{"gene":"VDR","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2002,"finding":"Crystal structures of the VDR DNA-binding domain (DBD) at 2.7–2.8 Å resolution in complex with three different response elements (osteopontin SPP, canonical DR3, and osteocalcin OC) revealed the chemical basis for differential affinity at distinct response elements. The homodimeric protein-protein interface is stabilized by van der Waals interactions and is predominantly non-polar. Structure-based mutations in the asymmetric homodimeric interface created a VDR DBD defective in homodimerization but capable of heterodimerization with the RXR DBD, defining the dimerization interface.","method":"X-ray crystallography (2.7–2.8 Å), structure-based site-directed mutagenesis, in vitro heterodimerization assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures at near-atomic resolution combined with mutagenesis to validate functional interface; multiple orthogonal methods in a single rigorous study","pmids":["11980721"],"is_preprint":false},{"year":2000,"finding":"Homology modeling of the VDR ligand-binding domain (LBD) with docking of 1,25-(OH)2D3 identified specific hydrogen-bond interactions: the 1α-OH group forms a pincer-type hydrogen bond with R274 and S237, and the 25-OH group contacts H397. Mutation analysis confirmed these residues are required for high-affinity ligand binding and transactivation.","method":"Homology modeling, docking simulation, site-directed mutagenesis","journal":"Current pharmaceutical design","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural modeling validated by mutagenesis, but single lab and abstract does not detail full reconstitution or crystallographic confirmation","pmids":["10828304"],"is_preprint":false},{"year":2011,"finding":"In skeletal muscle cells, 1α,25(OH)2D3 induces rapid non-genomic signaling via the VDR. Short-term 1α,25(OH)2D3 treatment causes reverse translocation of VDR from nucleus to plasma membranes, where it forms a complex in caveolae with TRPC3 (a capacitative Ca2+ entry channel). VDR also forms complexes with Src kinase, linking it to MAPK cascade activation. These events stimulate adenylyl cyclase/cAMP/PKA, PLC/DAG+IP3/PKC, Ca2+ messenger, and MAPK pathways.","method":"Subcellular fractionation, co-immunoprecipitation, caveolae isolation, second-messenger assays","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and fractionation showing VDR-TRPC3 and VDR-Src complexes with downstream signaling readouts; single lab but multiple orthogonal methods","pmids":["21664245"],"is_preprint":false},{"year":2015,"finding":"VDR transcriptionally regulates ATG16L1 as a direct target gene. Low intestinal VDR levels are associated with abnormal Paneth cells, impaired autophagy, and dysbiosis with reduced ATG16L1 expression. Butyrate increases intestinal VDR expression and suppresses inflammation in a colitis model.","method":"Transcriptional reporter assays, VDR knockdown, mouse colitis model, ChIP","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays establishing VDR as direct transcriptional activator of ATG16L1, with in vivo validation; single lab","pmids":["26218741"],"is_preprint":false},{"year":2020,"finding":"VDR activation protects against cisplatin-induced acute kidney injury by inhibiting ferroptosis. Mechanistically, VDR transcriptionally activates GPX4 (a key regulator of ferroptosis), as confirmed by luciferase reporter assay. VDR knockout mice showed markedly increased ferroptotic cell death and worse kidney injury. siRNA knockdown of GPX4 largely abolished the protective effect of VDR agonist paricalcitol.","method":"Luciferase reporter assay, VDR knockout mouse, siRNA knockdown, ferroptosis phenotype assays (lipid peroxidation, MDA, 4-HNE measurement), in vivo cisplatin AKI model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and pharmacological approaches (KO mouse, VDR agonist, GPX4 siRNA) plus reporter assay confirming VDR→GPX4 direct transcriptional regulation; multiple orthogonal methods","pmids":["31996668"],"is_preprint":false},{"year":2020,"finding":"In an acidic tumor microenvironment, VDR is exported from the nucleus (its nuclear export signal is sensitive to acidosis), reducing its transcriptional activity. VDR directly binds to vitamin D response elements (VDREs) in the SOX2 promoter and transcriptionally represses SOX2, as shown by ChIP-seq and ATAC-seq. Loss of nuclear VDR in acidosis allows SOX2 upregulation, increasing colorectal cancer stemness and drug resistance.","method":"ChIP-seq, ATAC-seq, nuclear