Ah receptor activation coordinates intestinal epithelial cell programing
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE176330 | GEO | 2023/12/31
REPOSITORIES: GEO
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Project description:We establish that six tryptophan metabolites are essentially not CYP1A1 substrates and the level of these metabolite in mouse serum are not affected by a lack of CYP1A1 or any other Aryl hydrocarbon Receptor (AHR) dependent metabolic pathway expression in vivo. These results establish that tryptophan metabolites that circulate at significant levels in vivo are not subject to an autoregulatory feedback loop between the AHR and CYP1A1.
2023-02-22 | ST002491 | MetabolomicsWorkbench
Project description:Signaling via the arylhydrocarbon receptor (AhR) is thought to contribute to exacerbation of allergic asthma by anthropogenic pollution. The physiological role of AhR and its downstream targets CYP1 family members upon exposure to aeroallergens remain unknown. We seek to characterize the role of the AhR pathway for the regulation of allergic airway inflammation (AAI). We employed knockout animals of the AhR and its downstream target cytochrome P450 enzymes CYP1A1, CYP1A2 and CYP1B1 and subjected them to preclinical allergic asthma models (ragweed and house dust mite) to assess the role of AhR and CYP1 family members in allergic airway inflammation. Histological, transcriptional and functional assays were used to uncover relevant cell types and mechanistic insights. In the ragweed model, AhRKO/KO and CYP1B1KO/KO but not CYP1A2 KO/KO or CYP1A2KO/KO animals showed exacerbation of AAI including elevated infiltration of cells in the bronchoalveolar lavage fluid and increased serum levels of IgE and allergen-specific IgG1. AhR KO/KO and CYP1B1KO/KO animals showed also more severe reactions in HDM-induced allergic AAI. Bone marrow chimeras as well as qPCR analysis and immune fluorescence histology indicate that expression of CYP1B1 in non-hematopoietic cells – presumably lung epithelial cells – is necessary to prevent exacerbation of HDM-induced AAI. Mechanistically, we show that CYP1B1 deficiency leads to enhanced expression and activity of CYP1A1 in lung epithelial cells and thus potentially to deprivation from endogenous AhR ligands. Transcriptional analysis of primary lung epithelial cells indicates a functional link of the AhR to regulation of circadian clock genes at baseline and massive alteration of gene expression upon allergen exposure.
2022-05-23 | GSE158715 | GEO
Project description:Indoxyl sulfate (IS) is a uremic toxin and ligand of the aryl-hydrocarbon receptor (Ahr), a transcriptional regulator. Elevated serum IS may contribute to the progression of kidney disease. Therefore, we assessed mouse podocyte damage mediated by IS. Ahr was predominantly localized to the podocyte nucleus in vivo and in vitro. In isolated glomeruli, IS-exposure for 2 – 24 h induced Cyp1a1 expression, the most sensitive biomarker of Ahr activation. Mice exposed to IS for 4–8 weeks exhibited microalbuminuria, and mild glomerular injury characterized by ischemic changes, partial podocyte foot process effacement, as well as vascular and tubulointerstitial damage. Chronically IS-exposed kidneys exhibited decreased mRNA, decreased protein levels, and altered staining patterns for podocin, synaptopodin, and non-muscle myosin IIA (Myh9). Immortalized podocytes, upon differentiation, exhibited Ahr nuclear translocation beginning 30 min after 1 mM IS-exposure. At 2 h, there was a dose-dependent decrease in podocyte mRNA expression of WT1, Podxl, Snypo, Myh9, Actn4, and Cd2ap. After 24 h of exposure to IS, podocytes were smaller, had fewer actin/Myh9 fibers, and decreased viability. Ahr-RNAi decreased mRNA expression of podocyte-specific proteins and inhibited Cyp1a1 induction by IS-exposure. Combinations of Ahr-RNAi and IS-exposure further decreased Myh9 expression. In immortalized human podocytes, IS treatment caused cell injury, decreased mRNA expression of podocyte-specific proteins, integrins, collagens, cytoskeletal proteins, and bone morphogenetic proteins, and increased cytokine and chemokine expression. Thus, chronic IS-exposure causes glomerular damage by activating Ahr, altering podocyte function, differentiation, and morphology, and inducing a pro-inflammatory phenotype. Podocyte cells treated with Indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand, mediates progressive glomerular disease by damaging podocytes Human podocyte cell line treated with or without 3-Indoxyl sulfate (1mM/0.1%DMSO) in three replications
2014-10-14 | E-GEOD-51834 | biostudies-arrayexpress
Project description:To establish better understanding of specific epithelial cells found across different regions of the small intestine in pigs, we utilized single-cell RNA sequencing (scRNA-seq) to recover and analyze epithelial cells from duodenum, jejunum, and ileum. Cells identified included crypt cells, enterocytes, BEST4 enterocytes, goblet cells, and enteroendocrine (EE) cells. Overall, results provide new information on regional localization and transcriptional profiles of epithelial cells in the pig small intestine.
