A C/EBPα–Wnt connection in gut homeostasis and carcinogenesis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE123925 | GEO | 2018/12/24
REPOSITORIES: GEO
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Project description:Wnt signals control three functions of intestinal crypts: maintenance of Lgr5 stem cells, proliferation of transit-amplifying daughters and formation of Paneth cells. Here, we study how the Wnt effector β-catenin/Tcf4 cooperates with the Wnt-activated transcription factor Ascl2 to control a stem cell transcription program. DNA elements that are co-occupied and synergistically regulated by Ascl2 and Tcf4 specifically map to stem cell genes. In vitro, Tcf4-/- mini-guts are rescued by Ascl2 expression, while Ascl2-/- organoids are rescued by Wnt signaling. A direct auto-activatory loop leads to an on/off expression pattern of Ascl2 with a threshold that depends on the previous state. Wnt/R-spondin1 activates this loop. This mechanism interprets Wnt levels in crypts and translates this continuous signal into a discrete Ascl2 âonâ or âoffâ decision. In turn Ascl2, together with β-catenin/Tcf, activates stem cell genes. Thus, Ascl2 forms a transcriptional 'stemness switch' that is both Wnt-responsive and Wnt-dependent Examination of Tcf4, B-catenin and Ascl2 DNA occupancy in murine intestinal organoids and human colorectal cancer cell lines *** Original raw files unavailable due to loss during backup ***
2016-07-15 | E-GEOD-84456 | biostudies-arrayexpress
Project description:The gut and liver have been recognized to mutually communicate through the biliary tract, portal vein and systemic circulation, but it remains unclear how this gut-liver axis regulates intestinal physiology. Through hepatectomy, transcriptomics and proteomics profiling, we identified pigment epithelium-derived factor (PEDF), as a liver-derived soluble Wnt inhibitor, that can restrain intestinal stem cells (ISC) hyperproliferation for gut homeostasis by competing with Wnt ligands and suppressing Wnt/beta-catenin signaling pathway. In turn, microbial danger signals from intestinal inflammation can be sensed by the liver to repress PEDF production via peroxisome proliferator-activated receptor-alpha (PPAR alpha), liberating ISC proliferation to accelerate tissue repair in the gut. Further, treatment of mice with fenofibrate, a clinical agent of PPARalpha agonist for hypolipidemia enhances the susceptibility of colitis via PEDF activity. Therefore, we identified a distinct role of PEDF to calibrate ISC expansion for intestinal homeostasis via reciprocal interactions between the gut and liver.
2023-03-03 | MSV000091409 | MassIVE
Project description:Canonical Wnt signaling output is mediated by β-catenin, which interacts with LEF/TCF transcription factors and recruits a general transcriptional activation complex to its C-terminus. Its N-terminus binds BCL9/9L proteins, which bind co-activators that in mammals contribute to fine-tuning the transcriptional output. We found that a BCL9/9L-dependent gene expression signature was strongly associated with patient outcome in colorectal cancer and that stem cell and mesenchymal genes determine its prognostic value. Abrogating BCL9/9L-β-catenin signaling in independent mouse colorectal cancer models resulted in virtual loss of these traits, and oncogenic intestinal organoids lacking BCL9/9L proteins proved no longer tumorigenic. Our findings suggest that the BCL9/9L arm of Wnt-β-catenin signaling sustains a stemness-to-differentiation equilibrium in colorectal cancer, which critically affects disease outcome. Mutational activation of the Wnt pathway is a key oncogenic event in colorectal cancer. Targeting the pathway downstream of activating mutations is challenging, and the therapeutic window is limited by intestinal toxicity. Contrasting with phenotypes caused by inactivating key Wnt pathway components, ablation of BCL9/9L proteins in adult mice indicated that they were dispensable for intestinal homeostasis, consistent with their role in tuning transcription. Cancer stem cells are increasingly recognized as responsible for tumor recurrence. The correlation between stemness traits in colorectal cancer models and BCL9/9L-β-catenin signaling suggests that high Wnt signaling output is required for their maintenance. Our findings suggest that pruning Wnt-β-catenin signaling might be well tolerated and prove sufficient for trimming stemness traits and improving disease outcome. Examination of Bcl9/9l-knockout versus wild-type transcriptome in murine AOM-DSS tumors, APC-Kras tumors and healthy colocyte extracts.
