Role of Sox9 in Yap activated hepatocytes
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ABSTRACT:
PROVIDER: PRJNA610896 | ENA |
REPOSITORIES: ENA
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Project description:Hepatocyte specific TBG promoter-driven Cre,GFP and YAP S127A expression was achieved by retro orbital injection of AAV. RNA-seq was performed for hepatocytes isolated by FACS.
2021-11-17 | GSE146589 | GEO
Project description:Primary isolated hepatocytes derived from wildtype mice are compared with hepatocytes isolated from YAP(S127A) transgenic mice (Tschaharganeh at al., 2013 Gastroenterology, PMID 23419361). YAP induction was done for 8 weeks and livers showed hyperplasia without signs of malignant transformation.
2017-10-19 | GSE89284 | GEO
Project description:Objective: YAP impairs hepatocyte regeneration in alcohol-related hepatitis (AH) but its impact on fibrogenesis remains unknown. Our aim was to describe fibrogenesis during AH and the relationship between impaired hepatocyte regeneration and fibrogenesis. Design: Fibrosis distribution and colocalization of YAP and αSMA were assessed by immunostaining. Extracellular matrix (ECM) composition in patients with severe AH (n=22) or alcohol-related cirrhosis (Cirrh, n=24) and healthy livers (Ctrl, n=15) was assessed by bulk and spatial proteomics and PCR. We generated organoids from AH and Cirrh livers and evaluated their impact on myofibroblasts in a 3D coculture model. Cirrh organoids were transduced with an active YAP and cocultured with myofibroblasts. Myofibroblasts were also cultured with medium from transduced (YAP medium) or not-transduced hepatocytes (CTRL medium).
2025-09-09 | PXD044031 | Pride
Project description:Assessment of Hepatocytes in response to Yap/Taz knockout and also CCl4 injury
2019-09-01 | GSE113756 | GEO
Project description:Background and aims: The Hippo pathway and its downstream effectors YAP and TAZ (YAP/TAZ) are heralded as important regulators of organ growth and regeneration. However, different studies provided contradictory conclusions about their role during regeneration of different organs ranging from promoting proliferation to inhibiting it. Here, we resolve the function of YAP/TAZ during regeneration of the liver, where Hippo’s role in growth control has been studied most intensely. Methods: We evaluated liver regeneration after CCl4 toxic liver injury in mice with conditional deletion of Yap/Taz in hepatocytes and/or biliary epithelial cells and measured the behavior of different cell types during regeneration by histology, RNA-sequencing and flow cytometry. Results: We found that YAP/TAZ were activated in hepatocytes in response to CCl4 toxic injury. However, their targeted deletion in adult hepatocytes did not noticeably impair liver regeneration. In contrast, Yap/Taz deletion in adult bile ducts caused severe defects and delay in liver regeneration. Mechanistically, we show that Yap/Taz mutant bile ducts degenerated, causing cholestasis which stalled the recruitment of phagocytic macrophages and the removal of cellular corpses from injury sites. Elevated bile acids activated PXR, which was sufficient to recapitulate the phenotype observed in mutant mice. Conclusions: Our data show that YAP/TAZ are practically dispensable in hepatocytes for liver development and regeneration. Rather, YAP/TAZ play an indirect role in liver regeneration by preserving bile duct integrity and securing immune cell recruitment and function.
2020-11-02 | GSE157088 | GEO
Project description:Comparson of Biphenotypic hepatocytes with Mature Hepatocytes Biphenotypic hepatocytes were isolated from DDC-injured liver as Sox9+EpCAM- cells. Gene expression profile of biphenotypic hepatocytes were compared with that of Mature hepatocytes.
2016-03-02 | E-GEOD-78778 | biostudies-arrayexpress
Project description:Bile acid (BA) production is a critical metabolic function of the liver, and its disruption leads to various liver diseases including hepatocellular carcinoma (HCC). However, the underlying molecular mechanism remained elusive. Here, we report that BA metabolism is directly controlled by a previously unidentified repressor function of YAP, a transcriptional activator known to promote HCC formation. We show in hepatocytes, activated YAP suppressed Fxr, a BA-sensing nuclear receptor that critically regulates BA production and export. The repressor function of activated YAP induced cholestasis damaged the liver, and altered liver and serum BA concentrations and composition. Specifically, YAP activation inhibited expression of an Fxr target gene, Bsep (Abcb11), impairing BA exportation and injuring hepatocytes. Elevated BA in the blood due to hepatocyte injury further activated hepatic YAP, resulting in a vicious cycle leading to HCC. In both mouse liver and human HCC patient samples, transcriptomic analysis negatively correlated YAP and Fxr activities. Mechanistically, Fxr was found to bind Teads in a DNA-binding-independent manner; and Teads recruited YAP to epigenetically reprogram Fxr by replacing the histone acetyltransferase, P300, with the histone deacetylase, HDAC1. Importantly, alleviating YAP repressor function in BA metabolism by activating Fxr with its agonist GW4064, inhibiting HDAC1 with Entinostat, or overexpressing Bsep, reduced cholestatic phenotypes including hepatic injury, fibrosis, and inflammation, alleviating the HCC caused by YAP activation. Our results identify Yap's transcriptional repressor role as a key driver of Yap-induced HCC and BA metabolism as a potential therapeutic target for HCC.
