Basal IFNλ2/3 expression regulates tight junction formation in human epithelial cells
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ABSTRACT:
PROVIDER: PRJNA1171017 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR30935040_1.fastq.gz | Fastqsanger.gz | |||
| SRR30935040_2.fastq.gz | Fastqsanger.gz | |||
| SRR30935041_1.fastq.gz | Fastqsanger.gz | |||
| SRR30935041_2.fastq.gz | Fastqsanger.gz |
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Project description:Time-resolve proximity proteomics of tight junction. To understand how the tight junction belt is assembled and positioned, we combined APEX2 proximity proteomics of the main junctional scaffold protein ZO-1 with a calcium switch tissue formation assay.This combination allowed us to synchronize the initiation of junction assembly in the entire tissue by the addition of calcium to the culture medium and quantify the time evolution of the junctional proteome during the assembly process using proximity proteomics.
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Project description:MicroRNA (miRNA)-mediated mRNA regulation directs many homeostatic and pathological processes, but how miRNAs coordinate aberrant esophageal inflammation during eosinophilic esophagitis (EoE) is poorly understood. Here, we report a deregulatory axis where microRNA-155 (miR-155) regulates epithelial barrier dysfunction by selectively constraining tight junction CLDN7 (claudin-7). MiR-155 is elevated in the esophageal epithelium of biopsies from patients with active EoE and in cell culture models. miR-155 localisation using in situ hybridisation (ISH) in patient biopsies, and intra-epithelial compartmentalisation of miR-155 shows expression predominantly within the basal epithelia. Epithelial miR-155 activity was evident through diminished target gene expression in 3D organotypic cultures, particularly in relatively undifferentiated basal cell states. Mechanistically, generation of a novel cell line with enhanced epithelial miR-155 stable overexpression induced a functionally deficient epithelial barrier in 3D air-liquid interface epithelial cultures measured by transepithelial electrical resistance (TEER). Histological assessment of 3D esophageal organoid cultures overexpressing miR-155 showed notable dilated intra-epithelial spaces. Unbiased RNA-sequencing analysis and immunofluorescence determined a defect in epithelial barrier tight junctions and revealed a selective reduction in the expression of critical esophageal tight junction molecule, claudin-7. Together, our data reveal a previously unappreciated role for miR-155 in mediating epithelial barrier dysfunction in esophageal inflammation.
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Project description:Epithelium barrier integrity is assumed at least in part by the presence of junctions between cells. Tight-junction formation may be necessary for Sertoli cells to cease dividing and to support germ cell development. Microarray analysis of P20 Cldn11 +/- and Cldn11-/- testes confirmed the impact od Cldn11 deficiency on cell cytoskeleton and junction-related genes. Keywords: transcriptomic analysis
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Project description:Tight junctions (TJs) are cell-cell adhesion structures that function as barriers between epithelial cells to avoid dehydration, regulate ion permeability and prevent invasion of bacteria and viruses. Disruption of TJs is causative of various inflammatory diseases including inflammatory bowel diseases (IBD), atopic dermatitis and asthma. We identified TJ-inducing small peptides from mouse peritoneum-conditioned medium. The peptides, which we designate junction-inducing peptide like a zipper (Jipper), are 35-40 residue peptides corresponding to the C-terminal region of alpha1-antitrypsin (A1AT), the serine protease inhibitor abundant in circulating blood. Both mouse and human synthetic Jippers, as well as the human A1AT C-terminal peptides cleaved by matrix metalloproteinases (MMPs), induces TJs at cell-cell boundary of epithelial cells. Our study identifies the TJ-inducing peptides in mammalian tissues, and provides a basis for a clinically relevant strategy against TJ barrier-disrupted diseases.
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Project description:Epithelium barrier integrity is assumed at least in part by the presence of junctions between cells. Tight-junction formation may be necessary for Sertoli cells to cease dividing and to support germ cell development. Microarray analysis of P20 Cldn11 +/- and Cldn11-/- testes confirmed the impact od Cldn11 deficiency on cell cytoskeleton and junction-related genes. Keywords: transcriptomic analysis Two-condition experiment: P20 Cldn11 +/- vs. P20 Cldn11 -/- testes. A pool of RNA from P20 Cldn11 +/- group was used as the reference group. Each P20 Cldn11 -/- was compared to reference group. Three biological replicates were processed in dye swap.
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Project description:The IKK kinase was previously found to activate multiple oncogenic and therapy-resistance pathways, including ATM/DDR, BRD4, and JAK/STAT3, independently of canonical NF-B signaling. Here, we show that suppression of IKK, either genetically or pharmacologically, imposes a pro-metastatic activity on colorectal cancer (CRC) patient-derived organoid (PDO) cells, which is linked to an increase in the protein levels of the tight junction protein ZO-1 and CLDN2, and a shift in their migratory mode towards collective migration. Analysis of single-cell (sc)RNA-seq data revealed an accumulation of the tight junction signature in the metastatic populations. Specifically, PDO cells contain three distinct epithelial cell clusters (C2, C4 and C8) with concomitant enrichment of the tight junction and metastasis-associated EpiHR signatures, whose unique genetic signatures are upregulated upon depletion of IKK and enriched in PDO-derived metastases. CLDN2 inhibition or depletion abolishes the metastatic activity of IKK KO PDO cells in vivo. By analyzing human paraffin-embedded CRC specimens, we have detected the presence of vascular tumor infiltrates with cluster-like or glandular phenotypes and high levels of ZO-1 and CLDN2-positive junctions. Collectively, our results suggest that high levels of tight junction proteins in CRC cells impose a pro-metastatic collective CRC cell migration, which can be detected in the vascular infiltrates at diagnosis. We propose that after validation, this type of exploration could be standardized in clinical routine and CLDN2 and the elements defining tight junction-enriched tumor clusters could be considered as metastasis biomarkers and candidate therapeutic target for CRC.
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Project description:Tight Junction Claudins-associated vascular heterogeneity determines organotypic metastasis
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Project description:We have previously shown that IKKa coordinates the activation of several oncogenic and therapy-resistant pathways, including ATM/DDR, BRD4, and JAK/STAT3, independently of canonical NF-kB signaling. Here, we found that IKKa suppression, either genetically or pharmacologically, led to stabilization of ZO-1 protein and increased CLDN2 expression, resulting in altered tight junction distribution. IKKa KO cells showed a shift in their migratory mode towards collective migration, which is associated with superior metastatic capacity in vivo. Analysis of single-cell (sc)RNA-seq data from a mouse model of CRC revealed an accumulation of the tight junction signature, including ZO-1 and CLND2, in the metastatic populations. scRNA-seq analysis of patient-derived organoid (PDO5) identified three distinct epithelial cell clusters (C2, C4 and C8) that show a significant enrichment for the metastasis-specific EpiHR signature and the tight junction signature. In particular, C2 and C8 display unique genetic signatures that are significantly upregulated in IKKa KO cells and enriched in the PDO5 IKKa KO-derived metastases. Analysis of human paraffin-embedded CRC specimens led to the identification of vascular tumor infiltrates with ZO-1 and CLDN2-positive cluster-like or glandular phenotypes. The concomitant presence of low CHUCK (IKKa) and high TJP1 (ZO-1) RNA levels is sufficient to predict poor prognosis in CRC patients. These results suggest that the presence of collectively migrating cancer cells in the vascular infiltrates, characterized by high levels of tight junction proteins, could be standardized as a prognostic tool to predict metastasis. We anticipate the use of drugs targeting tight junction elements for metastasis prevention.
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