Department of Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
Wuhan Ammunition Life-tech Company, Ltd., CN, Wuhan, Hubei Province, China.
PeerJ. 2024 Aug 23;12:e17916. doi: 10.7717/peerj.17916. eCollection 2024.
Aberrant DNA methylation patterns play a critical role in the development of hepatocellular carcinoma (HCC). However, the molecular mechanisms associated with these aberrantly methylated genes remain unclear. This study aimed to comprehensively investigate the methylation-driven gene expression alterations in HCC using a multi-omics dataset.
Whole genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) techniques were used to assess the methylation and gene expression profiles of HCC tissues (HCCs) and normal adjacent tissues (NATs). The candidate genes' potential function was further investigated using single-cell RNA sequencing (scRNA seq) data.
We observed widespread hypomethylation in HCCs compared to NATs. Methylation levels in distinct genomic regions exhibited significant differences between HCCs and NATs. We identified 247,632 differentially methylated regions (DMRs) and 4,926 differentially expressed genes (DEGs) between HCCs and NATs. Integrated analysis of DNA methylation and RNA-seq data identified 987 methylation-driven candidate genes, with 970 showing upregulation and 17 showing downregulation. Four genes involved in the retinol metabolic pathway, namely , , , and , were identified as hyper-downregulated genes. Their expression levels could stratify HCCs into three subgroups with distinct survival outcomes, immune cell infiltration, and tumor microenvironments. Validation of these findings in an independent dataset yielded similar outcomes, confirming the high concordance and potential prognostic value of these genes. ScRNA seq data revealed the low expression of these genes in immune cells, emphasizing their role in promoting malignant cell proliferation and migration. In conclusion, this study provides insights into the molecular characteristics of HCC, revealing the involvement of retinol metabolism-related genes in the development and progression of HCC. These findings have implications for HCC diagnosis, prognosis prediction, and the development of therapeutic targets.
异常的 DNA 甲基化模式在肝细胞癌（HCC）的发展中起着关键作用。然而，与这些异常甲基化基因相关的分子机制仍不清楚。本研究旨在使用多组学数据集全面研究 HCC 中甲基化驱动的基因表达变化。
全基因组亚硫酸氢盐测序（WGBS）和 RNA 测序（RNA-seq）技术用于评估 HCC 组织（HCCs）和正常相邻组织（NATs）的甲基化和基因表达谱。使用单细胞 RNA 测序（scRNA seq）数据进一步研究候选基因的潜在功能。
我们观察到 HCC 与 NATs 相比表现出广泛的低甲基化。不同基因组区域的甲基化水平在 HCC 和 NATs 之间存在显著差异。我们在 HCC 和 NATs 之间鉴定了 247632 个差异甲基化区域（DMRs）和 4926 个差异表达基因（DEGs）。对 DNA 甲基化和 RNA-seq 数据的综合分析确定了 987 个甲基化驱动的候选基因，其中 970 个基因上调，17 个基因下调。参与视黄醇代谢途径的四个基因，即、、和，被鉴定为高度下调基因。它们的表达水平可以将 HCC 分为三个具有不同生存结果、免疫细胞浸润和肿瘤微环境的亚组。在独立数据集上验证这些发现得到了相似的结果，证实了这些基因的高度一致性和潜在的预后价值。scRNA seq 数据显示这些基因在免疫细胞中的低表达，强调了它们在促进恶性细胞增殖和迁移中的作用。总之，本研究提供了 HCC 分子特征的深入了解，揭示了视黄醇代谢相关基因在 HCC 发生和发展中的参与。这些发现对 HCC 的诊断、预后预测和治疗靶点的开发具有重要意义。