export signal analysis, VDR overexpression, SOX2 reporter assays, in vivo mouse CRC model","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq and ATAC-seq with VDR overexpression and in vivo validation establishing VDR→SOX2 repression; multiple orthogonal methods","pmids":["32900990"],"is_preprint":false},{"year":2020,"finding":"Overexpression of VDR in rat tibialis anterior muscle in vivo via electrotransfer increased myofibre area (hypertrophy), total protein and RNA accretion, mTOR signaling (translational efficiency), ribosomal expansion, satellite cell content, and extracellular matrix remodelling gene-sets, with no effects on protein breakdown markers. RNA-Seq identified downstream transcriptional programs. VDR expression correlated with hypertrophy in humans after resistance exercise training.","method":"In vivo electrotransfer VDR overexpression in rat muscle, stable isotope tracer (D2O) MPS measurement, RNA-Seq, human resistance exercise training transcriptomics","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo gain-of-function with protein synthesis, signaling, and transcriptomic readouts, corroborated by human data; multiple orthogonal methods","pmids":["32771696"],"is_preprint":false},{"year":2014,"finding":"Genome-wide ChIP-seq analysis across six cellular models identified 23,409 non-overlapping VDR binding sites. De novo motif analysis showed that direct repeat sequences spaced by 3 nucleotides (DR3-type) are preferentially enriched at highly ligand-responsive VDR loci across all cell types, indicating that DR3 elements are a core determinant of VDR occupancy and ligand responsiveness. The majority of VDR binding sites do not contain a DR3 sequence, suggesting widespread non-canonical binding.","method":"ChIP-seq (six datasets), MACS peak calling, de novo motif analysis, HOMER screening","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — re-analysis of six independent ChIP-seq datasets with unified methodology; replicated across multiple labs' data","pmids":["24787735"],"is_preprint":false},{"year":2017,"finding":"The pioneer transcription factor PU.1 modulates VDR signaling genome-wide in human monocytes. 1,25(OH)2D3 significantly increased PU.1 binding at 6,498 genomic loci that overlap with VDR sites. PU.1 knockdown altered transcriptional activation of 1,25(OH)2D3 target genes. Chromatin accessibility at PU.1 sites was the major discriminator of regulatory outcomes. No direct physical interaction between PU.1 and VDR was detected.","method":"ChIP-seq (PU.1 and VDR cistrome mapping), PU.1 siRNA knockdown, chromatin accessibility analysis, 1,25(OH)2D3 treatment of THP-1 monocytes","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and knockdown with defined transcriptional readouts; single lab, no physical interaction detected (explicitly negative for direct PU.1-VDR binding)","pmids":["28232093"],"is_preprint":false},{"year":2006,"finding":"Elevated co-repressors NCoR2/SMRT (in prostate cancer) and NCoR1 (in breast cancer) attenuate VDR transcriptional and anti-proliferative responses to 1α,25(OH)2D3. siRNA knockdown of NCoR2/SMRT in prostate cancer cells restored VDR transcriptional activity and anti-proliferative responses. Overexpression of NCoR1 in non-malignant breast epithelial cells suppressed VDR actions. Co-treatment with HDAC inhibitors (TSA, NaB) plus 1α,25(OH)2D3 synergistically induced GADD45α and p21waf1/cip1 and inhibited proliferation.","method":"siRNA knockdown of co-repressors, NCoR1 overexpression, proliferation assays, gene expression assays, co-treatment experiments in primary tumor material and cell lines","journal":"Anticancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA and overexpression with defined transcriptional and proliferative readouts; single lab, two orthogonal approaches","pmids":["16886664"],"is_preprint":false},{"year":2012,"finding":"In prostate cancer cells (PC-3), VDR inappropriately recruits the co-repressor NCOR1 to the promoter regions of target genes IGFBP3 and G0S2. ChIP assays showed that VDR-induced NCOR1 enrichment at VDR-binding regions correlates with suppressed transcriptional responses and local H3K9 hypoacetylation, proposing a mechanism by which transient co-repressor binding triggers stable DNA methylation-based silencing.","method":"Chromatin immunoprecipitation (ChIP), time-resolved gene expression analysis, comparison between non-malignant RWPE-1 and PC-3 prostate cells","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating VDR-NCOR1 co-occupancy