Reprogramming the Liver in Obesity: Methylation, Transcription Factors, and Proteomic Insights

A transomic study integrating the methylome, transcriptome, and proteome demonstrates how obesity remodels the hepatic proteome through coordinated epigenetic and transcriptional changes, with direct implications for NAFLD/NASH biomarkers and therapeutic targeting. The primary mechanistic insight is that shifts in transcription factor networks—supported by focal DNA methylation changes at select regulatory loci—drive most proteomic remodeling in obesity.

The investigators performed genome-wide DNA methylation profiling alongside RNA sequencing and proteome-scale quantitation in hepatocyte-enriched liver samples from lean and obese mammalian models. They applied pathway-level enrichment and transcription factor activity inference to the integrated dataset, mapped promoter and enhancer methylation, overlaid TF binding motifs and ChIP-derived sites, and correlated transcript with protein abundance to connect regulatory layers. The comparative framework directly contrasted obese versus lean livers across methylome, transcriptome, and proteome layers to define multilayer associations.

Methylation changes were focal rather than global, concentrated at specific CpG sites and regulatory regions. These localized alterations preferentially associated with decreased protein expression in components of the complement and coagulation cascades, implicating epigenetic repression of immune-related hepatic modules. Local promoter or enhancer methylation can restrict transcription factor access or alter gene-body regulation, producing downstream reductions in protein abundance; overall, methylation most strongly implicated complement and coagulation programs in the obese liver.

Across the integrated data, inferred transcription factor expression and activity explained a larger share of gene and protein variance than promoter-proximal methylation. In particular, the transcription factor Hnf4a emerged as a high-confidence driver: TF-activity inference, concordant correlations between Hnf4a target transcripts and proteins, and proteomic concordance supported its central role in hepatic reprogramming. These lines of evidence point to altered TF networks—rather than widespread promoter methylation—as the dominant force in obesity-associated proteomic remodeling.

Translationally, proteins showing obesity-specific methylation changes together with TF-driven regulation represent prioritized biomarker and therapeutic candidates.