The main Transcription factor of Notch signalling RBPJ inhibits the formation of combined HCC-iCCA
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PROVIDER: PRJNA873952 | ENA |
REPOSITORIES: ENA
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Project description:Background & Aims: Combined HCC-iCCA is a rare liver tumor type and is often not well separated from HCC and iCCA. In this study, we analyzed major differences between combined HCC-iCCA and iCCA. Methods: We first characterized major differences between combined HCC-iCCA and iCCA by GSEA analysis. Consequently, we used CCl4 to induce chronic liver disease and subsequent liver carcinoma formation in mice. We forced the formation of combined HCC-iCCA through liver specific deletion of Rbpj, a key component of the Notch signaling pathway, in a Trp53 deficient background. Notch and p53 signaling pathways are involved in cellular differentiation processes and belong to the most affected pathways in liver carcinogenesis. Results: We show that combined HCC-iCCA can be separated from iCCA through differences in development related pathways, metabolism, cell to cell interaction and immune related pathways in human patients and in mice. Dysregulation of Notch signaling through a hepatocyte-specific Rbpj knockout resulted in an increased tumor burden and a high frequency of combined HCC-iCCA formation. In addition, hepatocytic loss of Rbpj forced M2 macrophage polarization and a tumor promoting environment. Conclusions: Dysregulation of Notch signaling is involved in tumor differentiation. Loss of Rbpj triggers the formation of combined HCC-iCCA which is associated by a pro-tumorigenic environment. Our study highlights the importance of dysfunctional Notch signalling through Rbpj deletion in hepatocytes. Rbpj loss affects tumor differentiation and the tumor microenvironment which can be linked to a combined HCC-iCCA phenotype seen in human patients.
2023-08-31 | GSE212095 | GEO
Project description:Notch signalling plays crucial roles in mediating cell fate choices in all metazoans largely by specifying the transcriptional output of one cell in response to a neighbouring cell. The DNA-binding protein RBPJ is the principle effector of this pathway in mammals and together with the transcription factor moiety of Notch (NICD) it regulates the expression of target genes. The prevalent view presumes that RBPJ statically occupies consensus binding sites while exchanging repressors for activators in response to NICD. We present the first specific RBPJ chromatin immunoprecipitation and high-throughput sequencing study in mammalian cells. To dissect the mode of transcriptional regulation by RBPJ and identify its direct targets, whole genome binding profiles were generated for RBPJ, its coactivator p300, NICD and the histone H3 modifications H3K4me3, H3K4me1 and H3K27ac in myogenic cells under active or inhibitory Notch signalling conditions. Our results demonstrate dynamic binding of RBPJ in response to Notch activation at essentially all sites co-occupied by NICD. Additionally, we identify a distinct set of sites where RBPJ recruits neither NICD nor p300, and binds DNA statically, irrespective of Notch activity. These findings significantly modify our views on how RBPJ and Notch signalling mediate their activities and consequently impact on cell fate decisions. ChIP (chromatin immunoprecipitation) is followed by deep sequencing to generate genome-wide patterns of RBP-J binding in mouse C2C12 cells under various conditions. Cells were either Notch activated by exposure to immobilized ligand or by overexpression of NICDGFP, or Notch inhibited by treatment with DAPT. Notch activation and inhibition treatments were applied for 6h and 24h. In addition to RBP-J, p300 and NICDGFP were profiled by ChIP-Seq and gene expression was assessed by RNA-Seq.
2013-05-13 | E-GEOD-37184 | biostudies-arrayexpress
Project description:Notch signalling plays crucial roles in mediating cell fate choices in all metazoans largely by specifying the transcriptional output of one cell in response to a neighbouring cell. The DNA-binding protein RBPJ is the principle effector of this pathway in mammals and together with the transcription factor moiety of Notch (NICD) it regulates the expression of target genes. The prevalent view presumes that RBPJ statically occupies consensus binding sites while exchanging repressors for activators in response to NICD. We present the first specific RBPJ chromatin immunoprecipitation and high-throughput sequencing study in mammalian cells. To dissect the mode of transcriptional regulation by RBPJ and identify its direct targets, whole genome binding profiles were generated for RBPJ, its coactivator p300, NICD and the histone H3 modifications H3K4me3, H3K4me1 and H3K27ac in myogenic cells under active or inhibitory Notch signalling conditions. Our results demonstrate dynamic binding of RBPJ in response to Notch activation at essentially all sites co-occupied by NICD. Additionally, we identify a distinct set of sites where RBPJ recruits neither NICD nor p300, and binds DNA statically, irrespective of Notch activity. These findings significantly modify our views on how RBPJ and Notch signalling mediate their activities and consequently impact on cell fate decisions.