2023-01-18 | GSE208613 | GEO
Project description:The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that regulates the expression of xenobiotic detoxification genes and is a critical mediator of gene-environment interactions. In addition, many AHR target genes that have been identified by genome-wide profiling have morphogenetic functions, suggesting that AHR activation may play a role in embryonic development. To address this hypothesis, we studied the consequences of AHR activation by TCDD, its prototypical ligand, during spontaneous mouse ES cell differentiation into contractile cardiomyocytes. Treatment with TCDD or shRNA-mediated AHR knockdown significantly decreased the ability of cardiomyocytes to contract and the expression of cardiac markers in these cells. An AHR-positive embryonic stem cell lineage was generated that expressed puromycin resistance and eGFP under the control of the AHR-responsive Cyp1a1 promoter. Cells of this lineage were over 90% pure and expressed AHR as well as cardiomyocyte markers. Analysis of temporal trajectories of global gene expression in these cells shows that activation of the AHR/TCDD axis disrupts the concerted expression of genes that regulate multiple signaling pathways involved in cardiac and neural morphogenesis and differentiation, including dozens of genes encoding homeobox transcription factors and Polycomb and Trithorax Group genes. More than 50% of the homeobox factors so regulated do not have AhRE sites in their promoters, indicating that AHR activation may establish a complex regulatory network that reaches beyond direct AHR signaling and is capable of disrupting various aspects of embryonic development, including cardiomyocyte differentiation. mRNA profiles of WT and selected AHR positive cells at different differentiation days treated with and without TCDD in duplicates
2013-06-15 | E-GEOD-47964 | biostudies-arrayexpress
Project description:High numbers of goblet cells in airways contribute to the mucus obstruction characteristic of asthmatic airways. Allergen challenged mice exhibit robust expression of goblet cells within airway surface epithelium. This study looks at the temporal analysis of IL-13 exposed murine airways to elucidate pathways that result in differentiation of airway epithelial cells to goblet cells.
2008-06-13 | E-GEOD-481 | biostudies-arrayexpress
Project description:The Aryl hydrocarbon Receptor (AhR) is a signal regulated transcription factor, which is canonically activated by the direct binding of xenobiotics. In addition, switching cells from adherent to suspension culture also activates the AhR, representing a non-xenobiotic, physiological activation of AhR signaling. Here, we show that the AhR is recruited to target gene enhancers in both ligand (YH439) treated and suspension cells, suggesting a common mechanism of target gene induction between these two routes of AhR activation. However, gene expression profiles critically differ between xenobiotic and suspension activated AhR signaling. Por, and Cldnd1 were regulated predominately by ligand treatments, while in contrast, ApoER2 and Ganc were regulated predominately by the suspension condition. Classic xenobiotic metabolizing AhR targets such as Cyp1a1, Cyp1b1, and Nqo1 were regulated by both ligand and suspension conditions. Temporal expression patterns of AhR target genes were also found to vary, with examples of transient activation, transient repression, or sustained alterations in expression. Furthermore, sequence analysis coupled with ChIP assays and reporter gene analysis identified a functional XRE (xenobiotic response element) within the mouse Tiparp gene that features a concatemer of 4 XRE cores (GCGTG) residing in the first intron ~1.2kb downstream of the Tiparp transcription start site. Our data suggest that this XRE concatemer site concurrently regulates the expression of both Tiparp gene and its cis anti-sense non-coding RNA following ligand or suspension induced AhR activation. This work lends novel insights into how AhR signaling drives different transcriptional programs via the ligand versus suspension modes of activation. Reference: Murray IA et al. (2005) Evidence that ligand binding is a key determinant of Ah receptor-mediated transcriptional activity. Arch Biochem Biophys 442(1):59-71. Reference: Monk SA et al. (2001) Transient expression of CYP1A1 in rat epithelial cells cultured in suspension. Arch Biochem Biophys 393(1):154-162. Reference: Chua SW et atl. (2006) A novel normalization method for effective removal of systematic variation in microarray data. Nucleic acids research 34(5):e38. 18 microarray samples consisting of AhR null and reconstituted hepatocytes subjected to 10M-NM-<M YH439, 0.1% DMSO carrier control or grown in suspension culture for 8 hours in 3 biologial replicates.
