DNA Methylation and Target Gene Expression in Fatty Liver Progression From Simple Steatosis to Advanced Fibrosis

IF 5.2 2区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Liver International Pub Date : 2025-02-21 DOI:10.1111/liv.70040

Jin Li, Xiaoqin Liu, Tran T. Tran, Miryoung Lee, Robert Y. L. Tsai

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Abstract

Background and Aim

Metabolic dysfunction-associated steatotic liver diseases (MASLD), also known as non-alcoholic fatty liver diseases (NAFLD), have become a leading risk factor for hepatocellular carcinoma (HCC) in Western countries. NAFLD progresses from simple steatosis to HCC, with advanced liver fibrosis (ALF) and metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic steatohepatitis (NASH) representing the two preceding high-risk stages.

Methods

We analysed changes in the DNA methylation landscape from simple steatosis to ALF or NASH and determined their relevance in gene regulation and HCC survival. Methylomic datasets generated from applying the Illumina 450K BeadChip on human MASLD/NAFLD liver samples were analysed using integrative data analyses to identify differentially methylated regions (DMRs) associated with ALF (F3/4 vs. F0/1) or non-fibrotic NASH (NASH-F0/1 vs. NAFLD-F0/1).

Results

Gene Set Enrichment Analysis (GSEA) of genes associated with fibrosis-DMRs showed enrichment in xenobiotic metabolism, UV response and hypoxia pathways. Expression of 25 DMR-associated genes showed significant associations with HCC survival outcomes, including 16 genes with fibrosis-DMRs and 2 with NASH-DMRs mapped to their promoter regions. Binding motifs of seven transcription factors (TFs) were enriched in fibrosis-DMRs. Four DMR-associated genes (ESR1, TYW3, CLGN and TUBB) displayed an inverse relationship between promoter methylation and gene expression during human MASLD progression, which was further validated in a mouse MASLD model.

Conclusions

We propose a model in which changes in promoter DNA methylation during NAFLD progression regulate gene expression, impacting HCC survival outcomes.

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从单纯脂肪变性到晚期纤维化的脂肪肝进展过程中的 DNA 甲基化和靶基因表达

背景与目的代谢功能障碍相关脂肪变性肝病（MASLD），又称非酒精性脂肪性肝病（NAFLD），在西方国家已成为肝细胞癌（HCC）的主要危险因素。NAFLD从单纯脂肪变性发展为HCC，晚期肝纤维化（ALF）和代谢功能障碍相关脂肪性肝炎（MASH）或非酒精性脂肪性肝炎（NASH）代表前两个高危阶段。方法分析DNA甲基化景观的变化，从单纯脂肪变性到ALF或NASH，并确定其与基因调控和HCC生存的相关性。将Illumina 450K BeadChip应用于人类MASLD/NAFLD肝脏样本产生的甲基化数据集使用综合数据分析来识别与ALF （F3/4 vs. F0/1）或非纤维化NASH （NASH-F0/1 vs. NAFLD-F0/1）相关的差异甲基化区域（DMRs）。结果基因集富集分析（Gene Set Enrichment Analysis， GSEA）显示，纤维化- dmrs相关基因在外源代谢、紫外线反应和缺氧途径中富集。25个dmr相关基因的表达与HCC生存结果显著相关，其中16个基因与纤维化- dmrs相关，2个基因与NASH-DMRs相关。7个转录因子的结合基序在纤维化- dmrs中富集。四种dmr相关基因（ESR1, TYW3， CLGN和TUBB）在人类MASLD进展过程中显示启动子甲基化与基因表达呈反比关系，这在小鼠MASLD模型中得到进一步验证。我们提出了一个模型，在该模型中，NAFLD进展过程中启动子DNA甲基化的变化调节基因表达，影响HCC的生存结果。

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来源期刊

Liver International 医学-胃肠肝病学

CiteScore

13.90

自引率

4.50%

发文量

348

审稿时长

2 months

期刊介绍： Liver International promotes all aspects of the science of hepatology from basic research to applied clinical studies. Providing an international forum for the publication of high-quality original research in hepatology, it is an essential resource for everyone working on normal and abnormal structure and function in the liver and its constituent cells, including clinicians and basic scientists involved in the multi-disciplinary field of hepatology. The journal welcomes articles from all fields of hepatology, which may be published as original articles, brief definitive reports, reviews, mini-reviews, images in hepatology and letters to the Editor.