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

doi:10.1007/s11684-023-1008-8

Front. Med.

2024, Vol. 18

Issue (1) : 109-127 https://doi.org/10.1007/s11684-023-1008-8

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

Guoqiang Li^1,^2,³, Peng Pu^1,^2,³, Mengqiao Pan², Xiaoling Weng², Shimei Qiu⁴, Yiming Li^1,^2,³, Sk Jahir Abbas², Lu Zou^1,^2,³, Ke Liu^1,^2,³, Zheng Wang⁵, Ziyu Shao⁶, Lin Jiang^3,⁶, Wenguang Wu^1,^2,³, Yun Liu^2,³(

), Rong Shao⁷(

), Fatao Liu^2,³(

), Yingbin Liu^1,^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

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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

Corresponding Author(s): Yun Liu,Rong Shao,Fatao Liu,Yingbin Liu

About author:

Li Liu and Yanqing Liu contributed equally to this work.

Just Accepted Date: 30 August 2023 Online First Date: 19 September 2023 Issue Date: 22 April 2024

Cite this article:

Guoqiang Li,Peng Pu,Mengqiao Pan, et al. Topological reorganization and functional alteration of distinct genomic components in gallbladder cancer[J]. Front. Med., 2024, 18(1): 109-127.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1008-8
https://academic.hep.com.cn/fmd/EN/Y2024/V18/I1/109

Fig.1 Workflow of the experimental strategy and whole-genome profiles of chromosomal interactions. (A) Scheme showing the experimental methods using Hi-C sequencing, RNA-seq, and CTCF/H3K27ac ChIP-seq to analyze the different levels of three genomic elements, including compartments, TADs, and loops. The samples involved two pairs of primary GBC cancer and the corresponding adjacent normal tissues (GBC-1 and GBC-2), one line of human normal epithelial cells (HBEC), and two GBC cell lines (GBC-SD and NOZ). (B) Heatmap of the contact matrices of gallbladder tissues from GBC-1 patient, HBECs, and GBC cell lines (GBC-SD) at 1 Mb resolution. The horizontal and vertical axes represent the chromosome position, and the color depth denote the intensity of interaction. Inserted black rectangles indicate strong interchromosomal interactions. (C) The 100 highest interchromosomal interactions in GBC-SD cells. Lines connect the 100 highest interactions, in which blue lines depict the interchromosomal interactions overlapping with translocation events identified by WGS data. Scatter plot: copy number variants, red: integer copy numbers > 2, black: = 2, green: < 2. (D) PTPRD genes affected by translocation events in the junction region of rearranged green and purple genome fragments. The black circle indicates strong interchromosomal interactions.

Fig.2 Compartment and TAD reorganization in GBC. (A) A fragment of compartments A (positive values, red) and B (negative values, blue) within chromosome 4 was determined based on the Hi-C eigenvectors (PC1) in seven cell/tissue samples. (B) Pie charts showing the alterations in genomic compartments detected in the two comparison groups: cancer tissues versus normal tissues and GBC cell lines versus HBEC. “A to A” represents compartment A in both samples, “B to B” denotes compartment B in both samples, “A to B” refers to compartments that were compartment A in normal but compartment B in GBC-SD cells or cancer tissues, and “B to A” indicates compartments that were compartment B in normal but compartment A in GBC-SD cells or cancer tissues (C–E). The levels of gene expressions, CTCF, and H3K27ac ChIP-seq signal with

l o g 2 F C

in four types of genomic compartment switching in GBC-SD cells and HBECs. Significant differences were calculated using the Wilcoxon rank-sum test, and the medians are labeled. (F, G) Size and number of TADs identified in tissues and cells. (H) The average insulation score in each sample at the 500 kb flank of the boundaries. Tissue samples (GBC-1) and cell lines (HBEC, GBC-SD, and NOZ) were analyzed and displayed. (I) Inter- and intra-TAD interaction activities are shown with the difference between GBC cells and HBECs.

