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. HainerYang Liu

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number1899
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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