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GRHL2 derepression triggers pathophysiological hepatocyte to cholangiocyte transdifferentiation [RNAseq_HepG2_EZHi]

ABSTRACT: Transcriptome of human HepG2 cells treated or not with Ezh1/2 inhibitors (UNC1999 and Valmetostat Tosylate).

ORGANISM(S): Homo sapiens

PROVIDER: GSE281712 | GEO | 2025/12/30

REPOSITORIES: GEO

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GRHL2 derepression triggers pathophysiological hepatocyte to cholangiocyte transdifferentiation

Project description:HepG2 cells were used for GRHL2 ChIP-seq

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GRHL2 derepression triggers pathophysiological hepatocyte to cholangiocyte transdifferentiation

Project description:GRHL2 derepression triggers pathophysiological hepatocyte to cholangiocyte transdifferentiation

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GRHL2 derepression triggers pathophysiological hepatocyte to cholangiocyte trans-differentiation

Project description:This SuperSeries is composed of the SubSeries listed below.

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GRHL2 derepression triggers pathophysiological hepatocyte to cholangiocyte transdifferentiation [RNAseq_HepG2_EZHi]

Project description:GRHL2 derepression triggers pathophysiological hepatocyte to cholangiocyte transdifferentiation [RNAseq_HepG2_EZHi]

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GRHL2 derepression triggers pathophysiological hepatocyte to cholangiocyte trans-differentiation

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Hepatocyte-to-cholangiocyte conversion occurs through transdifferentiation independently of proliferation in zebrafish.

Project description:Background and aimsInjury to biliary epithelial cells (BECs) lining the hepatic bile ducts leads to cholestatic liver diseases. Upon severe biliary damage, hepatocytes can convert to BECs, thereby contributing to liver recovery. Given a potential of augmenting this hepatocyte-to-BEC conversion as a therapeutic option for cholestatic liver diseases, it will be important to thoroughly understand the cellular and molecular mechanisms of the conversion process.Approach and resultsTowards this aim, we have established a zebrafish model for hepatocyte-to-BEC conversion by employing Tg(fabp10a:CFP-NTR) zebrafish with a temporal inhibition of Notch signaling during regeneration. Cre/loxP-mediated permanent and H2B-mCherry-mediated short-term lineage tracing revealed that in the model, all BECs originate from hepatocytes. During the conversion, BEC markers are sequentially induced in the order of Sox9b, Yap/Taz, Notch activity/ epcam , and Alcama/ krt18 ; the expression of the hepatocyte marker Bhmt disappears between the Sox9b and Yap/Taz induction. Importantly, live time-lapse imaging unambiguously revealed transdifferentiation of hepatocytes into BECs: hepatocytes convert to BECs without transitioning through a proliferative intermediate state. In addition, using compounds and transgenic and mutant lines that modulate Notch and Yap signaling, we found that both Notch and Yap signaling are required for the conversion even in Notch- and Yap-overactivating settings.ConclusionsHepatocyte-to-BEC conversion occurs through transdifferentiation independently of proliferation, and Notch and Yap signaling control the process in parallel with a mutually positive interaction. The new zebrafish model will further contribute to a thorough understanding of the mechanisms of the conversion process.

| S-EPMC10023500 | biostudies-literature

An Ezh2 and Ezh1 dual inhibitor, UNC1999, re-shapes the landscape of H3K27me3 versus H3K27ac in MLL-AF9-transformed murine leukemia

Project description:Ezh2 and EZH1 are histone H3 lysine 27 (H3K27)-specific methyltransferases. Their hyperactive mutations and overexpression were found in cancer including various hematological malignancies. UNC1999 is a highly selective inhibitor for both enzymes. It suppresses H3K27 tri- and di-methylation globally and inhibits growth of MLL-rearranged acute leukemia. Here we performed ChIP-Seq to profile how UNC1999 affects distribution of H3K27me3 and its antagonizing H3K27ac in MLL-AF9-immortalized leukemia cells. We also performed ChIP-seq of SUZ12, an essential common cofactor of EZH2 and EZH1 following compound treatments. We treated MLL-AF9 transformed murine leukemia cells with DMSO, UNC1999 or UNC2400 (an inactive analog compound of UNC1999). Cells were then collected and used for ChIP-Sequencing of Input, H3K27me3, SUZ12, and H3K27ac.

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ZO-2/Tjp2 suppresses Yap and Wwtr1/Taz-mediated hepatocyte to cholangiocyte transdifferentiation in the mouse liver.

Project description:TJP2/ZO-2-inactivating mutations in humans cause progressive cholestatic liver disease. Liver-specific deletion of Tjp2 in the mouse (Tjp2 cKO mice) leads to mild progressive cholestasis without an overt degradation of the bile-blood barrier (BBB). These mice are more susceptible to cholic acid (CA) induced liver injury. Interestingly, while initially also more susceptible, Tjp2 cKO mice develop tolerance to a DDC-supplemented diet. The DDC diet induces an exacerbated ductular reaction in Tjp2 cKO mice, which arises from the transdifferentiation of hepatocytes to cholangiocytes. Consequently, this transdifferentiation is only observed if Tjp2 is inactivated in hepatocytes, but not if deleted in cholangiocytes. The DDC-diet-induced hepatocyte transdifferentiation in Tjp2 cKO mice requires Yap and Wwtr1/Taz, whose protein expression is upregulated in hepatocytes lacking Tjp2, but is independent of Notch2. Although inactivating Tjp2 is sufficient for the upregulation of Yap and Wwtr1/Taz protein, efficient transdifferentiation requires the DDC-diet insult. Thus, Tjp2 negatively regulates Yap/Taz-mediated transdifferentiation of hepatocytes to cholangiocytes in response to DDC-diet-induced liver injury. Furthermore, transdifferentiation is regulated at multiple levels and the type of injury inflicted on the Tjp2 deficient liver plays an important role in the resulting pathophysiology.

| S-EPMC9508083 | biostudies-literature

An Ezh2 and Ezh1 dual inhibitor, UNC1999, re-shapes the landscape of H3K27me3 versus H3K27ac in MLL-AF9-transformed murine leukemia

2014-10-30 | GSE62437 | GEO

ChIP-seq analysis of IMR32

Project description:In the present study, we found that EZH1 depletion in MYCN-amplified neuroblastoma cells resulted in significant cell death as well as xenograft inhibition. EZH1 depletion decreased the level of H3K27me1; the interaction and protein stabilization of MYCN and EZH1 appear to play roles in epigenetic transcriptional regulation. Transcriptome analysis of EZH1-depleted cells resulted in down-regulation of the cell cycle progression-related pathway. In particular, GSEA revealed down-regulation of reactome E2F-mediated regulation of DNA replication along with key genes of this process, TYMS, POLA2, and CCNA1. TYMS and POLA2 were transcriptionally activated by MYCN and EZH1-related epigenetic modification. Treatment with the EZH1/2 inhibitor UNC1999 also induced cell death, decreased H3K27 methylation, and reduced the levels of TYMS in NB cells. Previous reports indicated neuroblastoma cells are resistant to 5-fluorouracil (5-FU) and TYMS (encoding thymidylate synthetase) has been considered the primary site of action for folate analogues. Intriguingly, UNC1999 treatment significantly sensitized MYCN-amplified neuroblastoma cells to 5-FU treatment, suggesting that EZH inhibition may be an effective strategy for development of a new epigenetic treatment for neuroblastoma.

2022-07-28 | GSE209740 | GEO

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