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

作　　者：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 Yingbin Liu 

机构地区：[1]Department of Biliary-Pancreatic Surgery,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,200127,China [2]State Key Laboratory of Oncogenes and Related Genes,Shanghai Cancer Institute,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

出　　处：《Frontiers of Medicine》2024年第1期109-127,共19页医学前沿（英文版）

基　　金：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).

摘　　要：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.

关 键 词：3D genome cancer TADS loop gene regulation 

分 类 号：R735.8[医药卫生—肿瘤]