Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Type I Interferons Control Proliferation and Function of Intestinal Epithelium

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE76512 | GEO | 2016/01/05

SECONDARY ACCESSION(S): PRJNA307598

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Type I Interferons Control Proliferation and Function of Intestinal Epithelium

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 1Î± (CK1Î±), which controls ubiquitination and degradation of both Î²-catenin and the IFNAR1 chain of the IFN receptor. Ablation of CK1Î± leads to activation of both Î²-catenin and IFN pathway and prevents unlimited proliferation of intestinal epithelial cells despite constitutive Î²-catenin activity. IFN signaling contributes to activation of the p53 pathway and appearance of apoptotic and senescence markers in the CK1Î±-deficient gut. Concurrent genetic ablation of CK1Î± 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 Î²-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

Discrete regulation of β-catenin-mediated transcription governs identity of intestinal epithelial stem cells [scRNA-Seq]

Project description:The homeostasis of the gut epithelium relies upon continuous renewal and proliferation of crypt-resident intestinal epithelial stem cells (IESCs). Wnt/β-catenin signaling is required for IESC maintenance, however, it remains unclear how this pathway selectively governs the identity and proliferative decisions of IESCs. Here, we demonstrate that C-terminally-recruited transcriptional co-factors of β-catenin act as all-or-nothing regulators of Wnt-target gene expression. Blocking their interactions with β-catenin rapidly induces loss of IESCs and intestinal homeostasis. Conversely, N-terminally recruited co-factors fine-tune β-catenin’s transcriptional output to ensure proper self-renewal and proliferative behaviour of IESCs. Impairment of N-terminal interactions triggers transient hyperproliferation of IESCs, resulting in exhaustion of the self-renewing stem cell pool. IESC mis-differentiation, accompanied by intrinsic and extrinsic stress signalling results in a process resembling aberrant "villisation" of intestinal crypts. Our data suggest that IESC-specific Wnt/β-catenin output requires discrete regulation of transcription by transcriptional co-factors.

2020-04-21 | GSE148942 | GEO

Discrete regulation of β-catenin-mediated transcription governs identity of intestinal epithelial stem cells [RNA-Seq]

2020-04-21 | GSE148941 | GEO

Discrete regulation of β-catenin-mediated transcription governs identity of intestinal epithelial stem cells [ATAC-Seq]

2020-04-21 | GSE148940 | GEO

IRF3 prevents colorectal tumorigenesis via inhibiting the nuclear translocation of β-catenin

Project description:Occurrence of Colorectal cancer（CRC）is relevant with gut microbiota. However, role of IRF3, a key signaling mediator in innate immune sensing, has been barely investigated in CRC. Here, we unexpectedly found that the IRF3 deficient mice are hyper-susceptible to the development of intestinal tumor in AOM/DSS and Apcmin/+ models. Genetic ablation of IRF3 profoundly promotes the proliferation of intestinal epithelial cells via aberrantly activating Wnt signaling. Mechanically, IRF3 in resting state robustly associates with the active β-catenin in the cytoplasm, thus preventing its nuclear translocation and cell proliferation, which can be relieved upon microbe-induced activation of IRF3. In accordance, the survival of CRC is clinically correlated with the expression level of IRF3. Therefore, our study identifies IRF3 as a negative regulator of the Wnt/β-catenin pathway and a potential prognosis marker for Wnt-related tumorigenesis, and describes an intriguing link between gut microbiota and CRC via the IRF3-β-catenin axis.

2020-09-16 | GSE155777 | GEO

Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience III

Project description:To induce chronic IFN-I activation, we injected wildtype and Ifnar1–/– mice with five treatments of DMXAA, a STING agonist, followed by snRNA-seq analysis of hippocampal tissues. In wildtype mice, we showed that microglia had the strongest IFN response to STING activation of all cell types. Ablation of interferon alpha and beta receptor 1 (IFNAR1) abolished microglial IFN-I response and suppression of neuronal MEF2C transcriptional network

2023-04-26 | GSE226382 | GEO

Transcription profiling of mouse intestinal crypts upon deletion of beta-catenin

Project description:The Wnt signaling pathway is deregulated in over 90% of human colorectal cancers. Î² Catenin, the central signal transducer of the Wnt pathway, can directly modulate gene expression by interacting with transcription factors of the TCF/LEF-family. In the present study we investigate the role of Wnt signaling in the homeostasis of intestinal epithelium using tissue-specific, inducible beta-catenin gene ablation in adult mice. Block of Wnt/beta-catenin signaling resulted in rapid loss of transient-amplifying cells and crypt structures. Importantly, intestinal stem cells were induced to terminally differentiate upon deletion of beta-catenin resulting in a complete block of intestinal homeostasis and fatal loss of intestinal function. Transcriptional profiling of mutant crypt mRNA isolated by laser capture micro dissection confirmed those observations and allowed to identify genes potentially responsible for the functional preservation of intestinal stem cells. Experiment Overall Design: laser capture microdissection of intestinal crypts, control vs. beta-catenin mutant (2days after induction of deletion by tamoxifen), two rounds of amplification of mRNA

2008-06-16 | E-GEOD-8818 | biostudies-arrayexpress

Gut-liver axis calibrates intestinal stem cell fitness via PEDF

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

IFN-I and CD8 T cells increase intestinal barrier permeability after chronic viral infection

Project description:Intestinal barrier leakage constitutes a potential therapeutic target for many inflammatory diseases and represents a disease progression marker during chronic viral infections. The causes of altered gut barrier remain, however, mostly unknown. By using murine infection with lymphocytic choriomeningitis virus we demonstrated that, in contrast to an acute viral strain, a persistent viral isolate led to long-term viral replication in hematopoietic and mesenchymal, but not epithelial (IEC), cells in the intestine. Viral persistence drove sustained intestinal epithelial barrier leakage, which was characterized by increased paracellular flux of small molecules and was associated with enhanced colitis susceptibility. IFN-I signaling caused tight junction dysregulation in IEC, promoted gut microbiome shifts and enhanced intestinal CD8 T cell responses. Notably, both IFN-I receptor blockade and CD8 T cell depletion prevented infection-induced barrier leakage. Our study demonstrated that infection with a virus that persistently replicated in intestinal mucosa increased epithelial barrier permeability, and revealed IFN-I and CD8 T cells as causative factors of intestinal leakage during chronic infections.

2020-08-26 | GSE155120 | GEO

A C/EBPα–Wnt connection in gut homeostasis and carcinogenesis

Project description:We explored the connection between C/EBPα (CCAAT/enhancer binding protein α) and Wnt signaling in gut homeostasis and carcinogenesis. C/EBPα was expressed in human and murine intestinal epithelia in the transit amplifying region of the crypts and was absent in intestinal stem cells and Paneth cells with activated Wnt signaling. In human colorectal cancer and murine APCMin/+ polyps, C/EBPα was absent from nuclear β-catenin–positive tumor cells. In chemically induced intestinal carcinogenesis, C/EBPα KO in murine gut epithelia increased tumor volume. C/EBPα deletion extended the S-phase cell zone in intestinal organoids and activated typical proliferation gene expression signatures, including that of Wnt target genes. Genetic activation of β-catenin in organoids attenuated C/EBPα expression. Comparing gene expression of wild type and C/EBPα KO organoids by RNA sequencing aimed to identify C/EBPα dependent alterations in gene expression.

2018-12-24 | GSE123925 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data