RNA-Sequencing analysis of liver tissue from healthy WT mice and Foxa3-Cre YAP1 knockout mice at 3-4 months of age

We developed a mouse model of bile duct paucity by deleting Yes-associated protein 1 (YAP1) in foregut endoderm progenitors, using the Foxa3 promoter to drive Cre expression. YAP1 KO mice are viable postnatally and survive long-term despite a complete failure of intrahepatic bile duct development, resembling the liver phenotype of Alagille syndrome. We also observed no functional biliary regeneration over time. Adult YAP1 KO mice suffer from severe chronic cholestasis, but show minimal hepatocellular injury, suggesting that the hepatocytes have adapted to preserve liver function and reduce damage from the toxicity of bile acids and bilirubin. We used RNA-seq to analyze the gene expression patterns of whole liver tissue of adult YAP1 KO mice compared to WT, and found significant changes in metabolic activity, bile acid synthesis and transport that reflect hepatocyte reprogramming for survival. Overall design: We analyzed 6 healthy liver tissue samples (3 male, 3 female) and 6 YAP1 KO liver tissue samples (3 male, 3 female).

本研究通过利用Foxa3启动子驱动Cre重组酶表达，在前肠内胚层祖细胞中敲除Yes相关蛋白1（Yes-associated protein 1，YAP1），构建了胆管缺乏症小鼠模型。YAP1敲除小鼠可在出生后存活并长期生存，尽管其肝内胆管发育完全失败，该表型与阿拉基尔综合征（Alagille syndrome）的肝脏表型相似。本研究同时观察到，随时间推移无功能性胆道再生发生。成年YAP1敲除小鼠会出现严重的慢性胆汁淤积，但肝细胞损伤极轻微，这提示肝细胞已发生适应性改变，以维持肝脏功能并减轻胆汁酸与胆红素毒性所致的损伤。本研究通过RNA测序（RNA-seq）分析了成年YAP1敲除小鼠与野生型（Wild Type，WT）小鼠的全肝组织基因表达谱，发现其代谢活性、胆汁酸合成与转运发生显著改变，这些改变反映了肝细胞为存活而发生的重编程。实验设计：本研究共分析了6份健康肝组织样本（3份雄性，3份雌性）以及6份YAP1敲除小鼠肝组织样本（3份雄性，3份雌性）。