Large-scale chromatin topological remodeling accompanies hepatocellular carcinoma progression
- 1Innovation Center for Cancer Research, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital
- 2Department of Hepatopancreatobiliary Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital
Abstract
Multistep hepatocarcinogenesis of hepatocellular carcinoma (HCC) is associated with dynamic alterations in chromatin topology. Previous studies have primarily compared three-dimensional (3D) genomic structure between tumor and normal adjacent tissues, largely overlooking the role of cirrhosis, a major precancerous lesion and risk factor in HCC pathogenesis. Here, we systematically analyzed chromatin conformation changes across paired tumor, cirrhotic, and normal adjacent tissues to identify stage-specific structural alterations during hepatocarcinogenesis. We constructed high-resolution 3D genomic maps using pore chromatin conformation capture (Pore-C), complemented by chromatin immunoprecipitation sequencing (ChIP-seq), RNA-seq, and whole-genome sequencing (WGS), to investigate key chromatin topological remodeling events in HCC development. Significant alterations in A/B compartments, topologically associating domains (TADs), and chromatin loops were observed across different tissue types and patients. Comparisons between normal liver and cirrhotic tissues revealed predominant enhancement of inter‑chromosomal interactions; comparisons between cirrhotic and HCC tissues showed predominant elevation of intra‑chromosomal interactions. Across normal, cirrhotic and HCC disease states, we observed compaction of the highly active A compartments and concomitant decompaction of the silent B compartments. In general, both cirrhosis and tumor exhibited more transcriptionally active compartment states compared to normal adjacent tissues. TAD size and numbers were more conserved within tissues from the same individual than across different patients with the same tissue type. Few TAD boundaries were gained or lost consistently. Integrative analysis with H3K27ac identified genomic regions co-occurring with loop formation and enhancer activation. In normal adjacent tissue, the CXCL12 gene locus maintained a well-defined chromatin loop structure that was disrupted in tumor tissues. Corresponding RNA-seq analysis confirmed significant downregulation of CXCL12 expression in tumors. By integrating SVs identified from Pore-C datasets and the Chinese Liver Cancer Atlas (CLCA), we identified SV-induced neo-loops, which were more prone to transcriptional alterations and could promote cell proliferation by activating choline metabolism and phospholipase D signaling pathways. Comparing the three disease states, cirrhosis represents an intermediate state with reversed patterns of chromosomal interactions relative to normal liver and HCC. Although canonical A/B compartment shifts involved limited genomic regions, we consistently observed progressive compaction of compartment A and decompaction of compartment B. Compared with normal tissues, HCC exhibits the disruption of CXCL12 chromatin loop and a significant reduction in enhancer signals, accompanied by a marked downregulation of CXCL12 expression in tumor tissues. SV-induced neo-loops were key events influencing gene expression. The proteins encoded by these genes are highly involved in homologous recombination, and drove cell proliferation via specific signaling pathways. Our findings revealed that stage-specific chromatin structural changes and provided novel insights into the mechanisms of gene dysregulation in hepatocarcinogenesis.
Related
- Dynamic three-dimensional chromatin remodeling in lung disease: mechanistic principles, pathogenic regulatory networks, and translational challenges
- The BAF chromatin remodeling subunit ARID1B coordinates cell-cycle exit and motor neuron differentiation
- CFDP1 is required for histone variant H2A.Z deposition by the human SRCAP chromatin remodeling complex
- integrating single-cell transcriptomics and chromatin accessibility profiling to decipher the molecular landscape of Hepatocellular carcinoma
- SWI/SNF chromatin remodeling complexes in metabolic disorders: integrating tissue-specific epigenetic mechanisms.
BibTeX
@article{jiang2026largescale,
title = {{Large-scale chromatin topological remodeling accompanies hepatocellular carcinoma progression}},
author = {Fengle Jiang and Zheting Zhang and Zhaoshuo Chen and Shaohua Xu and Shuxian Cai and Jingfeng Liu and Jianmin Wang},
journal = {Scientific Reports},
year = {2026},
month = sep,
doi = {10.1038/s41598-026-71859-7},
url = {https://doi.org/10.1038/s41598-026-71859-7},
note = {CC BY},
}
RIS
TY - JOUR
TI - Large-scale chromatin topological remodeling accompanies hepatocellular carcinoma progression
AU - Fengle Jiang
AU - Zheting Zhang
AU - Zhaoshuo Chen
AU - Shaohua Xu
AU - Shuxian Cai
AU - Jingfeng Liu
AU - Jianmin Wang
PY - 2026
DA - 2026/09/01
JO - Scientific Reports
DO - 10.1038/s41598-026-71859-7
UR - https://doi.org/10.1038/s41598-026-71859-7
AB - Multistep hepatocarcinogenesis of hepatocellular carcinoma (HCC) is associated with dynamic alterations in chromatin topology. Previous studies have primarily compared three-dimensional (3D) genomic structure between tumor and normal adjacent tissues, largely overlooking the role of cirrhosis, a major precancerous lesion and risk factor in HCC pathogenesis. Here, we systematically analyzed chromatin conformation changes across paired tumor, cirrhotic, and normal adjacent tissues to identify stage-specific structural alterations during hepatocarcinogenesis. We constructed high-resolution 3D genomic maps using pore chromatin conformation capture (Pore-C), complemented by chromatin immunoprecipitation sequencing (ChIP-seq), RNA-seq, and whole-genome sequencing (WGS), to investigate key chromatin topological remodeling events in HCC development. Significant alterations in A/B compartments, topologically associating domains (TADs), and chromatin loops were observed across different tissue types and patients. Comparisons between normal liver and cirrhotic tissues revealed predominant enhancement of inter‑chromosomal interactions; comparisons between cirrhotic and HCC tissues showed predominant elevation of intra‑chromosomal interactions. Across normal, cirrhotic and HCC disease states, we observed compaction of the highly active A compartments and concomitant decompaction of the silent B compartments. In general, both cirrhosis and tumor exhibited more transcriptionally active compartment states compared to normal adjacent tissues. TAD size and numbers were more conserved within tissues from the same individual than across different patients with the same tissue type. Few TAD boundaries were gained or lost consistently. Integrative analysis with H3K27ac identified genomic regions co-occurring with loop formation and enhancer activation. In normal adjacent tissue, the CXCL12 gene locus maintained a well-defined chromatin loop structure that was disrupted in tumor tissues. Corresponding RNA-seq analysis confirmed significant downregulation of CXCL12 expression in tumors. By integrating SVs identified from Pore-C datasets and the Chinese Liver Cancer Atlas (CLCA), we identified SV-induced neo-loops, which were more prone to transcriptional alterations and could promote cell proliferation by activating choline metabolism and phospholipase D signaling pathways. Comparing the three disease states, cirrhosis represents an intermediate state with reversed patterns of chromosomal interactions relative to normal liver and HCC. Although canonical A/B compartment shifts involved limited genomic regions, we consistently observed progressive compaction of compartment A and decompaction of compartment B. Compared with normal tissues, HCC exhibits the disruption of CXCL12 chromatin loop and a significant reduction in enhancer signals, accompanied by a marked downregulation of CXCL12 expression in tumor tissues. SV-induced neo-loops were key events influencing gene expression. The proteins encoded by these genes are highly involved in homologous recombination, and drove cell proliferation via specific signaling pathways. Our findings revealed that stage-specific chromatin structural changes and provided novel insights into the mechanisms of gene dysregulation in hepatocarcinogenesis.
SN - 2045-2322
ER -