A temporal map of gene expression pattern during zebrafish liver regeneration

Abstract

Highlights: Zebrafish is a valuable model for developing therapeutic strategies to augment liver regeneration  Liver regeneration in zebrafish is not well studied and pathways poorly understood  We develop a hepatocyte ablation model of liver injury and regeneration in adult zebrafish  We generate a comprehensive transcriptomic map of various stages of liver injury and regeneration  We discover a novel regulation of cholesterol biosynthesis pathways during liver regeneration Abstract:Background & Aims: Zebrafish is increasingly being used to study liver injury and regeneration. However, very little is known about molecular players that respond to injury and participate in liver regeneration. Here we aim to generate a temporal map of gene expression changes at injury and during regeneration of the adult zebrafish liver. Methods:We use a metronidazole-nitroreductase (MTZ-nfsb) based system to selectively ablate hepatocytes in adult zebrafish to create a model for liver injury and regeneration. Through RNA sequencing of liver samples at multiple time points we 2 generate a comprehensive temporal map of gene expression changes during injury and regeneration.Results: Gene expression reveals that soon after injury the immediate early transcription factor MYC induces a battery of genes that respond to the metronidazole-induced ROS by activating oxido-reductase pathways and apoptosis machinery. Upon injury, liver cells down regulate genes encoding complement proteins, bile acid and lipid biosynthesis pathway in a concerted manner. Midway through regeneration, we discover a spike of cholesterol biosynthesis and protein folding machinery genes suggesting an important role for these pathways in liver regeneration. Conclusions:The temporal transcriptomic map of liver regeneration would serve as a framework for further studies in understanding, and for screening for compounds that augment liver regeneration. General significance:Using a hepatocyte specific ablation of zebrafish liver, we create a model of adult liver regeneration. This model was used to generate a comprehensive transcriptomic map of gene expression trends during liver regeneration. This temporal map lays the groundwork to study important events in liver regeneration.