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Project description:A C/EBPα–Wnt connection in gut homeostasis and carcinogenesis
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Project description:β-catenin-dependent canonical Wnt signaling plays a plethora of roles in organ development, tissue homeostasis and cancer. Here we identified an upstream enhancer of Ctnnb1 - ieCtnnb1 - that controls intestinal homeostasis. ieCtnnb1 is specifically active in crypts of small and large intestines. Single-cell sequencing revealed that ieCtnnb1 knockout (ieCtnnb1KO) biased epithelial composition and functions of small intestinal crypts – leaning toward absorptive functions at the expense of secretive roles. Deletion of ieCtnnb1 hampered epithelial turnovers in physiologic and regenerative conditions. In contrast, deletion of ieCtnnb1 prevents occurrence and progression of Wnt/β-catenin driving colorectal cancers. The human ieCTNNB1 specifically drives reporter in intestinal crypts and contains a SNP that is associated with CTNNB1 expression levels in human gastrointestinal epithelia. The enhancer activity of ieCTNNB1 in colorectal cancer tissues is higher than that in adjacent normal tissues and positively correlates with CTNNB1 expression levels. Key trans-factors that bind to ieCTNNB1 and regulate CTNNB1 transcription were identified. Together, these findings revealed an enhancer-dependent mechanism that controls the dosage of Wnt signaling, hence homeostasis of intestinal epithelia.
2024-10-02 | GSE233977 | GEO
Project description:β-catenin-dependent canonical Wnt signaling plays a plethora of roles in organ development, tissue homeostasis and cancer. Here we identified an upstream enhancer of Ctnnb1 - ieCtnnb1 - that controls intestinal homeostasis. ieCtnnb1 is specifically active in crypts of small and large intestines. Single-cell sequencing revealed that ieCtnnb1 knockout (ieCtnnb1KO) biased epithelial composition and functions of small intestinal crypts – leaning toward absorptive functions at the expense of secretive roles. Deletion of ieCtnnb1 hampered epithelial turnovers in physiologic and regenerative conditions. In contrast, deletion of ieCtnnb1 prevents occurrence and progression of Wnt/β-catenin driving colorectal cancers. The human ieCTNNB1 specifically drives reporter in intestinal crypts and contains a SNP that is associated with CTNNB1 expression levels in human gastrointestinal epithelia. The enhancer activity of ieCTNNB1 in colorectal cancer tissues is higher than that in adjacent normal tissues and positively correlates with CTNNB1 expression levels. Key trans-factors that bind to ieCTNNB1 and regulate CTNNB1 transcription were identified. Together, these findings revealed an enhancer-dependent mechanism that controls the dosage of Wnt signaling, hence homeostasis of intestinal epithelia.
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Project description:Wnt pathway-driven proliferation and renewal of the intestinal epithelium must be tightly controlled to prevent development of cancer and barrier dysfunction. Although type 1 interferons (IFN) produced in the gut under influence of microbiota are known for their anti-proliferative effects, the role of these cytokines in regulating intestinal epithelial renewal is largely unknown. Here we report a novel role for IFN in the context of intestinal knockout of casein kinase 1α (CK1α), which controls ubiquitination and degradation of both β-catenin and the IFNAR1 chain of the IFN receptor. Ablation of CK1α leads to activation of both β-catenin and IFN pathway and prevents unlimited proliferation of intestinal epithelial cells despite constitutive β-catenin activity. IFN signaling contributes to activation of the p53 pathway and appearance of apoptotic and senescence markers in the CK1α-deficient gut. Concurrent genetic ablation of CK1α and IFNAR1 leads to intestinal hyperplasia, robust attenuation of apoptosis, and rapid and lethal loss of the barrier function. These data indicate that IFN plays an important role in controlling proliferation and function of intestinal epithelium in the context of β-catenin activation. Two conditions were examined, with 2 replicates for each condition, yielding 4 samples in total.