2012-08-09 | E-GEOD-37144 | biostudies-arrayexpress
Project description:Differentiation and specialisation of epithelial cells in the small intestine is regulated in two ways. First, there is differentiation along the crypt-villus axis of the intestinal stem cells into absorptive enterocytes, Paneth, goblet, tuft, enteroendocrine or M-cells, which is mainly regulated by WNT. Second, there is specialization along the cephalocaudal axis with different absorptive and digestive functions in duodenum, jejunum and ileum that is controlled by several transcription factors such as GATA4. However, so far it is unknown whether location-specific functional properties are intrinsically programmed within stem cells or if continuous signalling from mesenchymal cells is necessary to maintain the location-specific identity of the small intestine. By using the pure epithelial organoid technique, we show that region-specific gene expression profiles are conserved throughout long-term cultures of both mouse and human intestinal stem cells and correlated with differential Gata4 expression. Furthermore, the human organoid culture system demonstrates that Gata4-regulated gene expression is only allowed in absence of WNT signalling. These data show that location-specific function is intrinsically programmed in the adult stem cells of the small intestine and that their differentiation fate is independent of location-specific extracellular signals. In light of the potential future clinical application of small intestine-derived organoids, our data imply that it is important to generate GATA4-positive and GATA4-negative cultures to regenerate all essential functions of the small intestine. RNA sequencing of intestinal crypts, villi and cultured organoids derived from mouse duodenum, jejunum and ileum
2014-01-07 | E-GEOD-53297 | biostudies-arrayexpress
Project description:Indoxyl sulfate (IS) is a uremic toxin and ligand of the aryl-hydrocarbon receptor (Ahr), a transcriptional regulator. Elevated serum IS may contribute to the progression of kidney disease. Therefore, we assessed mouse podocyte damage mediated by IS. Ahr was predominantly localized to the podocyte nucleus in vivo and in vitro. In isolated glomeruli, IS-exposure for 2 – 24 h induced Cyp1a1 expression, the most sensitive biomarker of Ahr activation. Mice exposed to IS for 4–8 weeks exhibited microalbuminuria, and mild glomerular injury characterized by ischemic changes, partial podocyte foot process effacement, as well as vascular and tubulointerstitial damage. Chronically IS-exposed kidneys exhibited decreased mRNA, decreased protein levels, and altered staining patterns for podocin, synaptopodin, and non-muscle myosin IIA (Myh9). Immortalized podocytes, upon differentiation, exhibited Ahr nuclear translocation beginning 30 min after 1 mM IS-exposure. At 2 h, there was a dose-dependent decrease in podocyte mRNA expression of WT1, Podxl, Snypo, Myh9, Actn4, and Cd2ap. After 24 h of exposure to IS, podocytes were smaller, had fewer actin/Myh9 fibers, and decreased viability. Ahr-RNAi decreased mRNA expression of podocyte-specific proteins and inhibited Cyp1a1 induction by IS-exposure. Combinations of Ahr-RNAi and IS-exposure further decreased Myh9 expression. In immortalized human podocytes, IS treatment caused cell injury, decreased mRNA expression of podocyte-specific proteins, integrins, collagens, cytoskeletal proteins, and bone morphogenetic proteins, and increased cytokine and chemokine expression. Thus, chronic IS-exposure causes glomerular damage by activating Ahr, altering podocyte function, differentiation, and morphology, and inducing a pro-inflammatory phenotype. Podocyte cells treated with Indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand, mediates progressive glomerular disease by damaging podocytes
2014-10-14 | GSE51834 | GEO
Project description:To ascertain whether the activation of AhR in intestinal epithelial cells (IECs) directly contributes to the enhanced production of Muc2, we generated conditional AhR knockout mice with deficiency in IECs (AhRΔIEC). Subsequently, the expression of genes involved in mucin production, along with the markers indicative of mature goblet cells and proliferation in the context of colitis, with or without I3C treatment was evaluated. We used microarrays to detail the global programme of gene expression to identify the distinct classes of up-regulated and downlregulated genes among the experimental groups.
2023-09-16 | GSE242891 | GEO