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. We analyzed 6 healthy liver tissue samples (3 male, 3 female) and 6 YAP1 KO liver tissue samples (3 male, 3 female).我们通过利用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），构建了胆管缺乏的小鼠模型。YAP1敲除小鼠虽肝内胆管发育完全失败，但出生后即可存活且可长期存活，其肝脏表型与阿拉基尔综合征（Alagille syndrome）相似。我们同时观察到，随时间推移未出现功能性胆道再生。成年YAP1敲除小鼠会出现严重慢性胆汁淤积，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造成的损伤。我们通过RNA测序（RNA-seq）对比分析了成年YAP1敲除小鼠与野生型（Wild Type, WT）全肝组织的基因表达谱，发现代谢活性、胆汁酸合成与转运相关基因出现显著变化，这些变化反映了肝细胞为存活而发生的重编程。本次研究共分析6份健康肝组织样本（3份雄性，3份雌性）与6份YAP1敲除肝组织样本（3份雄性，3份雌性）。