E-MTAB-7029
Ontology highlight
ABSTRACT:
PROVIDER: E-MTAB-7029 | ExpressionAtlas | 2025-01-23
REPOSITORIES: ExpressionAtlas
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| E-MTAB-7029-analysis-methods.tsv | Tabular | |||
| E-MTAB-7029-analytics.tsv | Tabular | |||
| E-MTAB-7029-atlasExperimentSummary.Rdata | Rdata | |||
| E-MTAB-7029-configuration.xml | Xml | |||
| E-MTAB-7029-g3_g1-mvaPlot.png | Other |
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Project description:TCF/LEF dependent and independent regulation of Wnt/beta-catenin transcription
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Project description:TCF/LEF dependent and independent regulation of Wnt/beta-catenin transcription
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Project description:In colorectal cancer, p53 is commonly inactivated, associated with chemo-resistance, and marks the transition from non-invasive to invasive disease. Cancers, including colorectal cancer, are thought to be diseases of aberrant stem cell populations, as stem cells are able to self-renew, making them long-lived enough to acquire mutations necessary to manifest the disease. We have shown that extracts from sweet sorghum stalk components eliminate colon cancer stem cells (CCSC) in a partial p53-dependent fashion. However, the underlying mechanisms are unknown. In the present study, CCSC were transfected with short hairpin-RNA against p53 (CCSC p53 shRNA) and treated with sweet sorghum phenolics extracted from different plant components (dermal layer, leaf, seed head and whole plant). While all components demonstrated anti-proliferative and pro-apoptotic effects in CCSC, phenolics extracted from the dermal layer and seed head were more potent in eliminating CCSC by elevating caspases 3/7 activity, PARP cleavage, and DNA fragmentation in a p53-dependent and p53-independent fashion, respectively. Further investigations revealed that the anti-proliferative and pro-apoptotic effects were associated with decreases in beta-catenin protein levels, and beta-catenin targets cyclin D1, cMyc, and survivin. These results suggest that the anti-proliferative and pro-apoptotic effects of sweet sorghum extracts against human colon cancer stem cells are via suppression of Wnt/beta-catenin pro-survival signaling in a p53-dependent (dermal layer) and partial p53-independent (seed head) fashion. LCMS used to identify phenolic compounds associated with extract activity
2014-05-01 | MTBLS69 | MetaboLights
Project description:Aberrant activation of β-catenin is a common event in Acute Myeloid Leukemia (AML), and is recognized as an independent predictor of poor prognosis. Although increased β-catenin signaling in AML has been associated with AML1-ETO and PML-RARα translocation products, and activating mutations in the FLT3 receptor, it remains unclear which mechanisms activate β-catenin in AML more broadly. Here, we describe a novel link between interleukin-3 (IL-3) signaling and the regulation of β-catenin in myeloid transformation and AML. Using a murine model of HoxB8 and IL-3 cooperation we show that IL-3 modulates β-catenin protein levels, and Cre-induced deletion of β-catenin abolishes IL-3 dependent growth and colony formation. In the erythroleukemic cell line TF-1.8, we observed increased β-catenin protein levels and nuclear localization in response to IL-3, which correlated with transcriptional induction of β-catenin target genes. Furthermore, IL-3 promoted β-catenin accumulation in a subset of AML patient samples, and microarray gene expression analysis of these cells revealed induction of WNT/β-catenin and TCF4 transcriptional gene signatures in an IL-3 dependent manner. This study is the first to link β-catenin activation to IL-3 and suggests that targeting IL-3 signaling may be an effective approach for the inhibition of β-catenin activity in some patients with AML. AML patient samples (AML1-4) were cultured in the presence or absence of hIL-3 for 6 or 16h.
2014-02-13 | E-GEOD-51402 | biostudies-arrayexpress
Project description:To identify novel regulators and therapeutic targets of β-catenin-driven colorectal cancer development, genome-scale CRISPR-cas9 screens of Wnt/β-catenin were conducted and identified KMT2A as a key player of β-catenin-driven CRC progression. RNA-seq data was integrated with CHIP-seq and other experiments to assess the effect of KMT2A knockout on the transcriptomic profiling of CRC cells.
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Project description:We isolated ca. 500 forelimbs at 10 days post coitum, and performed ChIP-seq using anti-Bcl9 antibodies. Bcl9 is a beta-catenin transcriptional cofactor, therefore it allows the identification of binding sites of the canonical Wnt signalling-dependent transcriptional complex. This experiment allowed to define that, in this developmental context, Bcl9 acts as a beta-catenin dedicated partner. Moreover, it established a series of genome-wide Bcl9 (therefore Wnt/beta-catenin) tissue-specific target loci, thereby assessing the genetic relationship existing between Wnt signaling and other signalling cascades (e.g. the Bmp pathway).
