Topological reorganization and functional alteration of distinct genomic components in gallbladder cancer
Guoqiang Li1,2,3, Peng Pu1,2,3, Mengqiao Pan2, Xiaoling Weng2, Shimei Qiu4, Yiming Li1,2,3, Sk Jahir Abbas2, Lu Zou1,2,3, Ke Liu1,2,3, Zheng Wang5, Ziyu Shao6, Lin Jiang3,6, Wenguang Wu1,2,3, Yun Liu2,3(), Rong Shao7(), Fatao Liu2,3(), Yingbin Liu1,2,3()
1. Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China 2. Shanghai Cancer Institute, State Key Laboratory of Oncogenes and Related Genes, Shanghai 200127, China 3. Shanghai Key Laboratory of Biliary Tract Disease, Shanghai 200082, China 4. Department of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200082, China 5. Shanghai Tenth People’s Hospital of Tongji University, Shanghai 200072, China 6. Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200082, China 7. Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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.
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