Super-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis
Open Access
- 20 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-17
- https://doi.org/10.1038/s41467-020-15718-7
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01CA101753-14, P30CA047904, R33CA225494, R01CA185363)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35GM133732)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
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