at target gene promoters with transcriptional readouts; single lab, single method type","pmids":["23098689"],"is_preprint":false},{"year":2013,"finding":"Stable expression of wild-type human VDR in VDR-knockout murine mammary tumor cells restored 1,25D-induced growth inhibition and target gene regulation (PDGFB, VEGFA, NFKBI). VDR point mutations W286R and R274L (reducing/abolishing ligand binding) abolished responses at physiological doses. VDR mutation G46D (abrogating DR3 binding) provided only partial growth inhibition, demonstrating that non-canonical (non-DR3) genomic or non-genomic VDR signaling contributes to anti-cancer effects.","method":"Stable transfection of WT and mutant hVDR into VDR-null cells, proliferation assays, gene expression analysis, site-directed mutagenesis","journal":"Molecular carcinogenesis","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with multiple point mutants defining ligand-binding and DNA-binding requirements; multiple orthogonal methods in one rigorous study","pmids":["23681781"],"is_preprint":false},{"year":2017,"finding":"VDR transcriptionally regulates HSD3B1 in mouse Leydig cells by binding to candidate vitamin D response elements (VDREs) in the upstream region of the Hsd3b1 gene, as confirmed by dual-luciferase reporter assay. VDR and HSD3B1 overexpression increased testosterone synthesis. HSD3B1 overexpression downregulated LPL and upregulated ANGPTL4, linking VDR→HSD3B1 to lipid metabolism regulation in Leydig cells.","method":"Dual-luciferase reporter assay, VDR deletion (testicular proteome data), VDR and HSD3B1 overexpression, RT-qPCR, western blot, testosterone ELISA","journal":"Genes & genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-luciferase confirming VDRE-driven HSD3B1 transcription with functional overexpression readout; single lab","pmids":["35254654"],"is_preprint":false},{"year":2022,"finding":"1,25D/VDR inhibits ferroptosis in pancreatic β cells by downregulating the transcription factor FOXO1. Proteomic sequencing identified FOXO1 as a downstream VDR target. VDR knockdown reversed 1,25D effects on cell viability, ROS, iron, GPX4, and ACSL4. FOXO1 knockdown independently reduced β cell ferroptotic death, phenocopying VDR activation.","method":"Proteomic sequencing (identifying FOXO1 as VDR target), VDR siRNA knockdown, FOXO1 siRNA knockdown, ROS and iron assays, western blot for GPX4/ACSL4, STZ-induced T2DM rat model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic target identification plus reciprocal knockdown experiments with defined ferroptosis phenotype; single lab","pmids":["36581217"],"is_preprint":false},{"year":2023,"finding":"VDR transcriptionally represses NLRP6 in intestinal epithelial cells by binding to VDREs in the NLRP6 promoter, as demonstrated by ChIP and ATAC-seq. VD3-mediated VDR activation abolished NLRP6 inflammasome assembly (suppressing NLRP6, ASC, and Caspase-1), with protective effects against ulcerative colitis confirmed in NLRP6-/- mice and siRNA-NLRP6 cells.","method":"ChIP assay, ATAC-seq, VDR agonist treatment, NLRP6 knockout mice, siRNA knockdown, RNA-seq, colitis mouse model","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP and ATAC-seq establishing direct VDR→NLRP6 repression, validated in both genetic knockout and siRNA models in vivo and in vitro; multiple orthogonal methods","pmids":["36845152"],"is_preprint":false},{"year":2023,"finding":"RAR and VDR compete for heterodimerization with their shared partner RXR in live cells in an agonist-dependent manner, and this competition is manifested in their DNA binding. Fluorescence correlation spectroscopy showed that coexpression of RAR and VDR with RXR leads to reduced DNA-bound fraction of each receptor when the other's agonist is present. RAR dominates over VDR for RXR binding in the absence of agonist or when both agonists are present. RXR agonist increases RAR DNA binding at the expense of VDR.","method":"Fluorescence correlation spectroscopy (FCS) in live cells, agonist treatment, co-expression of RAR/VDR/RXR","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell FCS is a rigorous direct measurement; single lab with systematic agonist conditions, but no structural or in vitro reconstitution","pmids":["36639026"],"is_preprint":false},{"year":2024,"finding":"Vitexin directly binds the VDR protein and facilitates VDR nuclear translocation to exert transcriptional activity. ChIP-seq and dual-luciferase reporter assays established that VDR transcriptionally activates PBLD (phenazine