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.
Highlights
Genomic DNA is folded into a higher-order structure that regulates transcription and maintains genomic stability
Aberrant chromatin structure is a characteristic of cancer cells, but what happens in early carcinogenesis when cells still appear normal prior to tumor formation? Is the structural disruption a one-hit event or a gradual evolving process throughout carcinogenesis? Is there a common feature in chromatin structure underlying all stages of carcinogenesis in multiple tumor types? Answering these questions will have significant clinical implications to improve cancer risk stratification and early detection
This result validated the ability of PathSTORM to achieve similar resolution of higher-order chromatin structures on pathological tissues compared to standard stochastic optical reconstruction microscopy (STORM)
Summary
Genomic DNA is folded into a higher-order structure that regulates transcription and maintains genomic stability. 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. 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. The causal relationship between dysregulated heterochromatin function and increased genomic instability is a well-recognized mechanism to promote cancer progression, this phenotype was largely inferred by biochemical analysis of chromatin-associated proteins and DNA sequences. The underlying molecular-scale chromatin structure of dysregulated heterochromatin function in tumorigenesis remains largely unknown This is due, in part, to the lack of sufficient resolution to visualize molecular-scale higher-order chromatin structure below the resolution limit of a conventional light microscope. Characteristic higher-order chromatin structure throughout tumorigenesis has not been fully characterized on pathological tissue, in part due to challenges in imaging pathological tissue such as autofluorescence, stronger scattering, and non-uniform background
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