Exploring the sex-dependent effects of midnolin loss on hepatic transcription and chromatin accessibility.

Midnolin (Midn) is a ubiquitin-like domain-containing nuclear protein that interacts with the proteasome and mediates ubiquitin-independent degradation of transcription factors. Although Midn has been implicated in pancreatic β-cell metabolism, immune regulation, and hepatocellular carcinoma (HCC) progression, its physiological role in normal liver remains poorly defined. To investigate Midn function in vivo, we generated a liver-specific Midn eXpressed/Trapped/Restored [XTR] conditional-by-inversion gene-trap mouse model. Transcriptomic and chromatin accessibility profiling were performed using RNA-seq and ATAC-seq in male and female livers. Midn loss resulted in sex-dependent transcriptional alterations. In male liver, differential expression analysis revealed prominent changes in lipid-associated pathways, including fatty acid biosynthesis, steroid metabolism, and retinoic acid and bile acid metabolism. In females, fewer but biologically coherent transcriptional changes were observed, with enrichment of metabolic and membrane-associated gene categories. ATAC-seq in female liver identified modest changes in chromatin accessibility and enrichment of transcription-factor motifs associated with nuclear receptor and hepatic metabolic regulatory programs, whereas exploratory analysis in male liver using a less stringent statistical threshold suggested potential accessibility changes involving similar programs related to hepatocyte identity and metabolism. Together, these findings suggest that Midn contributes to hepatic transcriptional regulation and may influence chromatin accessibility in a sex-dependent manner. Our study provides insight into Midn function in liver homeostasis and establishes a foundation for investigating how Midn-dependent proteasomal control may contribute to metabolic liver disease and HCC.