Post-transcriptional regulation of the epithelial cell response to colitis
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ABSTRACT:
PROVIDER: PRJNA445600 | ENA |
REPOSITORIES: ENA
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Project description:Aim: RNA binding proteins (RBPs) are emerging as critical regulators of gut homeostasis via post-transcriptional control of key growth and repair pathways. IMP1 (IGF2 mRNA Binding Protein 1) is ubiquitously expressed during embryonic development and Imp1 hypomorphic mice exhibit severe gut growth defects. In the present study, we investigated the mechanistic contribution of intestinal epithelial IMP1 to gut homeostasis and response to injury. Method: We evaluated IMP1 expression in patients with Crohn’s disease followed by unbiased ribosome profiling in IMP1 knockout cells. Concurrently, we measured differences in histology and cytokine expression in mice with intestinal epithelial-specific Imp1 deletion (Imp1ΔIEC) following dextran sodium sulfate (DSS)- colitis. Based on ribosome profiling analysis, we evaluated changes in autophagy in Imp1ΔIEC mice as well as in silico and in vitro approaches to evaluate direct protein:RNA interactions. Finally, we analyzed the consequence of genetic deletion of Atg7 in Imp1ΔIEC mice using colitis and irradiation models. Results: IMP1 was robustly upregulated in Crohn’s disease patients and Imp1 loss lessened DSS-colitis severity. Unbiased ribosome-profiling revealed that IMP1 may coordinate translation of multiple pathways important for intestinal homeostasis, including cell cycle and autophagy, which we verified by Western blotting. Mechanistically, we observed evidence for increased autophagy flux in Imp1ΔIEC mice, reinforced through in silico and biochemical analyses revealing direct binding of IMP1 to autophagy transcripts. Finally, we found genetic deletion of Atg7 reversed the phenotype observed in DSS- or irradiation-challenged Imp1ΔIEC mice. Conclusions: IMP1 acts as a post-transcriptional regulator of gut epithelial repair, in part through modulation of autophagy. This study highlights the need for examining post-transcriptional regulation as a critical mechanism in inflammatory bowel disease.
2018-12-31 | GSE112305 | GEO
Project description: Not available
| S-EPMC6593052 | biostudies-literature
Project description:The intestinal epithelial regeneration is driven by intestinal stem cells under homeostatic conditions. Differentiated intestinal epithelial cells, such as Paneth cells, are capable of acquiring multipotency and contributing to regeneration upon loss of intestinal stem cells. Paneth cells also support intestinal stem cell survival and regeneration. We report here that depletion of an RNA-binding protein named polypyrimidine tract binding protein 1 (PTBP1) in mouse intestinal epithelial cells causes intestinal stem cell death and epithelial regeneration failure. Mechanistically, we show that PTBP1 inhibits neuronal-like splicing programs in intestinal crypt cells, which is critical for maintaining intestinal stem cell stemness. This function is achieved at least in part through promoting the non-productive splicing of its paralog PTBP2. Moreover, PTBP1 inhibits the expression of an AKT inhibitor PHLDA3 in Paneth cells and permits AKT activation, which presumably maintains Paneth cell plasticity and function in supporting intestinal stem cell niche. We show that PTBP1 directly binds to a CU-rich region in the 3’ UTR of Phlda3, which we demonstrate to be critical for downregulating the mRNA and protein levels of Phlda3. Our results thus reveal the multifaceted in vivo regulation of intestinal epithelial regeneration by PTBP1 at the post-transcriptional level.
2023-01-18 | GSE185499 | GEO
Project description:Objective: Ulcerative colitis (UC) is a chronic disease with rising incidence and unclear etiology. The application of mass spectrometry-based post-genomic analysis methods shall support the development of molecular biomarker signatures providing status information with regard to UC pathomechanisms. Design: Pathomechanisms characteristic for UC were assessed by proteome profiling of human tissue specimen, obtained from five distinct colon locations each of 12 patients. Systemic disease-associated alterations were investigated by mass spectrometry-based multi-omics analyses comprising proteins, metabolites and eicosanoids of plasma obtained from UC patients during disease and upon remission in comparison to healthy controls. Results: Proteome profiling results identified colitis-associated activation of neutrophils, macrophages, B- and T-cells, platelets, fibroblasts and endothelial cells and indicated hypoxic stress, as well as a general reduction of mitochondrial proteins accompanying the establishment of apparent healing-promoting activities as well as scar formation. While the immune cells mainly contributed pro-inflammatory proteins, the colitis-associated epithelial cells, fibroblasts, endothelial cells and platelets predominantly formed anti-inflammatory and healing-promoting proteins. Blood plasma proteomics indicated chronic inflammation and platelet activation, whereas plasma metabolomics identified disease-associated deregulation of bile acids, eicosanoids and gut microbiome-derived metabolites. Upon remission, several, but not all, molecular candidate biomarker levels recovered to normal levels. These findings may indicate that pathomechanisms related to gut functions, gut microbiome status, microvascular damage and metabolic dysregulation associated with hypoxia may do not resolve uniformly upon remission. Conclusions: The establishment of disease-associated biomarker profiles related to molecular UC pathomechanisms may support the establishment of bioassays with improved prognostic power aiding individualized therapy.
