Systems-level analysis of transcriptome reorganization during liver regeneration

Abstract

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 bulk RNA sequencing temporal data of liver regeneration after two-thirds partial hepatectomy (PHx) using network inference and mathematical modeling approaches. The reconstruction of the dynamic regulatory network reveals the overall coordination of metabolism, RNA splicing, and cell cycle during liver regeneration. A temporal shift in the gene expression pattern corresponding to increased hepatocyte proliferation and decreased hepatocyte function is observed with HNF4A as a key transcriptional activator. A mathematical model of the HNF4A regulatory circuit shows the emergence of different states corresponding to compensatory metabolism, proliferation, and epithelial-to-mesenchymal transition as observed in single-cell RNA sequencing data of 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 behaviour.