2019-02-21 | E-MTAB-7652 | biostudies-arrayexpress
Project description:Introduction. States of vasopressin excess can exist either with or without hyponatremia, depending on water intake. Here, we set up a mouse model of vasopressin-excess without hyponatremia to address the consequences of vasopressin excess that are independent of serum sodium. Methods. A mouse vasopressin-excess model was created by infusing desmopressin for 5 days without a forced water load. Control mice were infused with vehicle. Results. RNA-seq in microdissected cortical collecting ducts (CCDs) from vasopressin-excess mice showed significant changes in 153 transcripts including the expected increases in aquaporin-2 (AQP2) and AQP3 along with increases in several other targets of V2-receptor-mediated signaling in principal cells. In addition, there were decreases in abundances of many transcripts known to be targets of regulation by the Wnt/frizzled/β-catenin pathway. The vasopressin-excess model also manifested marked increases in phosphorylation of β-catenin at a known protein kinase A (PKA) site, viz. Ser552. CRISPR-mediated mutation of this PKA-target site in mice resulted in extensive changes in the transcriptomes of microdissected CCDs after desmopressin-infusion, heavily weighted toward increases in known transcriptional targets of the Wnt/β-catenin pathway. ATAC-seq in microdissected CCDs from DDAVP-infused mice revealed decreases in chromatin accessibility at promoters of many genes regulated in the Wnt/β-catenin pathway. Conclusion. We conclude that vasopressin-excess is associated with vasopressin/PKA-dependent repression of Wnt/Frizzled/β-catenin target gene expression, mediated in part by PKA-dependent phosphorylation of Ser552 of β-catenin. The repression is associated with decreasing chromatin accessibility in the promoter-TSS regions of target genes. The findings suggest that normonatremic vasopressin-excess is not necessarily benign.
2025-07-03 | GSE301404 | GEO
Project description:Background: Wnt signaling maintains the undifferentiated state of intestinal crypt progenitor cells by inducing the formation of nuclear TCF4/beta-catenin complexes. In colorectal cancer, activating mutations in Wnt pathway components cause inappropriate activation of TCF4/beta-catenin -driven transcription. Despite the passage of a decade after the discovery of TCF4 and beta-catenin as the molecular effectors of the Wnt signal, few transcriptional activators essential and unique to the regulation of this transcription program have been found. Methodology/Principal Findings: Using proteomics, we identified the leukemia-associated Mllt10/Af10 and the methyltransferase Dot1l, as Tcf4/beta-catenin interactors in mouse small intestinal crypts. Mllt10/Af10-Dot1l, essential for transcription elongation, are recruited to Wnt target genes in a beta-catenin -dependent manner, resulting in H3K79 methylation over their coding regions in vivo in proliferative crypts of mouse small intestine, in colorectal cancer and Wnt-inducible HEK293T cells. Depletion of MLLT10/AF10 in colorectal cancer and Wnt-inducible HEK293T cells followed by expression array analysis identifies MLLT10/AF10 and DOT1L as essential activators dedicated to Wnt target gene regulation. In contrast, previously published b-catenin coactivators p300 and beta-catenin displayed a more pleiotropic target gene expression profile controlling Wnt and other pathways. tcf4, mllt10/af10 and dot1l are co-expressed in Wnt-driven tissues in zebrafish and essential for Wnt-reporter activity. Intestinal differentiation defects in apc-mutant zebrafish can be rescued by depletion of Mllt10 and Dot1l, establishing these genes as activators downstream of Apc in Wnt target gene activation in vivo. Morpholino-depletion of mllt10/af10-dot1l in zebrafish results in defects in intestinal homeostasis and a significant reduction in the in vivo expression of direct Wnt target genes and in the number of proliferative intestinal epithelial cells. Conclusions/Significance: We conclude that Mllt10/Af10-Dot1l are essential, dedicated activators of Wnt-dependent transcription, critical for maintenance of intestinal proliferation and homeostasis. The methyltransferase Dot1l may present an attractive candidate for drug targeting in colorectal cancer. 6 samples for Ls174T cells: si-b-catenin against si-control and dyeswap of it, si-control, si-MLLT10, si-BRG1 and si-P300 are hybridized against common reference RNA; 6 samples of HEK293T cells: Wnt3A or control medium (CM) induction for 9 hours, si-MLLT10, si-DOT1L, si-BRG1 and si-P300 upon 9 hour Wnt3A induction are all hybridized against common reference RNA
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Project description:Wnt/β-catenin signaling is a highly conserved molecular pathway that plays a crucial role in stem/progenitor systems and cancer. β-catenin, the main Wnt pathway effector, has two pools within a cell: one for cell-cell adhesion at the membrane and the other for transcriptional functions in the nucleus. However, the mechanism by which β-catenin mediates both roles remain unclear. The tightly controlled, well characterized system of nephrogenesis is an ideal model to decouple the roles of β-catenin at the membrane and in the nucleus. In kidney development, a delicate balance of nephron progenitor cell self-renewal and differentiation is required for the mesenchymal to epithelial transition (MET) in nephrogenesis and is driven by Wnt/β-catenin signaling. Given an ability to isolate and manipulate large numbers of NPCs in tissue culture, we can dissect the dual nature of β-catenin as a transcriptional activator and component of a cell membrane complex in adhesion. We pioneered a method using CRISPR/Cas9 gene editing to rapidly remove β-catenin, Tcf/Lef factors and simultaneous cadherin genes in primary NPCs. We have characterized the effects of modulating β-catenin and integrated RNA-seq results from β-catenin’s removal with mouse ChIP-seq and mouse single cell RNA -seq data. Functional analysis of β-catenin removal provides strong evidence for β-catenin regulation of NPC proliferation, independent of a direct Lef/Tcf associated transcriptional program. Together these data suggest β-catenin mediates aggregation, the first step in MET, through β-catenin mediated cell adhesion complexes while simultaneous transcriptional activation within these structures initiates the nephrogenic program. The studies provide new insight into the direct transcriptional role of Lef/Tcf/β-catenin complexes associated with the initiation of a nephron forming program. Overall, this study enhances an understanding of the molecular mechanisms underlying kidney development and the dual nature of β-catenin stem/progenitor systems at large.
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2022-06-09 | PXD032138 | Pride