2023-04-11 | PXD030775 | Pride
Project description:A role for ZNF598 in post-transcriptional gene regulation
| PRJNA477345 | ENA
Project description:Post-Transcriptional Regulation of Mouse Neurogenesis by Pumilio Proteins
| PRJNA376393 | ENA
Project description:IBD is a complex autoimmune disease characterized by dysregulated interactions between host immune responses and microbiome at the intestinal epithelium interface. Here we identified shared protein alterations in intestinal epithelial differentiation and function between IBD and Citrobacter rodentium infected FVB mice. We discovered that prophylactic treatment with the mucosal healing therapy IL-22.Fc in the infected FVB mice reduced disease severity and rescued the mice from lethality. Notably, we observed an emergence of intermediate undifferentiated intestinal epithelial cells upon infection, with disrupted expression of the solute transporter machinery as well as components critical for intestinal barrier integrity. Multi-omics analyses revealed that with IL-22.Fc treatment several disease associated changes were prevented (including disruption of the solute transporter machinery), and proper physiological homeostatic functions of the intestine was restored. Taken together, we unveiled the disease relevance of the C. rodentium induced colitis model to IBD and demonstrated the protective role of the mucosal healing therapy IL-22.Fc in ameliorating the epithelial dysfunction.
2023-10-05 | PXD024688 | Pride
Project description:In the present study, we demonstrated that mice deficient in chemerin or IEC-specific CMKLR1 expression were highly susceptible to DSS-induced colitis and subsequent tumorigenesis, which was reversed by suppressing colonic neutrophilic inflammation using CXCR2 inhibitor. Surprisingly, we found that lack of the Chemerin-CMKLR1 signaling specifically reduced colonic epithelial expression of lactoperoxidase (LPO), an epithelial peroxidase which could utilize H2O2 to oxidase thiocyanates to antibiotic compound (Bafort et al., 2014). Importantly, we demonstrated that impaired epithelial LPO expression accounted for outgrowth of potentially pathogenic Gram-negative bacteria following epithelial injury, which led to overproduction of CXCL1/2 and pathological neutrophilic inflammation in mice with epithelial Chemerin-CMKLR1 signaling deficiency. Finally, lack of epithelial Chemerin-CMKLR1 signaling impaired early host defense against enteric bacteria, which was reversed by LPO supplementation. Taken together, our study uncovers a critical role of epithelial Chemerin-CMKLR1 signaling in restricting pathological colonic neutrophilia via potentiating LPO-mediated epithelial innate defense, thereby rendering protection against microbiota-driven colitis and tumorigenesis.
2022-06-30 | GSE178308 | GEO
Project description:Hexokinases (HK) catalyze the first step of glycolysis and thereby limit its pace. HK2 is highly expressed in the gut epithelium, plays a role in immune responses and is upregulated in inflammation and ulcerative colitis 1-3. Here, we examined the microbial regulation of HK2 and its impact on intestinal inflammation by generating mice lacking HK2 specifically in intestinal epithelial cells (Hk2∆IEC). Hk2∆IEC mice were less susceptible to acute intestinal inflammation upon challenge with dextran sodium sulfate (DSS). Analyzing the epithelial transcriptome from Hk2∆IEC mice during acute colitis revealed downregulation of cell death signaling and mitochondrial dysfunction dependent on loss of HK2. Using intestinal organoids derived from Hk2∆IEC mice and Caco-2 cells lacking HK2, we identified peptidyl-prolyl cis-trans isomerase (PPIF) as a key target of HK2-mediated regulation of mitochondrial permeability and repression of cell-death during intestinal inflammation. The microbiota strongly regulated HK2 expression and activity. The microbially-derived short-chain fatty acid (SCFA) butyrate repressed HK2 expression and oral supplementation protected wildtype but not Hk2∆IEC mice from DSS colitis. Our findings define a novel mechanism how butyrate may act as a protective factor for intestinal barrier homeostasis and suggest targeted HK2 inhibition as a promising therapeutic avenue in intestinal inflammation.
2021-12-01 | GSE158026 | GEO
Project description:Even though proteins are produced from mRNA, the correlation between mRNA levels and protein abundances is moderate in most studies, occasionally attributed to complex post-transcriptional regulation. To address this, we generated a paired transcriptome/proteome time course dataset with 14 time points during Drosophila embryogenesis. Despite a limited mRNA-protein correlation (ρ = 0.54), mathematical models describing protein translation and degradation explain 84% of protein time-courses based on the measured mRNA dynamics without assuming complex post-transcriptional regulation, and allow for classification of most proteins into four distinct regulatory scenarios. By performing an in-depth characterization of the putatively post-transcriptionally regulated genes, we postulated that the RNA-binding protein Hrb98DE is involved in post-transcriptional control of sugar metabolism in early embryogenesis and partially validated this hypothesis using Hrb98DE knockdown. In summary, we present a systems biology framework for the identification of post-transcriptional gene regulation for large-scale time-resolved transcriptome and proteome data.
2018-10-26 | PXD011238 | Pride