Effects of TNFR2 deletion on the development of mouse colonic epithelial organoids
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ABSTRACT:
PROVIDER: PRJNA662609 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12619000.fastq.gz | Fastqsanger.gz | |||
| SRR12619001.fastq.gz | Fastqsanger.gz | |||
| SRR12619002.fastq.gz | Fastqsanger.gz | |||
| SRR12619003.fastq.gz | Fastqsanger.gz | |||
| SRR12619004.fastq.gz | Fastqsanger.gz |
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Project description:Colonic epithelial repair is a key determinant of health. After injury, repair initiates through phenotypic reprogramming of wounded epithelium to a regenerative state permissive for the activation of alternative stem cell populations and healing. Although cytokine signals such as interferons may help induce regenerative reprogramming, the signals that modify this state as the wound resolves remain largely unknown. Here we examined whether cytokine signaling mediated by tumor necrosis factor receptor 2 (TNFR2) influenced the wound repair process. We examined mice with targeted deletion of the Tnfrsf1b (TNFR2) gene in intestinal/colonic epithelium (Vil1::Cre;Tnfr2-f/f) and compared their transcriptional profiles to control (Tnfr2-f/f) mice. We sorted EpCAM+ (epithelial) cells from Vil1::Cre;Tnfr2-f/f and control DSS-treated mice and performed bulk RNA-Seq. Comparison of transcript expression profile before and after DSS-induced colitis in control (Tnfr2-f/f) mice revealed upregulation of pathways associated with metabolic regulation, ribosomal function, oxidative stress, TNF signaling, and focal adhesions after DSS treatment. Pathway enrichment analysis demonstrated elevated regenerative (“fetal”) intestinal signaling, reduced inflammation, and increased proliferative signaling in Vil1::Cre;Tnfr2-f/f colonic epithelium after DSS treatment. The knockout epithelium also showed reduced expression of markers of differentiated colonic epithelium and elevated expression of progenitor cell signaling. Thus, the transcriptional data were consistent with increased regenerative signaling in TNFR2-knockout epithelium, suggesting that TNFR2 has a role in restraining the relatively undifferentiated regenerative state.
2023-08-22 | GSE230329 | GEO
Project description:Colonic epithelial repair is a key determinant of health. After injury, repair initiates through phenotypic reprogramming of wounded epithelium to a regenerative state permissive for the activation of alternative stem cell populations and healing. Although cytokine signals such as interferon help induce regenerative reprogramming, the signals that modify this state as the wound resolves remain largely unknown. Here we show that, during healing, the late upregulation of a cytokine receptor, tumor necrosis factor (TNF) receptor 2 (R2, TNFR2, Tnfrsf1b), clears the phenotype of regenerative signaling and restores homeostatic patterns of epithelial differentiation. Mice lacking epithelial-specific expression of TNFR2 also failed to complete colon ulcer healing, suggesting that full repair requires coordination of both regenerative and homeostatic epithelial phenotypes. In single-cell RNA-seq experiments, we find that colonic epithelial organoids grown from Tnfr2-/- mice retain a highly enriched census of progenitor cells and reduced representation of differentiated cells, consistent with TNFR2's role in promoting differentiation. These results demonstrate how epithelial cells adapt to inflammatory cues to choreograph repair.
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Project description:PURPOSE: The goal of this study was to determine the gene expression networks regulated by tumor necrosis factor receptor 2 (TNFR2, or Tnfrsf1b) and to evaluate their potential bearing on immune cell subsets and inflammatory bowel disease (IBD). METHODS: mRNA-seq was performed on isolated distal colons from TNFR2-knockout and wildtype mice. Differentially expressed transcripts were compared to human ulcerative colitis microarray datasets on Gene Expression Omnibus and to mouse immunological expression datasets at the Immunological Genome Project. RESULTS: We identified 252 mouse transcripts whose expressions were significantly altered by the loss of TNFR2. The majority of these transcripts (228 of 252, ~90%) were downregulated in TNFR2-/- colons. TNFR2-regulated genes were able to positively discriminate between ulcerative colitis patients and healthy individuals with ~80% accuracy. Many TNFR2-regulated genes were also highly expressed in CD8+ T cells. CONCLUSIONS: Downregulation of TNFR2 is associated with a gene expression profile that is prominent in IBD and supportive of the role of CD8+ T cells in IBD pathogenesis. MANUSCRIPT ABSTRACT: Increased tumor necrosis factor (TNF) production has been associated with inflammatory bowel disease (IBD), and anti-TNF therapy is a common therapeutic for this patient population. However, the role of TNF or its receptors (TNFR1 and TNFR2) in the immunopathogenesis of inflammatory bowel disease (IBD) remains unclear. Here we report that TNFR2 is protective in spontaneous (IL-10 knockout) and chemically (azoxymethane/dextran sodium sulfate)-induced mouse models of colitis and colitis-associated cancer. Mechanistically, TNFR2-deficiency in hematopoietic cells significantly increased incidence and severity of colitis and colitis-associated