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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE291359 | GEO | 2025/04/21

REPOSITORIES: GEO

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Project description:Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases. Total RNA isolated using TRI Reagent (Sigma, St. Louis, MO) was purified with an RNeasy mini kit (Qiagen, Valencia, CA). Twenty micrograms cRNA was hybridized to a mouse GeneChip (U74Av2, Affymetrix, Santa Clara, CA) at the Siteman Cancer Center GeneChip facility as described by the manufacturer. Analyses used one mouse per chip. Gene expression changes were analyzed using Affymetrix MicroArray Suite 4.0 and GeneChip 3.1 Expression Analysis and Statistical Algorithms (Affymetrix). The complete methodology and full data sets for all 6 analyzed chips are available at http://bioinformatics.wustl.edu.beckerproxy.wustl.edu This study compares the injury and repair processed in wild-type mice after BDL.

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

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