Systems-level analysis of transcriptome reorganization during liver regeneration

Area of Science:

• Molecular Biology
• Systems Biology
• Regenerative Medicine

Background:

• Tissue homeostasis relies on reversible cell cycle transitions between quiescence (G0) and proliferation.
• The liver exhibits significant regenerative capacity following injury or resection.
• Balancing metabolic demands with growth requirements during liver regeneration is critical.

Purpose of the Study:

• To elucidate the regulatory mechanisms governing liver regeneration.
• To understand the interplay between liver function and proliferation.
• To identify key regulators of the regenerative process.

Main Methods:

• Analysis of bulk RNA sequencing temporal data from liver regeneration after partial hepatectomy (PHx).
• Application of network inference and mathematical modeling to reconstruct dynamic regulatory networks.
• Utilizing single-cell RNA sequencing data to validate model predictions.

Main Results:

• Reconstruction of a dynamic regulatory network coordinating metabolism, RNA splicing, and cell cycle during liver regeneration.
• Identification of a temporal shift in gene expression favoring hepatocyte proliferation over function.
• Hepatocyte Nuclear Factor 4 Alpha (HNF4A) identified as a key transcriptional activator.
• A mathematical model of the HNF4A regulatory circuit predicted distinct states (compensatory metabolism, proliferation, epithelial-to-mesenchymal transition).
• Bistable inactivation of HNF4A was shown to control the initiation and termination of liver regeneration.

Conclusions:

• HNF4A plays a central role in orchestrating liver regeneration by controlling distinct cellular states.
• A mutually exclusive behavior emerges from HNF4A bistability, regulating regenerative processes.
• Understanding HNF4A's role provides insights into controlling liver regeneration and potential therapeutic strategies.