P53 terminates the regenerative state after colitis-associated injury
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ABSTRACT:
PROVIDER: PRJNA1069684 | ENA |
REPOSITORIES: ENA
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Project description:Cell clones that lack P53 signaling occur frequently in ulcerative colitis (UC) and are considered drivers in UC-associated colorectal cancer. Trp53 mutant cells often display decreased P53 signaling and have previously been shown to outcompete wild type (WT) cells in a mouse model of colitis (DSS colitis), but not in healthy mice. However, the mechanism responsible for the observed context-dependent effects of P53 are not understood. Therefore, we aimed to explore this by studying the behavior of Trp53-deficient cells specifically in injured mucosa. We have developed murine and organoid-based models to study the context dependent role of Trp53 knock-out (KO). We use inducible KO systems in mouse models of DSS colitis to study the loss of Trp53 in the injury and regenerative state. Colon organoids are employed to recapitulate the in vivo findings in order to elucidate the pathways involved.
2024-10-30 | GSE254312 | GEO
Project description:The samples are a part of a study aiming at diagnosing ulcerative colitis from genome-wide gene expression analysis of the colonic mucosa. Colonic mucosal samples were collected as endoscopic pinch biopsies from ulcerative colitis patients and from control subjects. Samples with and without macroscopic signs of inflammation were collected from the patients. Keywords: Disease state analysis
2007-10-31 | GSE9452 | GEO
Project description:High Yap and Mll1 promote a persistent regenerative cell state induced by Notch signaling and loss of p53
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Project description:Sex-dependent niche responses modulate steady-state and regenerative hematopoiesis
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Project description:The capacity to regenerate the spinal cord after an injury is a coveted trait that only a limited group of non-mammalian organisms can achieve. In Xenopus laevis, this capacity is only present during larval or tadpole stages, but is absent during postmetamorphic frog stages. This provides an excellent model for comparative studies between a regenerative and a non-regenerative stage to identify the cellular and molecular mechanisms that explain the difference in regenerative potential. Here, we used iTRAQ chemistry to obtain a quantitative proteome of the spinal cord 1 day after a transection injury, and used sham operated animals as controls. We quantified a total of 6,384 proteins, with 172 showing significant differential expression in the regenerative stage and 240 in the non-regenerative stage, with an overlap of only 14 proteins. Functional enrichment analysis revealed that while the regenerative stage downregulated synapse/vesicle and mitochondrial proteins, the non-regenerative stage upregulated lipid metabolism proteins, and downregulated ribosomal and translation control proteins. Furthermore, STRING network analysis showed that proteins belonging to these groups are highly interconnected, providing interesting candidates for future functional studies.
2018-01-25 | PXD006993 | Pride
Project description:The samples are a part of a study aiming at diagnosing ulcerative colitis from genome-wide gene expression analysis of the colonic mucosa. Colonic mucosal samples were collected as endoscopic pinch biopsies from ulcerative colitis patients and from control subjects. Samples with and without macroscopic signs of inflammation were collected from the patients. Experiment Overall Design: The series contain eight UC samples with macroscopic signs of inflammation, 13 UC smaples without macroscopic signs of inflammation, five control subjects.
2008-06-20 | E-GEOD-9452 | biostudies-arrayexpress
Project description:Background: The efficient regenerative abilities at larvae stages followed by a non-regenerative response after metamorphosis in froglets makes Xenopus an ideal model organism to understand the cellular responses leading to spinal cord regeneration. Methods: We compared the cellular response to spinal cord injury between the regenerative and non-regenerative stages of Xenopus laevis. For this analysis, we used electron microscopy, immunofluorescence and histological staining of the extracellular matrix. We generated two transgenic lines: i) the reporter line with the zebrafish GFAP regulatory regions driving the expression of EGFP, and ii) a cell specific inducible ablation line with the same GFAP regulatory regions. In addition, we used FACS to isolate EGFP + cells for RNAseq analysis. Results: In regenerative stage animals, spinal cord regeneration triggers a rapid sealing of the injured stumps, followed by proliferation of cells lining the central canal, and formation of rosette-like structures in the ablation gap. In addition, the central canal is filled by cells with similar morphology to the cells lining the central canal, neurons, axons, and even synaptic structures. Regeneration is almost completed after 20 days post injury. In non-regenerative stage animals, mostly damaged tissue was observed, without clear closure of the stumps. The ablation gap was filled with fibroblast-like cells, and deposition of extracellular matrix components. No reconstruction of the spinal cord was observed even after 40 days post injury. Cellular markers analysis confirmed these histological differences, a transient increase of vimentin, fibronectin and collagen was detected in regenerative stages, contrary to a sustained accumulation of most of these markers, including chondroitin sulfate proteoglycans in the NR-stage. The zebrafish GFAP transgenic line was validated, and we have demonstrated that is a very reliable and new tool to study the role of neural stem progenitor cells (NSPCs). RNASeq of GFAP::EGFP cells has allowed us to clearly demonstrate that indeed these cells are NSPCs. On the contrary, the GFAP::EGFP transgene is mainly expressed in astrocytes in non-regenerative stages. During regenerative stages, spinal cord injury activates proliferation of NSPCs, and we found that are mainly fated to form neurons and glial cells. Specific ablation of these cells abolished proper regeneration, confirming that NSPCs cells are necessary for functional regeneration of the spinal cord. Conclusions: The cellular response to spinal cord injury in regenerative and non-regenerative stages is profoundly different between both stages. A key hallmark of the regenerative response is the activation of NSPCs, which massively proliferate to reconstitute the spinal cord, and are differentiated into neurons. Also very notably, no glial scar formation is observed in regenerative stages, but a transient, glial scar-like structure is formed in non-regenerative stage animals.
2021-01-05 | GSE164204 | GEO
Project description:Chromatin modifications provide additional context-dependence for DNA sequence-based gene regulation. Binding sites of the transcription factor (TF) and important tumour suppressor p53 are unusually diverse with regards to their chromatin accessibility and histone modifications, suggesting different modes of binding. Here, we show that the ability of p53 to open chromatin and activate its target genes is locally restricted by its cofactor Trim24. The histone-binding domains of Trim24 limits the role of p53 at closed chromatin but not at accessible chromatin where Trim24 is blocked by histone 3 methylation at lysine 4. In turn, p53 regulates gene expression as a function of the naïve chromatin state prior to activation. These findings establish a novel mode of gene regulation by p53 in closed chromatin and illustrate how histone modification sensing cofactors can bridge local chromatin state and TF potency.
2023-05-05 | PXD033674 | Pride
Project description:Murine small intestinal crypts of six independent mice were isolated and cultured as 3D-Organoids. Expression of NICD and loss of p53 mutagenesis was induced by 24h treatment with 4OH-tamoxifen in three of the cultures, resulting in three mutant organoid lines. The other three organoid lines were not exposed to tamoxifen and served as controls. Of each organoid line a duplicate was taken resulting in six control and six mutant samples that were compared in the analysis.
2021-06-04 | E-MTAB-6588 | biostudies-arrayexpress