prevention.

Date: 2020
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DOI: 10.1038/s41467-020-15718-7

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