Pbrm1 loss induces a permissive chromatin state for cholangiocytic differentiation and cholangiocarcinoma formation

Background and Aims: The SWI/SNF ATP-dependent chromatin remodeling complex regulates transcrip-tional machinery access and is critical in normal physiology and cancer development. Pbrm1, a key subunit of this complex, is frequently mutated in intrahepatic cholan-giocarcinoma (ICC), though how its loss contributes to tumorigenesis remains poor-ly understood. This study aims to explore the role of Pbrm1 in liver physiology and its involvement in ICC development. Methods: Liver-specific Pbrm1 knockout (Pbrm1 KO) mice were generated to assess the ef-fects of Pbrm1 loss under various conditions. These mice were exposed to a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to induce cholestatic injury and were also subjected to a high-fat diet to evaluate susceptibility to liver steatosis. Chromatin accessibility and gene expression under both normal and injury condi-tions were examined. Additionally, the impact of Pbrm1 loss was analyzed in com-bination with an activating KrasG12D mutation to study cancer development. Results: Pbrm1 KO mice exhibited increased susceptibility to cholestatic injury, with an en-hanced ductular reaction. Loss of Pbrm1 reduced chromatin accessibility at hepato-cyte-specific and metabolically important genes, though RNA expression remained unaffected during homeostasis. Following cholestatic injury, hepatocyte-specific gene expression was significantly reduced compared to wild-type controls. Pbrm1 KO mice also showed heightened vulnerability to high-fat diet-induced liver steato-sis. When combined with KrasG12D mutation, Pbrm1 KO/KrasG12D mice had shorter survival and were more likely to develop cholangiocarcinomas, whereas Pbrm1 wild type/KrasG12D mice predominantly developed hepatocellular neoplasms. Conclusion: Pbrm1 maintains chromatin accessibility for hepatocyte differentiation-related genes. Its loss promotes differentiation toward cholangiocytes during injury or tu-morigenesis, driving ICC development.