Chemical dissection of vtamin D activity
Ontology highlight
ABSTRACT:
ORGANISM(S): Cricetulus griseus
PROVIDER: GSE134965 | GEO | 2019/07/27
REPOSITORIES: GEO
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Project description:Complex autoimmune diseases have proven difficult to dissect down to their causative genetic mechanisms. As a result, epidemiological data from different human association studies are often merged to arrive at a working hypothesis. In one of such examples, lack of sun exposure and consequent lower serum vitamin D3 levels has been proposed to increase risk of autoimmunity, attributing vitamin D3 an immune regulatory role. However, conclusive evidence demonstrating its efficacy in treating autoimmune diseases is missing. In this study, we have used a forward genetics approach to positionally identify polymorphic nucleotides controlling T cell-dependent inflammatory diseases using congenic mouse strains. Here, we identify the vitamin D3 receptor (Vdr) as a driver of inflammation. Congenic mice carrying a polymorphic Vdr allele overexpressed the receptor selectively in activated T cells, thereby escaping systemic calcaemic side effects that often constitute a confounding factor in the study of immunomodulation by vitamin D3. Mice overexpressing Vdr in T cells developed more severe collagen-induced arthritis (CIA) and exhibited an enhanced antigen-specific CD4+ T cell response. Deficiency of vitamin D3 completely protected mice from CIA by limiting the activation of antigen-specific T cell responses, and arthritis susceptibility was restored by re-administration of vitamin D3. We demonstrate that vitamin D3 signalling specifically through Vdr predominantly acts to enhance T cell proliferation, thereby contributing to inflammation. In conclusion, our results demonstrate that genetically determined expression of VDR codetermines the pro-inflammatory behaviour of activated T cells. Furthermore, our data suggest that the anti-inflammatory properties of vitamin D3 might be limited by high expression of VDR at the site of inflammation.
2020-09-28 | PXD019876 | Pride
Project description:Gene expression profiling of macrophages derived from WT and Vdr deficient mice after stimulation with IFNgamma and/or 1alpha,25(OH)2D3 Keywords = macrophages Keywords = VDR Keywords = activated vitamin D3 Keywords = IFNgamma Keywords = KO mice Keywords: dose response
2005-04-21 | GSE2421 | GEO
Project description:The vitamin D receptor (VDR) has been knocked out in monocytic THP-1 cells after stimulation of ko and control cells with the the natural VDR ligand 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), quadruplicate mRNA-seq has been performed
2021-09-06 | GSE157514 | GEO
Project description:Analysis of mouse placenta retrieved at day 18.5pc from vitamin D (1,25-dihydroxyvitamin D3) receptor (Vdr) knockout, heterozygous and wild-type mice. Results provide insight into the molecular mechanisms underlying the effect of vitamin D on placental function. Vdr heterozygous males and females were mated to generate Vdr knockout, heterozygous and wild-type offspring. At day 18.5pc, mouse placentae were collected and RNA was extracted and assayed on Affymetrix MoGene 2.1 ST arrays to measure the effect of Vdr on global gene expression.
2015-08-04 | E-GEOD-61583 | biostudies-arrayexpress
Project description:Analysis of mouse placenta retrieved at day 18.5pc from vitamin D (1,25-dihydroxyvitamin D3) receptor (Vdr) knockout, heterozygous and wild-type mice. Results provide insight into the molecular mechanisms underlying the effect of vitamin D on placental function.
2015-08-04 | GSE61583 | GEO
Project description:The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), induces stable tolerogenesis in dendritic cells (DC). This process involves the Vitamin D receptor (VDR) which translocates to the nucleus, binds its cognate genomic sites and promotes epigenetic and transcriptional remodeling. In this study, we investigated the interplay between the vitamin D receptor (VDR) and transcription factors to induce DNA methylation changes, which might provide phenotypic stability to the tolerogenic phenotype of DCs.
2022-02-23 | GSE145584 | GEO
Project description:The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), induces stable tolerogenesis in dendritic cells (DC). This process involves the Vitamin D receptor (VDR) which translocates to the nucleus, binds its cognate genomic sites and promotes epigenetic and transcriptional remodeling. In this study, we investigated the interplay between the vitamin D receptor (VDR) and transcription factors to induce DNA methylation changes, which might provide phenotypic stability to the tolerogenic phenotype of DCs.