biosynthesis-like domain protein) via VDREs in its promoter. VDR/PBLD signaling promotes M1 macrophage polarization. In myeloid-specific VDR knockout mice, the protective effects of vitexin on colitis-associated colorectal cancer were abolished.","method":"Molecular docking, co-culture macrophage/cancer cell model, ChIP-seq, dual-luciferase reporter assay, VDR nuclear translocation imaging, myeloid-specific VDR KO mouse model","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq plus dual-luciferase confirming VDR→PBLD direct transcription, validated with myeloid-specific knockout; multiple orthogonal methods in one study","pmids":["39272040"],"is_preprint":false},{"year":2023,"finding":"Monotropein binds the VDR protein directly (confirmed by molecular docking, biolayer interferometry BLI, CESTA, and DARTS). VDR nuclear translocation is reduced in tumor-conditioned macrophages, and monotropein treatment restores nuclear VDR, activates VDR signaling, and promotes M1 macrophage polarization via the VDR/JAK1/STAT1 pathway. Normal and myeloid VDR knockout mice confirmed JAK1 upregulation and M1 polarization downstream of VDR.","method":"Molecular docking, BLI, CESTA, DARTS (target engagement), immunofluorescence for VDR localization, VDR knockout animals, western blot for JAK1/STAT1, macrophage polarization assays","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple target engagement methods plus KO animal validation; single lab","pmids":["37633235"],"is_preprint":false},{"year":2017,"finding":"In vivo ChIP-seq from mouse tissues identified tissue-specific regulatory regions controlling Vdr gene expression. A humanized VDR mouse expressing hVDR with a S208A mutation (serine 208 → alanine, abolishing phosphorylation at that site) showed unchanged target gene expression, normal serum calcium and PTH, and no alopecia, establishing that phosphorylation of hVDR at serine 208 is NOT required for transcriptional activity or in vivo function.","method":"ChIP-seq in mouse tissues, transgenic humanized VDR mouse models (mini-gene), hVDR-S208A knock-in mice, target gene expression, serum biochemistry","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo humanized mouse models with rigorous physiological readouts, ChIP-seq for regulatory region mapping; multiple orthogonal methods in one study (negative finding on S208 phosphorylation is mechanistically informative)","pmids":["28602960"],"is_preprint":false},{"year":2019,"finding":"Conditional deletion of Vdr specifically in myeloid cells (osteoclast precursors, monocytes, macrophages) did not alter bone or calcium homeostasis under normal or low-calcium diet conditions, and osteoclastogenesis from Vdr-null myeloid cells was equivalent to wildtype. This establishes that VDR signaling in osteoclast precursors is NOT required for bone homeostasis.","method":"Myeloid-specific Vdr conditional knockout (M-lysozyme-Cre), bone densitometry, calcium homeostasis measurements, in vitro osteoclastogenesis assay (M-CSF/RANKL, osteoblast co-culture), dietary calcium restriction challenge","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with multiple in vivo and in vitro readouts; clean negative result mechanistically placing VDR as dispensable in osteoclast precursors for bone homeostasis","pmids":["31561003"],"is_preprint":false},{"year":2021,"finding":"In C. elegans, the VDR ortholog DAF-12 acts cell-autonomously in specific cell types to control anatomical, molecular, and behavioral remodeling during dauer entry. Conditional alleles showed that DAF-12/VDR is required continuously both to initiate and maintain tissue remodeling (not only at entry). DAF-12/VDR also exhibits non-cell-autonomous function in nervous system remodeling, indicating interorgan signaling.","method":"Conditional genetic alleles (spatial and temporal control), tissue-specific rescue experiments, behavioral and anatomical phenotyping in C. elegans dauer model","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — C. elegans ortholog, conditional genetics establishing cell-autonomous and non-autonomous roles; single lab but rigorous genetic dissection (ortholog, not human VDR)","pmids":["33891586"],"is_preprint":false},{"year":2022,"finding":"miR-122 directly targets VDR mRNA (confirmed by dual-luciferase reporter assay). VDR in turn binds to the BS1 region of the SREBF1 promoter and inhibits SREBF1 expression (confirmed by ChIP). The miR-122/VDR/SREBF1 axis regulates adipogenesis: VDR overexpression inhibits adipogenesis, while exosomal miR-122 reverses this