Chromatin State Distinguishes Injury-Responsive from State-Stabilizing Transcriptional Programs in Hybrid...

Area of Science:

• Epigenetics and Genomics
• Hepatology and Liver Disease
• Cellular Biology

Background:

• Chromatin features distinguishing injured from healthy hepatocytes are poorly understood.
• Sox9-expressing hepatocytes exhibit hybrid hepatocyte/biliary identity.
• Chronic liver injury leads to expansion of Sox9+ metaplastic hepatocytes (MetHeps).

Purpose of the Study:

• To define the transcriptional and chromatin landscape of Sox9+ hepatocytes during liver injury.
• To elucidate the distinct chromatin mechanisms governing injury-responsive and state-associated gene programs.
• To investigate the role of chromatin accessibility and histone modifications in regulating hepatocyte plasticity.

Main Methods:

• Integrated functional genomics approach combining bulk RNA-seq, ATAC-seq, and CUT&Tag profiling (H3K27ac, H3K27me3).
• Analysis of Sox9+ hybrid hepatocytes (HybHeps) and metaplastic hepatocytes (MetHeps) under homeostatic and injury conditions.
• Projection of mouse-derived gene programs onto a human liver single-cell atlas.

Main Results:

• Three classes of differentially expressed genes (injury-responsive, state-associated, shared) are identified, each governed by distinct chromatin mechanisms.
• Injury-responsive transcription is driven by dynamic chromatin remodeling at NF-κB and AP-1 sites.
• HybHeps possess a permissive chromatin landscape at injury-responsive loci, enabling rapid inflammatory activation.
• SOX9+ hepatocytes in humans engage inflammatory pathways while reducing metabolic functions during injury.

Conclusions:

• A chromatin-based regulatory dichotomy exists between inflammatory responsiveness and hybrid hepatocyte cell state stability.
• Epigenetic priming in HybHeps facilitates rapid inflammatory responses upon injury.
• Differentiated epithelial cells integrate inflammatory signals while maintaining cell state through distinct chromatin mechanisms.