2013-05-13 | GSE37184 | GEO
Project description:Notch signaling is an evolutionarily conserved signal transduction pathway that is essential for metazoan development. At the molecular level, the key components of the Notch pathway are the NOTCH-family receptors, the ligands of the DSL (Delta, Serrate, Lag-2) family and the transcription factor CSL [CBF1/RBPJ, Su(H), Lag-1]. Upon ligand binding, the NOTCH Intra-Cellular Domain (NOTCH ICD) translocates into the nucleus and forms a complex with RBPJ to activate the transcription of target genes. In the absence of NOTCH ICD, RBPJ acts as a transcriptional repressor. Using a proteomic approach, we identified L3MBTL3 as a novel interactor of RBPJ. We discovered that L3MBTL3 competes with NOTCH ICD for binding to RBPJ. In the absence of NOTCH ICD, RBPJ recruits L3MBTL3 and its co-factor KDM1A [lysine (K)-specific demethylase 1A] to the promoters/enhancers of Notch target genes to promote H3K4me2 demethylation and transcriptional repression. In three distinct cell contexts in which Notch signaling governs cell fate, i.e., mature T-cells as well as brain and breast tumor cells, the loss of L3MBTL3 results in the de-repression of Notch target genes. Finally, the genetic analyses of the homologs of RBPJ and L3MBTL3 in Drosophila melanogaster and Caenorhabditis elegans demonstrate that the functional link between RBPJ/Su(H)/lag-1 and L3MBTL3/dL(3)mbt/lin-61 is evolutionarily conserved, thus identifying L3MBTL3 as a universal modulator of Notch signaling in metazoans.
2017-10-17 | PXD004196 | Pride
Project description:Dysregulation of the Notch-RBPJ signaling pathway has been found associated with various human diseases including cancers; however, precisely how this key signaling pathway is fine-tuned via its interactors and modifications is still largely unknown. In this study, using a proteomic approach, we identified FBXO42 as a novel RBPJ interactor. FBXO42 promotes RBPJ polyubiquitination on lysine (K) 175 via K63 linkage, which enhances the association of RBPJ with chromatin remodeling complexes and induces a global chromatin relaxation. Genetically depleting FBXO42 or pharmacologically targeting its E3 ligase activity attenuates the Notch signaling-related leukemia development in vivo. Taken together, our findings not only revealed FBXO42 as a critical regulator of the Notch pathway by modulating RBPJ-dependent global chromatin landscape changes, but also provide insights into the therapeutic intervention of the Notch pathway for leukemia treatment.
2022-10-13 | PXD034938 | Pride
Project description:We discovered a new class of small molecule inhibitor that disrupts the interaction between NOTCH and RBPJ, which is the main transcriptional effector of NOTCH signaling. RBPJ Inhibitor-1 (RIN1) also blocked the functional interaction of RBPJ with SHARP, a scaffold protein that forms a transcriptional repressor complex with RBPJ in the absence of NOTCH signaling. RIN1 induced changes in gene expression resembled siRNA silencing of RBPJ rather than inhibition at the level of NOTCH itself. RIN1 inhibits RBPJ in its repressing and activating contexts.
2019-07-18 | GSE134401 | GEO
Project description:The Notch signaling pathway regulates several processes including development and differentiation and its aberrant regulation leads to several diseases. The transciption factor RBPJ is the main mediator of the Notch signaling pathway, regulating both repression and activation of Notch target gens. Here, we first identified RBPJ target genes by analyzing the transcriptional effects of RBPJ depletion and the binding of RBPJ by ChIP-Seq in H1299 cells. Subsequently, we analyzed the gene expression profile upon 12 or 24 hours ISX9 treatment in H1299 cells focusing on the identified RBPJ target genes.
2026-06-24 | GSE288438 | GEO
Project description:Dysregulation of the Notch-RBPJ signaling pathway has been found associated with various human diseases including cancers; however, precisely how this key signaling pathway is fine-tuned via its interactors and modifications is still largely unknown. In this study, using a proteomic approach, we identified FBXO42 as a novel RBPJ interactor. FBXO42 promotes RBPJ polyubiquitination on lysine (K) 175 via K63 linkage, which enhances the association of RBPJ with chromatin remodeling complexes and induces a global chromatin relaxation. Genetically depleting FBXO42 or pharmacologically targeting its E3 ligase activity attenuates the Notch signaling-related leukemia development in vivo. Taken together, our findings not only revealed FBXO42 as a critical regulator of the Notch pathway by modulating RBPJ-dependent global chromatin landscape changes, but also provide insights into the therapeutic intervention of the Notch pathway for leukemia treatment.
2022-07-31 | GSE206985 | GEO
Project description:The Notch signaling pathway regulates several processes including development and differentiation and its aberrant regulation leads to several diseases. The transciption factor RBPJ is the main mediator of the Notch signaling pathway, regulating both repression and activation of Notch target gens. Here, we first identified RBPJ target genes by analyzing the transcriptional effects of RBPJ depletion and the binding of RBPJ by ChIP-Seq in H1299 cells. Subsequently, we analyzed the gene expression profile upon 12 or 24 hours ISX9 treatment in H1299 cells focusing on the identified RBPJ target genes. Finally, we analyzed the effects of 12 hours ISX9 treatment on the chromatin in H1299 cells by performing ChIP-Seq versus H3K4me1, H3K4me3 and H3K27ac.
2026-06-24 | GSE288439 | GEO
Project description:The Notch signaling pathway regulates several processes including development and differentiation and its aberrant regulation leads to several diseases. The transciption factor RBPJ is the main mediator of the Notch signaling pathway, regulating both repression and activation of Notch target gens. Here, we first identified RBPJ target genes by analyzing the transcriptional effects of RBPJ depletion and the binding of RBPJ by ChIP-Seq in H1299 cells. Subsequently, we analyzed the gene expression profile upon 12 or 24 hours ISX9 treatment in H1299 cells focusing on the identified RBPJ target genes. Finally, we analyzed the effects of 12 hours ISX9 treatment on the chromatin in H1299 cells by performing ChIP-Seq versus H3K4me1, H3K4me3 and H3K27ac.
2026-06-24 | GSE288448 | GEO