Topological reorganization and functional alteration of distinct genomic components in gallbladder cancer

Abstract

Altered three-dimensional architecture of chromatin influences various genomic regulators and subsequent gene expression in human cancer. However, knowledge of the topological rearrangement of genomic hierarchical layers in cancer is largely limited. Here, by taking advantage of in situ Hi-C, RNA-sequencing, and chromatin immunoprecipitation sequencing (ChIP-seq), we investigated structural reorganization and functional changes in chromosomal compartments, topologically associated domains (TADs), and CCCTC binding factor (CTCF)-mediated loops in gallbladder cancer (GBC) tissues and cell lines. We observed that the chromosomal compartment A/B switch was correlated with CTCF binding levels and gene expression changes. Increased inter-TAD interactions with weaker TAD boundaries were identified in cancer cell lines relative to normal controls. Furthermore, the chromatin short loops and cancer unique loops associated with chromatin remodeling and epithelial–mesenchymal transition activation were enriched in cancer compared with their control counterparts. Cancer-specific enhancer–promoter loops, which contain multiple transcription factor binding motifs, acted as a central element to regulate aberrant gene expression. Depletion of individual enhancers in each loop anchor that connects with promoters led to the inhibition of their corresponding gene expressions. Collectively, our data offer the landscape of hierarchical layers of cancer genome and functional alterations that contribute to the development of GBC.

Keywords

3D genome / cancer / TADs / loop / gene regulation

References

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81874181, 81902361, 3213000192, and 91940305); the National Science and Technology Major Projects for “Major New Drug Innovation and Development” (No. 2019ZX09301-158); the Shanghai Sailing Program (No. 19YF1433000); the Open Project Program of State Key Laboratory of Oncogenes and Related Genes (No. KF2120).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-023-1008-8 and is accessible for authorized users.

Compliance with ethics guidelines

Conflict of interest Guoqiang Li, Peng Pu, Mengqiao Pan, Xiaoling Weng, Shimei Qiu, Yiming Li, Sk Jahir Abbas, Lu Zou, Ke Liu, Zheng Wang, Ziyu Shao, Lin Jiang, Wenguang Wu, Yun Liu, Rong Shao, Fatao Liu, and Yingbin Liu declare no competing interests.

All the patients were subjected to accept the written informed consent before enrollment. The study was approved by the ethics committee of Xinhua hospital (No. XHEC-D-2021-071) and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study.

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