2025-02-10 | GSE272343 | GEO
Project description:YAP is a transcriptional co-activator of the hippo signaling pathway and is known for its oncogenic and regenerative activity across numerous tissue types. In particular, high YAP levels in patients with gastric cancer (GC) confer a lower survival rate and poor prognosis for these individuals. Therefore, there is a great need to develop targeted therapies against these aggressive tumors. However, the role of YAP and its underlying molecular mechanisms during gastric tumorigenesis are still poorly understood. Using genetic models, we demonstrate the oncogenic function of YAP in CLU+ gastric cells in vivo. YAP over-expression in CLU+ cells induced atrophy, metaplasia and hyperproliferation in the gastric corpus, while its deletion in a Notch activated gastric tumor model rescued metaplasia. Furthermore, we defined the YAP1 targetome in YAP activated gastric tumors, and showed that YAP1 binds to the active chromatin elements of spasmolytic polypeptide-expressing metaplasia (SPEM) related genes and activates their expressions in gastric tumors and ulcers. Together, these results reveal YAP1 as a critical regulator of metaplasia in the gastric corpus, and highlights YAP signaling as a possible therapeutic target to inhibit the progression of gastric tumors.
2023-11-07 | GSE199171 | GEO
Project description:YAP is a transcriptional co-activator of the hippo signaling pathway and is known for its oncogenic and regenerative activity across numerous tissue types. In particular, high YAP levels in patients with gastric cancer (GC) confer a lower survival rate and poor prognosis for these individuals. Therefore, there is a great need to develop targeted therapies against these aggressive tumors. However, the role of YAP and its underlying molecular mechanisms during gastric tumorigenesis are still poorly understood. Using genetic models, we demonstrate the oncogenic function of YAP in CLU+ gastric cells in vivo. YAP over-expression in CLU+ cells induced atrophy, metaplasia and hyperproliferation in the gastric corpus, while its deletion in a Notch activated gastric tumor model rescued metaplasia. Furthermore, we defined the YAP1 targetome in YAP activated gastric tumors, and showed that YAP1 binds to the active chromatin elements of spasmolytic polypeptide-expressing metaplasia (SPEM) related genes and activates their expressions in gastric tumors and ulcers. Together, these results reveal YAP1 as a critical regulator of metaplasia in the gastric corpus, and highlights YAP signaling as a possible therapeutic target to inhibit the progression of gastric tumors.
2023-11-07 | GSE199170 | GEO
Project description:The transcriptional cofactor yes-associated protein (YAP) functions as a proto-oncogene and a key effector of the canonical Hippo pathway. Phosphorylation at serine 127 (S127) by core Hippo kinases inhibits YAP activity, while phosphorylation at tyrosine 357 (Y357) by SRC-family kinases promotes its activation. YAP activation has been implicated in many cancers, including primary liver cancers (PLCs). Owing to the inherent plasticity of the liver, PLCs may arise from different cells of origin. However, it is unknown whether the level of YAP activation favors liver tumorigenesis from specific cells of origin or instead promotes lineage commitment in a single cell of origin across the PLC spectrum. To assess the role of YAP tyrosine phosphorylation in liver tumorigenesis, C57BL/6 mice underwent biliary transfection with the Sleeping Beauty transposon system to deliver myr-AKT and YAP S127A (YAP-S) or YAP S127A/Y357F (YAP-SY). While YAP-S mice represent an established model of intrahepatic cholangiocarcinoma (iCCA), unexpectedly, a shift in tumor phenotype to hepatocellular carcinoma (HCC) was identified in YAP-SY mice. Transcriptome and pathway analysis revealed differential activation of cytokines and growth factors (e.g., TGFB1, TNF, IL1B, IL4, and INFG) and transcription factors (e.g., STAT3, PGR, AHR, STAT1, and NFKB) associated with this phenotypic switch. To determine the cell of origin, tumors were generated in lineage tracing mice (ROSA26mT/mG mice treated with AAV8-TBG-Cre), which demonstrated that HCC originated from hepatocytes and iCCA from cholangiocytes in the biliary transfection model. Finally, two tumor-derived cell lines with YAP-SY and constitutive AKT expression were isolated, representing a novel, transplantable murine syngeneic model with mixed features of HCC and iCCA.
2025-12-31 | GSE297845 | GEO