cancer characterized by a selective expansion of CD8+ T cells. We identified TNFR2-regulated genes in the colon that were specific for CD8+ T cells, interacted with multiple IBD risk genes, and are important regulators of CD8+ T cell biology. TNFR2 regulated CD8+ T-cell-specific genes that act as genetic susceptibility modifiers for IBD to mitigate the development of a pro-colitogenic milieu. Antibody-mediated depletion of CD8+ T cells prevented colonic inflammation and significantly reduced pathology in IL10-/-/TNFR2-/- deficient mice. Furthermore, adoptive transfer of TNFR2-/- naïve CD8+ T cells resulted in more severe disease than with wildtype naïve CD8+ T cells. Our findings provide insight into the disease modifier role of TNFR2 in the immunopathogenesis of IBD through the modulation of CD8+ T cell responses and support future investigation of this therapeutic target, especially in the subset of IBD patients with CD8+ T-cell dysfunction. Total RNA from distal colons of 8 week-old male wildtype C57Bl/6 and TNFR2-/- mice (n=3 each) was isolated using the PureLink RNA kit (Ambion, Life Technologies). RNA samples were submitted to the Genomic Services Lab at the HudsonAlpha Institute for Biotechnology (Huntsville, AL) for multiplex library preparation, mRNA enrichment, and sequencing. Sequencing was performed to an average depth of 50M paired-end 50bp reads per sample (HiSeq, Illumina, San Diego, CA). Data files containing raw reads were aligned to the mouse genome using Tophat2/Bowtie2. Alignments were assembled into transcript representations with Cufflinks, and statistical tests for differential expression were performed with Cuffdiff 2. An adjusted P value < 0.05 (q<0.05) from the Cuffdiff 2 output was used as the cutoff for statistical significance.
2015-08-11 | E-GEOD-65408 | biostudies-arrayexpress
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Project description:To identify the role of Brd4 in colorectal cancer (CRC) development , we performed Sleeping Beauty (SB) transposon mutagenesis in mice. We identified several candidate genes including Brd4. To provide functional validation, we knocked out Brd4 in mouse tumor organoids carrying an activating KrasG12D, and an inactivating ApcD716 allele, and performed RNAseq. Brd4 knockout colonic organoids showed deregulation of genes in IFNg signaling. We treated Brd4 knockout organoids with IFNg and found that Brd4 konckout organoids showed partial resistance to IFNg-induce cell death. The mechanism may explain the function of Brd4 in colon cancer development.
2024-11-24 | GSE248821 | GEO
Project description:PURPOSE: The goal of this study was to determine the gene expression networks regulated by tumor necrosis factor receptor 2 (TNFR2, or Tnfrsf1b) and to evaluate their potential bearing on immune cell subsets and inflammatory bowel disease (IBD). METHODS: mRNA-seq was performed on isolated distal colons from TNFR2-knockout and wildtype mice. Differentially expressed transcripts were compared to human ulcerative colitis microarray datasets on Gene Expression Omnibus and to mouse immunological expression datasets at the Immunological Genome Project. RESULTS: We identified 252 mouse transcripts whose expressions were significantly altered by the loss of TNFR2. The majority of these transcripts (228 of 252, ~90%) were downregulated in TNFR2-/- colons. TNFR2-regulated genes were able to positively discriminate between ulcerative colitis patients and healthy individuals with ~80% accuracy. Many TNFR2-regulated genes were also highly expressed in CD8+ T cells. CONCLUSIONS: Downregulation of TNFR2 is associated with a gene expression profile that is prominent in IBD and supportive of the role of CD8+ T cells in IBD pathogenesis. MANUSCRIPT ABSTRACT: Increased tumor necrosis factor (TNF) production has been associated with inflammatory bowel disease (IBD), and anti-TNF therapy is a common therapeutic for this patient population. However, the role of TNF or its receptors (TNFR1 and TNFR2) in the immunopathogenesis of inflammatory bowel disease (IBD) remains unclear. Here we report that TNFR2 is protective in spontaneous (IL-10 knockout) and chemically (azoxymethane/dextran sodium sulfate)-induced mouse models of colitis and colitis-associated cancer. Mechanistically, TNFR2-deficiency in hematopoietic cells significantly increased incidence and severity of colitis and colitis-associated cancer characterized by a selective expansion of CD8+ T cells. We identified TNFR2-regulated genes in the colon that were specific for CD8+ T cells, interacted with multiple IBD risk genes, and are important regulators of CD8+ T cell biology. TNFR2 regulated CD8+ T-cell-specific genes that act as genetic susceptibility modifiers for IBD to mitigate the development of a pro-colitogenic milieu. Antibody-mediated depletion of CD8+ T cells prevented colonic inflammation and significantly reduced pathology in IL10-/-/TNFR2-/- deficient mice. Furthermore, adoptive transfer of TNFR2-/- naïve CD8+ T cells resulted in more severe disease than with wildtype naïve CD8+ T cells. Our findings provide insight into the disease modifier role of TNFR2 in the immunopathogenesis of IBD through the modulation of CD8+ T cell responses and support future investigation of this therapeutic target, especially in the subset of IBD patients with CD8+ T-cell dysfunction.
2015-08-11 | GSE65408 | GEO