Abstract
Nasopharyngeal cancer (NPC), a cancer derived from epithelial cells in the nasopharynx, is a cancer common in China, Southeast Asia, and Africa. The three-dimensional (3D) genome organization of nasopharyngeal cancer is poorly understood. A major challenge in understanding the 3D genome organization of cancer samples is the lack of a method for the characterization of chromatin interactions in solid cancer needle biopsy samples. Here, we developed Biop-C, a modified in situ Hi-C method using solid cancer needle biopsy samples. We applied Biop-C to characterize three nasopharyngeal cancer solid cancer needle biopsy patient samples. We identified topologically associated domains (TADs), chromatin interaction loops, and frequently interacting regions (FIREs) at key oncogenes in nasopharyngeal cancer from the Biop-C heatmaps. We observed that the genomic features are shared at some important oncogenes, but the patients also display extensive heterogeneity at certain genomic loci. On analyzing the super enhancer landscape in nasopharyngeal cancer cell lines, we found that the super enhancers are associated with FIREs and can be linked to distal genes via chromatin loops in NPC. Taken together, our results demonstrate the utility of our Biop-C method in investigating 3D genome organization in solid cancers.
Highlights
The three-dimensional (3D) genome organization of the nucleus plays a vital role in the regulation of transcription (Hnisz et al, 2016, 2018)
Using Biop-C, we examined chromatin interactions in three nasopharyngeal cancer patient samples, which allowed us to identify super enhancers associated with frequently interacting regions (FIREs) and which loop to important oncogenes
Hi-C libraries from an Nasopharyngeal cancer (NPC) cell line, HK1, showed differences compared with chromatin interactions in the patient samples
Summary
The three-dimensional (3D) genome organization of the nucleus plays a vital role in the regulation of transcription (Hnisz et al, 2016, 2018). The core needle biopsies pose the challenge of both limited cell numbers as well as the requirement for tissue dissociation, which might lead to further loss or degradation of chromatin for analysis. Solid cancers represent approximately 90% of adult human cancers (American Cancer Society, 2020); an easy-to-use method for preparing Hi-C libraries from needle biopsy cancer samples would advance our understanding of how chromatin organization contributes to cancer pathogenesis in solid cancers. We present Biop-C, a modified in situ Hi-C method for the chromatin analysis in solid cancer tissues from needle biopsy samples. We prepared Hi-C libraries from an NPC cell line, HK1, and found differences between chromatin interactions in the patient samples as compared with the cell line, indicating the necessity of interrogating chromatin interactions in actual patient cancers, which Biop-C enables. These functional data suggest that there are differences in the chromatin interaction landscape between nasopharyngeal cancer and normal nasopharyngeal cell line, and targeting super enhancers by THZ1 can modulate the chromatin interactome and lead to losses in chromatin interactions, suggesting that epigenetic drugs may be able to affect chromatin interactions that are altered in nasopharyngeal cancer
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