Clinical and Molecular Hepatology最新文献

Background/aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. Aberrant DNA methylation, which is primarily maintained by DNA methyltransferase 1 (DNMT1), has been linked to metabolic dysregulation; however, its contribution to MASLD pathogenesis remains poorly defined. This study aimed to elucidate the role of DNMT1-mediated methylation in transcriptional regulation during MASLD progression and to determine whether DNMT1 inhibition can reverse disease-associated epigenetic and transcriptional alterations.

Methods: We conducted integrated analyses of the liver transcriptome (n = 131) and DNA methylome (n = 106) of patients with biopsy-proven MASLD. We evaluated the effect of DNMT1 inhibition with 5-aza-4'-thio-2'-deoxycytidine (Aza-TdC) on a diet-induced MASLD mouse model. Multiomics approaches, including DNA methylome profiling, lipidomics, bulk and single-nucleus RNA sequencing, and chromatin immunoprecipitation sequencing, were applied to elucidate the role of DNMT1-mediated DNA methylation in regulating pathogenic gene expression.

Results: DNA methylome profiling revealed increased methylation variability associated with increased DNMT1 expression in MASLD patients. DNMT1 inhibition ameliorated dysregulated lipid metabolism by reducing hepatic triacylglycerol accumulation and inflammation. Aza-TdC treatment partially reversed MASLD-related hypermethylation of hepatocyte nuclear factor 4 alpha (HNF4α)- and peroxisome proliferator-activated receptor alpha (PPARα)-regulated genes, restoring their transcriptional activity. Notably, Aza-TdC reactivated the gluconeogenic enzyme-encoding gene phosphoenolpyruvate carboxykinase 1 (PCK1), which was hypermethylated and transcriptionally repressed in MASLD. Targeted DNA methylation of the PCK1 promoter using CRISPRoff confirmed the direct epigenetic regulation of PCK1 expression.

Conclusions: Targeting DNMT1 may mitigate lipid dysregulation and inflammation by reversing hypermethylation and restoring HNF4α- and PPARα-dependent gene transcription, highlighting DNMT1 as a potential therapeutic target for MASLD.

Background: Hepatocellular carcinoma (HCC) is characterized by profound transcriptomic dysregulation, yet the mechanism(s) by which DNA methylation is coordinated with chromatin modifications to regulate alternative splicing during tumorigenesis remains poorly understood.

Methods: Using prospectively paired multi-omics data obtained from MASLD-HCC patients and coupled with a premalignant MASLD cohort we have uncovered a previously unrecognized gene-regulatory axis centered on TACC3 isoform switching.

Results: In the non-tumoral context, the TACC3-201 isoform directly engages the histone acetyltransferase KAT2A to coordinate the regulation of NOTCH4 signaling. In HCC, this regulatory axis is disrupted whereby FOXM1 overrides DNMT1-mediated methylation, upregulating TACC3, and decoupling TACC3 from the KAT2A-associated NOTCH4 co-expression module. This rewiring is licensing tumor-specific cell-cycle progression and epigenetic plasticity. Thus, FOXM1 reshapes the TACC3-KAT2A interaction, while DNMT1 drives context-dependent DNA methylation, activating the CDK1-inhibitory kinase PKMYT1.

Conclusion: We uncovered TACC3-KAT2A as an emerging regulatory axis caused by alternative splicing in HCC and propose FOXM1-driven TACC3 inhibition to synergistically disrupt mitotic fidelity and transcriptional regulation, potentially offering new therapeutic avenues for HCC with reduced toxicity to the normal liver.