Xi XL, Yang YD, Liu HL, Jiang J, Wu B. Chromatin accessibility module identified by single-cell sequencing underlies the diagnosis and prognosis of hepatocellular carcinoma. World J Hepatol 2025; 17(6): 107329 [DOI: 10.4254/wjh.v17.i6.107329]
Corresponding Author of This Article
Bin Wu, MD, PhD, Professor, Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China. wubin6@mail.sysu.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Hepatol. Jun 27, 2025; 17(6): 107329 Published online Jun 27, 2025. doi: 10.4254/wjh.v17.i6.107329
Chromatin accessibility module identified by single-cell sequencing underlies the diagnosis and prognosis of hepatocellular carcinoma
Xiao-Li Xi, Yi-Dong Yang, Hui-Ling Liu, Jie Jiang, Bin Wu
Xiao-Li Xi, Yi-Dong Yang, Hui-Ling Liu, Jie Jiang, Bin Wu, Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China
Co-first authors: Xiao-Li Xi and Yi-Dong Yang.
Author contributions: Xi XL and Yang YD analyzed the data and wrote the manuscript, they contributed equally to this article, they are the co-first authors of this manuscript; Xi XL, Liu HL, and Jiang J performed the research; Yang YD contributed new reagents and analytic tools; Wu B designed the research study; and all authors have read and approved the final manuscript.
Supported by the Science and Technology Planning Project of Guangzhou, No. 2024A03J0102; the Natural Science Foundation of Guangdong Province for Distinguished Young Scholar, No. 2022B1515020024; National Natural Science Foundation of China, No. 82070574; and the Key Research and Development Program of Guangzhou, No. 2023B03J1298.
Institutional review board statement: This study was approved by the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-Sen University, approval No. [2019]02-248-01.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The datasets obtained and explored in this study are available in the TCGA (https://portal.gdc.cancer.gov/) and GEO dataset. The original contributions presented in the study are included in the article. Further inquiries could be directed to the corresponding author.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Bin Wu, MD, PhD, Professor, Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China. wubin6@mail.sysu.edu.cn
Received: March 21, 2025 Revised: April 24, 2025 Accepted: May 29, 2025 Published online: June 27, 2025 Processing time: 97 Days and 6.6 Hours
Abstract
BACKGROUND
Hepatocellular carcinoma (HCC) is notorious for its aggressive progression and dismal prognosis, with chromatin accessibility dynamics emerging as pivotal yet poorly understood drivers.
AIM
To dissect how multilayered chromatin regulation sustains oncogenic transcription and tumor-stroma crosstalk in HCC, we combined multiomics single cell analysis.
METHODS
We integrated single-cell RNA sequencing and paired single-cell assay for transposase-accessible chromatin with sequencing data of HCC samples, complemented by bulk RNA sequencing validation across The Cancer Genome Atlas, Liver Cancer Institute, and GSE25907 cohorts. Cell type-specific chromatin architectures were resolved via ArchR, with regulatory hubs identified through peak-to-gene linkages and coaccessibility networks. Functional validation employed A485-mediated histone 3 lysine 27 acetylation suppression and small interfering RNA targeting DGAT1.
RESULTS
Malignant hepatocytes exhibited expanded chromatin accessibility profiles, characterized by increased numbers of accessible peaks and larger physical regions despite reduced peak intensity. Enhancer-like peaks enriched in malignant regulation, forming long-range hubs. Eighteen enhancer-like peak-related genes showed tumor-specific overexpression and diagnostic accuracy, correlating with poor prognosis. Intercellular coaccessibility analysis revealed tumor-stroma symbiosis via shared chromatin states. Pharmacological histone 3 lysine 27 acetylation inhibition paradoxically downregulated DGAT1, the hub gene most strongly regulated by chromatin accessibility. DGAT1 knockdown suppressed cell proliferation.
CONCLUSION
Multilayered chromatin reprogramming sustains HCC progression through tumor-stroma crosstalk and DGAT1-related oncogenic transcription, defining targetable epigenetic vulnerabilities.
