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NOTCH-YAP1/TEAD-DNMT1 axis drives hepatocyte reprogramming into intrahepatic cholangiocarcinoma [RNA-Seq]

ABSTRACT: We reported the transcritpome in the healthy control liver of wild-type mice, liver bearing myrAKT-NICD driven ICC and livers bearing myrAKT-YAP driven Sox9 deleted HCC from liver-specific Sox9 knockout mice

ORGANISM(S): Mus musculus

PROVIDER: GSE145900 | GEO | 2023/07/25

REPOSITORIES: GEO

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NOTCH-YAP1/TEAD-DNMT1 axis drives hepatocyte reprogramming into intrahepatic cholangiocarcinoma [ChIP-Seq]

Project description:BACKGROUND AND AIM: Intrahepatic cholangiocarcinoma (ICC) is a liver tumor of increasing incidence and devastating prognosis. A critical barrier to developing an effective regimen for ICC is its intra- and inter-tumoral molecular heterogeneity, which may in part be due to its diverse cellular origin. We investigated clinical relevance and the molecular mechanisms underlying hepatocyte (HC)-driven ICC development. METHODS: Expression of ICC driver genes in human diseased livers at risk for ICC development were examined. Sleeping beauty and hydrodynamic tail vein injection based Akt-NICD/YAP1 ICC model was used to investigate pathogenetic roles of SOX9 and YAP1 in HC-driven ICC. These models and in silico studies led to identification of DNA methyltransferase-1 (DNMT1) as a YAP1 target, which was validated by both loss- and gain-of-function studies. RESULTS: Co-expression of AKT along with NICD/YAP1 in HC yielded ICC which resembled proliferative, Notch-activated, and stem cell-like subclasses of clinical ICC. NICD induced SOX9 and YAP1 in HC-driven ICC and deletion of either significantly delays ICC development. Yap1 deletion or TEAD inhibition, but not Sox9 deletion, impaired HC-to-biliary epithelial cell (BEC) reprogramming. DNMT1 was discovered as a novel downstream effector of YAP1-TEAD complex that directs HC-to-BEC/ICC fate-switch. DNMT1 loss prevented Notch/YAP1-dependent HC-driven cholangiocarcinogenesis, and DNMT1 re-expression restored ICC development following TEAD repression. Co-expression of DNMT1 with AKT was sufficient to induce tumor development including ICC. DNMT1 was detected in subset of HCs and dysplastic BECs in cholestatic human livers prone to ICC development. CONCLUSION: We identify a novel NOTCH-YAP1/TEAD-DNMT1 axis essential for of HC-to-BEC/ICC conversion, may be relevant in cholestasis-to-ICC pathogenesis in the clinic.

2023-07-25 | GSE200468 | GEO

NOTCH-YAP1/TEAD-DNMT1 axis drives hepatocyte reprogramming into intrahepatic cholangiocarcinoma [bulk RNA-Seq]

2023-07-25 | GSE200471 | GEO

YAP1 Exerts Its Transcriptional Control via TEAD-Mediated Activation of Enhancers.

Project description: Not available

| S-EPMC4546604 | biostudies-literature

Time series transcritpome in wild-type mice and XBP1 liver-specific knockout mice

Project description:We reported the liver transcritpome (taken at 2h interval for a total of 48 hrs) in the liver of wild-type mice and XBP1 liver-specific knockout mice

2019-11-26 | GSE130890 | GEO

Expression profiling of Notch constitutive activation in the liver of mice

Project description:Notch intracellular domain (NICD) is the active form of the Notch receptor. In this mouse model, NICD is inserted in the Rosa26 locus downstream of a loxP-STOP-LoxP (lsl) sequence and therefore NICD expression is dependant on Cre recombinase expression (Mono transgenic control Rosa26-lsl-NICD) . These mice are crossed with the AFP-Cre strain that expresses Cre in hepatoblasts due to its regulation by the AFP promoter and albumin enhancer (Double transgenic mutant AFP-Cre/Rosa26-lsl-NICD). Newborn mice at day 0 and day 2 are sacrificed and liver RNA samples from control monotransgenic Rosa26-lsl-NICD and from bitransgenic AFP-Cre/Rosa26-lsl-NICD (AFP-NICD) are obtained. Whole genome expression profiling of these samples is submitted. Five liver samples from Control mice and six liver samples from Mutant mice are analyzed using the Agilent Whole Mouse Genome Oligo Microarray G4122A platform. Array data was preprocessed and analyzed using GenePattern software and R.

2012-12-01 | E-GEOD-33560 | biostudies-arrayexpress

VGLL4 inhibits YAP1/TEAD signaling to suppress the epidermal squamous cell carcinoma cancer phenotype.

Project description: Not available

| S-EPMC8243851 | biostudies-literature

Expression profiling of Notch constitutive activation induced HCC in mice

Project description:Notch intracellular domain (NICD) is the active form of the Notch receptor. In this mouse model, NICD is inserted in the Rosa26 locus downstream of a loxP-STOP-LoxP (lsl) sequence and therefore NICD expression is dependant on Cre recombinase expression. These mice are crossed with the AFP-Cre strain that expresses Cre in hepatoblasts due to its regulation by the AFP promoter and albumin enhancer. Mice from 6 to 12 months are sacrificed and liver RNA samples from control monotransgenic Rosa26-lsl-NICD and confirmed HCC lesions from bitransgenic AFP-Cre/Rosa26-lsl-NICD (AFP-NICD) are obtained. Exon expression profiling of these samples are submitted. Four liver samples from monotransgenic mice (control) and five hepatocellular carcinoma samples from bitransgenic mice are analyzed using the Affymetrix GeneChip Mouse Gene 1.0 ST Array platform. Array data was preprocessed and analyzed using GenePattern software and R.

2012-12-01 | E-GEOD-33486 | biostudies-arrayexpress

Expression profiling of Notch constitutive activation in the liver of mice

2012-12-01 | GSE33560 | GEO

The novel potent TEAD inhibitor, K-975, inhibits YAP1/TAZ-TEAD protein-protein interactions and exerts an anti-tumor effect on malignant pleural mesothelioma.

Project description: Not available

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YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis.

Project description: Not available

| S-EPMC6718408 | biostudies-literature