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

Area of Science:

• Hepatology and Cancer Research
• Epigenetics and Molecular Biology
• Genomics and Bioinformatics

Background:

• Metabolic dysfunction-associated steatotic liver diseases (MASLD), formerly NAFLD, are a major risk factor for liver cancer (HCC).
• MASLD progression involves stages like simple steatosis, advanced liver fibrosis (ALF), and metabolic dysfunction-associated steatohepatitis (MASH/NASH).
• Understanding the epigenetic changes driving this progression is crucial for identifying HCC risk and developing targeted therapies.

Purpose of the Study:

• To investigate DNA methylation changes during MASLD progression.
• To determine the role of these methylation changes in gene regulation.
• To assess the association between DNA methylation patterns and hepatocellular carcinoma (HCC) survival.

Main Methods:

• Analysis of methylomic datasets from human MASLD/NAFLD liver samples using Illumina 450K BeadChip.
• Identification of differentially methylated regions (DMRs) associated with ALF and non-fibrotic NASH.
• Integrative data analysis to link DMRs with gene expression and HCC survival outcomes.

Main Results:

• Fibrosis-associated DMRs were enriched in pathways related to xenobiotic metabolism, UV response, and hypoxia.
• Expression of 25 DMR-associated genes significantly correlated with HCC survival, including genes linked to fibrosis and NASH.
• Four key genes (ESR1, TYW3, CLGN, TUBB) showed an inverse methylation-expression relationship during MASLD progression, validated in a mouse model.

Conclusions:

• Promoter DNA methylation changes are critical regulators of gene expression during MASLD progression.
• These epigenetic modifications influence hepatocellular carcinoma (HCC) survival outcomes.
• A model is proposed where DNA methylation dynamics drive liver disease advancement and cancer risk.