Systems-level analysis of transcriptome reorganization during liver regeneration

Tissue homeostasis and regeneration depend on the reversible transitions between quiescence (G0) and proliferation. The liver has a remarkable capacity to regenerate after injury or resection by cell growth and division. During regeneration, the liver needs to maintain the essential metabolic tasks and meet the metabolic requirements for hepatocyte growth and division. Understanding the regulatory mechanisms involved in balancing the liver function and proliferation demand after injury or resection is crucial. In this study, we analyzed high-resolution temporal RNA sequencing data of liver regeneration after two-thirds partial hepatectomy (PHx) using network inference and mathematical modeling approaches. The reconstruction of the dynamic regulatory network of liver regeneration reveals the trajectories of different metabolic pathways, protein processing in the endoplasmic reticulum (ER), ribosome biogenesis, RNA transport, spliceosome, immune response, and cell cycle. We further developed a mathematical model of the integrated circuit of liver regeneration that accounts for underlying features of compensatory metabolism, proliferation, and epithelial-to-mesenchymal transition during liver regeneration. We show that a mutually exclusive behavior emerges due to the bistable inactivation of HNF4A, which controls the initiation and termination of liver regeneration and different population-level expressions observed in single-cell RNA sequencing data of liver regeneration.