Fig.3 Characteristics of loops in GBC. (A) Venn diagrams showing the number of loop overlaps between samples (HBECs vs. cancer cells GBC-SD or NOZ; GBC-1 normal tissue vs. cancer tissue). (B and C) Length distribution of loops (HBEC specific, cancer specific, and common). Black arrows represent more and shorter loops in cancer-specific loops. (D) GO enrichment analysis of genes in HBEC- (purple) and NOZ-specific loops (red). (E) Heatmap of the contact matrices of HBEC and NOZ cells showing a unique loop at the SOX9 locus.

Fig.4 Association between CTCF and loops. (A) Venn diagrams showing the proportion of CTCF-related loops. Total loops, loops associated with at least one CTCF binding site, and loops associated with two CTCF binding sites are shown as red, blue, and green circles, respectively. (B) CTCF occupancy in loop anchors (black) or random regions (green). Heatmaps showing the CTCF signals as the RPKM of the CTCF signal. (C) Percentage of four different orientations of paired CTCF motifs in HBECs and GBC cells. (D) CTCF signal distribution between left and right loop anchors. The red dotted line represents the trend of CTCF binding on the left or right anchor. (E) A unique loop in the NOZ cell line at chr10 compared with HBECs. Red and blue triangles represent orientations of the CTCF motif.

Fig.5 Relationship between CTCF, loops, and gene expression. (A) Heatmap representing the level of gene expression, CTCF, and H3K27ac signal in GBC-SD vs. HBECs. (B) Heatmaps on the left represent the relative expressions (GBC-SD vs. HBECs) of genes with E-P loops. The ratios of Hi-C interaction normalized counts involved in the E-P loops of the corresponding genes are shown on the right. (C) Venn diagram showing the overlap of genes of the following three data sets: (1) E-P-regulated and upregulated genes in GBC-SD cells, (2) E-P-regulated and upregulated genes in NOZ cells, and (3) upregulated genes in the nine GBC tissue samples compared with the normal tissues (GEO accession number: GSE76633). (D) Expressions of seven genes with fold changes in cells (E). Hi-C heatmap, gene expression, CTCF, H3K27ac, and H3K4me3 signal and loops that presumably regulate the BMP4 and KRT19 genes. (F) Knockdown efficiency was measured by Western blotting in GBC-SD and NOZ cells transfected with siRNA: Si-BMP4#1, Si-BMP4#2, or the negative control (Si-Ctrl). (G) Cell proliferation was determined using CCK-8 assays.

Fig.6 Deletion of the candidate E led to the downregulation of BMP4 expression. (A) Paired sgRNAs (green and blue bars, position: chr14: 54 572 357–54 572 377 and chr14: 54 579 615–54 579 635, respectively) were designed to delete putative E (yellow, H3K27ac peak common to NOZ and GBC-SD cells, position: chr14: 54 573 050–54 577 278). Targeted sequences and predicted deletions are shown. (B) E deletion was identified by PCR and Sanger sequencing using paired primers on both sides of sgRNAs, which reflected a deletion of 7275 bp. (C and D) qPCR and Western blot validation of the reduced expression of BMP4 in E-deleted GBC cells compared with control cells. (E) Cell proliferation assays in E-deleted NOZ, GBC-SD cells, and edited cells overexpressing BMP4 or control cells.

Fig.7 Disruption of the CTCF binding site led to downregulation of BMP4 expression. (A) Schematic of CTCF motif disruption using the CRISPR?Cas9 system. (B) Sanger sequencing showed CTCF binding motif breakage based on the CRISPR?Cas9 system in WT and edited GBC-SD cells. The CTCF motif (red) and sgRNA (green) targeted sequence are highlighted. Various indels and frequencies were confirmed by TA cloning and Sanger sequencing. (C and D) qPCR and Western blot validation of the reduced expression of BMP4 in edited GBC-SD cells compared with WT cells.

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