2016-01-05 | E-GEOD-76512 | biostudies-arrayexpress
Project description:Wnt/b-catenin pathway is a key modulator of intestinal homeostasis by regulating stem cell biology during gut organogenesis and in adult life. DICKKOPF (DKK)-1 is a secreted inhibitor of Wnt/b-catenin signaling from plasma membrane receptors. We found that in human intestine, DKK-1 locates within the nucleus of differentiated enterocytes and enteroendocrine cells but not of proliferating and stem cells at the bottom of the crypts. DKK-1 is also nuclear in colon cancer cells locating at sites of active gene transcription. ChIP-seq and transcriptomic analysis both confirmed that DKK-1 binds chromatin and regulates gene expression. Thus, we demonstrate that DKK-1 is a multifunctional protein that inhibits Wnt/b-catenin signaling at plasma membrane and controls specific genes in the nucleus, suggesting that these functions are relevant for intestinal homeostasis. Analysis of DKK-1 location and associated roles in human colon cancer cells and crypts of small and large bowel.
2015-03-30 | E-GEOD-35272 | biostudies-arrayexpress
Project description:Wnt/b-catenin signaling supports intestinal homeostasis by regulating proliferation in the crypt. Multiple Wnts are expressed in Paneth as well as other intestinal epithelial and stromal cells. Ex vivo, Wnts secreted by Paneth cells can support intestinal stem cells when Wnt signaling is enhanced with supplemental R-Spondin 1 (RSPO1). However, in vivo, the source of Wnts in the stem cell niche is less clear. Genetic ablation of Porcn, an endoplasmic reticulum resident O-acyltransferase that is essential for the secretion and activity of all vertebrate Wnts, confirmed the role of intestinal epithelial Wnts in ex vivo culture. Unexpectedly, mice lacking epithelial Wnt activity (PorcnDel/Villin-Cre mice) had normal intestinal proliferation and differentiation, as well as successful regeneration after radiation injury, indicating epithelial Wnts are dispensable for these processes. Consistent with a key role for stroma in the crypt niche, intestinal stromal cells endogenously expressing Wnts and Rspo3 support the growth of PorcnDel organoids ex vivo without RSPO1 supplementation. Conversely, increasing pharmacologic PORCN inhibition, affecting both stroma and epithelium, reduced Lgr5 intestinal stem cells, inhibited recovery from radiation injury, and at the highest dose fully blocked intestinal proliferation. We conclude that epithelial Wnts are dispensable, and that stromal production of Wnts can fully support normal murine intestinal homeostasis. Microarray was performed on samples enriched for stromal or epithelial cells from small intestine from Porcn(Del)/Villin-Cre and Porcn(WT)/Villin-Cre male C57Bl/6 mice.
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Project description:Depending on the tumor type IκB kinase α (IKKα) can act as tumor promoter or tumor suppressor in various malignancies. Here we demonstrate a key function of IKKα in the suppression of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of IFNγ expressing M1-like myeloid cells. In IKKα mutant mice M1-like polarization is not controlled in a cell autonomous manner but depends rather on the interplay of both IKKα mutant tumor epithelia and immune cells. Tamoxifen-inducible β-catc.a. mice comprise an excellent model to study Wnt-dependent tumor initiation. These mice are characterized by IEC-restricted stabilization of β-catenin causing rapid expansion of intestinal crypts and loss of differentiated IEC. To further explore the underlying IKKα controlled pro-proliferative mechanism, we performed a microarray analysis comparing RNA isolated from wildtype, IkkαAA/AA, β-catc.a. or β-catc.a./IkkαAA/AA IEC 15 days after the first tamoxifen administration. and within 4 weeks β-catc.a. mice succumb to this marked crypt hyperproliferation
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