2022-02-23 | GSE145483 | GEO
Project description:Vitamin D induces anti-proliferative and differentiating effects in prostate cancer. Thus calcitriol, the hormonally active form of Vitamin D, and its analogs have been extensively studied in prostate cancer cells. Yet despite its importance, relatively little is known about the genome-scale mechanisms by which Vitamin D, through its cognate nuclear vitamin D receptor (VDR), exerts its regulatory functions at the genomic level. In this study, we defined VDR transcriptional networks in the LNCaP prostate cancer cell line by mapping the genomic binding sites of VDR and by identifying differentially expressed genes upon calcitriol treatment. We found that VDR and androgen receptor (AR) antagonistically regulate a subset of cell cycle-related genes that are over-expressed in prostate cancer tumors. The expression balance of these genes is partially regulated through the competition dynamics between AR and VDR binding to shared cis-regulatory elements. On such shared elements, we found that FOXA1 mediates this competition by serving as a pioneering factor for both AR and VDR binding. We also found significant enrichment of AR-, VDR-, and AR/VDR overlapping binding sites in prostate cancer-associated single-nucleotide polymorphism (SNP) intervals identified from genome-wide association studies (GWAS), providing genetic evidence to link AR, VDR and their crosstalk to prostate cancer susceptibilities. In particular, we found that in a cis-regulatory element of the RFX6 gene implicated in prostate cancer progression, an allelic variant increases prostate cancer risk by switching the antagonism between AR and VDR into a synergistic interaction. Examination of AR, VDR, and FOXA1 binding in LNCaP cells, in biological replicates
2015-08-01 | E-GEOD-64656 | biostudies-arrayexpress
Project description:WM164, a human melanoma line, was a gift from Dr M. Herlyn (Wistar Institute, Philadelphia, PA, USA). The cells were cultured using DMEM media supplemented with 10% serum (fetal bovine serum while growing cells and charcoal-treated serum during incubation with vitamin D compounds), 1% antibiotics and 5 g/mL insulin (Sigma-Aldrich, St. Louis, MO, USA). Cells were cultured in 75 cm2 plastic bottles (TPP–Techno Plastic Products AG, Trasadingen, Switzerland) with a filter in an incubator at 37 C with 5% CO2. CRISPR/Cas Knock out of the VDR. The clustered regularly interspaced short palindromic repeats (CRISPR) genetic engineering method was carried out to knock out VDR expression in the WM164 cell line as described in (Cancers 2021, 13, 3111. https://doi.org/10.3390/cancers13133111). The resulting cells with the VDR gene knocked out are designated as WM164 VDR KO, and the cells transduced with an “empty” lentivirus served as a control (WM164 scramble). VDR expression was checked for scramble and VDR KO lines before experiments were performed and further every 4 months after lentivirus treatment to ensure that VDR was not expressed in the WM164 KO. Sources of Vitamin D3 Compounds: Both 1,25(OH)2D3 and 25(OH)D3 were purchased from Sigma. 1,20(OH)2D3 and 20(OH)D3 were chemically synthesized. RNA SEQ: VDR-KO or scramble WM164 cells were plated onto 100 mm2 Petri dishes and treated with 1,25(OH)2D3, 25(OH)D3, 20(OH)D3, 1,20(OH)2D3 or ethanol (control) in triplicates. Cells were incubated in 10% charcoal-treated serum for 24 h. Cells were further harvested and RNA isolated using Absolutly RNA Miniprep Kit (Stratagen) . Approximately 120 ng/ul of each sample was sent for RNAseq analysis. BGI@CHOP genomics company sequenced the samples on Illumina HiSeq TM, analyzed, and sent us the results.
2024-06-01 | GSE248660 | GEO
Project description:Vitamin D induces anti-proliferative and differentiating effects in prostate cancer. Thus calcitriol, the hormonally active form of Vitamin D, and its analogs have been extensively studied in prostate cancer cells. Yet despite its importance, relatively little is known about the genome-scale mechanisms by which Vitamin D, through its cognate nuclear vitamin D receptor (VDR), exerts its regulatory functions at the genomic level. In this study, we defined VDR transcriptional networks in the LNCaP prostate cancer cell line by mapping the genomic binding sites of VDR and by identifying differentially expressed genes upon calcitriol treatment. We found that VDR and androgen receptor (AR) antagonistically regulate a subset of cell cycle-related genes that are over-expressed in prostate cancer tumors. The expression balance of these genes is partially regulated through the competition dynamics between AR and VDR binding to shared cis-regulatory elements. On such shared elements, we found that FOXA1 mediates this competition by serving as a pioneering factor for both AR and VDR binding. We also found significant enrichment of AR-, VDR-, and AR/VDR overlapping binding sites in prostate cancer-associated single-nucleotide polymorphism (SNP) intervals identified from genome-wide association studies (GWAS), providing genetic evidence to link AR, VDR and their crosstalk to prostate cancer susceptibilities. In particular, we found that in a cis-regulatory element of the RFX6 gene implicated in prostate cancer progression, an allelic variant increases prostate cancer risk by switching the antagonism between AR and VDR into a synergistic interaction. Gene expression profiling in LNCaP cells after 24hr treatment with different nuclear recpetor ligrands, with time-matching control, in triplicates Expression is assayed with Agilent G4112F.
2015-08-01 | E-GEOD-60956 | biostudies-arrayexpress