inhibition by suppressing VDR, thereby derepressing SREBF1 and promoting lipid accumulation.","method":"Dual-luciferase reporter assay (miR-122 targeting VDR 3'UTR), ChIP (VDR binding SREBF1 promoter), VDR overexpression, miR-122 inhibition, high-fat diet mouse model","journal":"Obesity (Silver Spring, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual-luciferase and ChIP confirming direct miR-122→VDR and VDR→SREBF1 regulatory links with in vivo validation; single lab","pmids":["35170865"],"is_preprint":false},{"year":2015,"finding":"In a murine model of cardiac steatosis (MHC-DGAT1 transgenic mice), VDR deficiency (VDR-/- background) synergistically worsened cardiomyopathy: double-mutant mice showed greater myocyte hypertrophy, increased interstitial fibrosis (collagen 1a1, collagen 3a1, osteopontin, MMP2 upregulation), and severely reduced ejection fraction (37% reduction) and fractional shortening (55% reduction) compared to either single mutant alone, establishing that VDR signaling restrains pathological cardiac remodeling.","method":"VDR-/- × MHC-DGAT1 Tg genetic cross, echocardiography (ejection fraction, fractional shortening), histology (fibrosis), gene expression (collagen, natriuretic peptide, ECM genes)","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (double KO/Tg) with quantitative cardiac phenotyping; single lab","pmids":["26429397"],"is_preprint":false},{"year":2013,"finding":"HIV infection of T cells induces VDR promoter CpG methylation via upregulation of DNMT3b, resulting in attenuated VDR expression. This epigenetic silencing activates RAS, increases ROS generation, and induces DNA double-strand breaks, leading to T cell apoptosis. Demethylating agent 5-azacytidine (AZA) reversed VDR hypermethylation and blocked HIV-induced T cell apoptosis.","method":"Bisulfite methylation analysis, DNMT3b expression measurement, demethylating agent (AZA) treatment, RAS activation assay, ROS/DSB quantification, apoptosis assays","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epigenetic writer (DNMT3b) identified with pharmacological reversal and downstream phenotypic readouts; single lab","pmids":["23390308"],"is_preprint":false}],"current_model":"VDR is a ligand-activated nuclear receptor that, upon binding 1,25(OH)2D3, heterodimerizes with RXR and binds DR3-type vitamin D response elements (VDREs) to transcriptionally activate or repress target genes including GPX4, ATG16L1, NLRP6, SOX2, PBLD, HSD3B1, and FOXO1; its activity is modulated by co-repressors (NCoR1, SMRT), pioneer factors (PU.1), competition with RAR for RXR, epigenetic silencing of its own promoter (by DNMT3b or HDACs), and context-dependent rapid non-genomic signaling through plasma-membrane complexes with TRPC3 and Src kinase in muscle cells."},"narrative":{"mechanistic_narrative":"VDR is a ligand-activated nuclear receptor that, upon binding 1,25(OH)2D3, regulates transcriptional programs governing tissue homeostasis, cell-fate, metabolism, and immunity [PMID:23681781, PMID:24787735]. Crystal structures of its DNA-binding domain bound to distinct response elements define an asymmetric, predominantly non-polar dimerization interface, and interface mutations generate a VDR DBD defective in homodimerization yet still able to heterodimerize, while homology modeling and mutagenesis of the ligand-binding domain identify the pincer hydrogen bonds (R274/S237 to the 1α-OH, H397 to the 25-OH) required for high-affinity ligand binding and transactivation [PMID:11980721, PMID:10828304]. Reconstitution with point mutants confirms that both ligand binding (W286R, R274L) and DR3 element binding (G46D) are needed for full activity, although the partial activity of the DR3-binding mutant indicates non-canonical genomic and non-genomic signaling also contributes [PMID:23681781]. Genome-wide, VDR occupies tens of thousands of sites with DR3-type direct repeats enriched at the most ligand-responsive loci, and its cistrome and outputs are shaped by chromatin accessibility set by the pioneer factor PU.1, by co-repressor recruitment (NCoR1, NCoR2/SMRT) that drives histone hypoacetylation and stable silencing of target genes, and by agonist-dependent competition with RAR for the shared partner RXR [PMID:24787735, PMID:28232093, PMID:16886664, PMID:23098689, PMID:36639026]. As a transcription factor VDR both activates targets (ATG16L1, GPX4, HSD3B1, PBLD) and represses others (SOX2, NLRP6, FOXO1, SREBF1), thereby controlling intestinal autophagy and inflammation, ferroptosis resistance, steroidogenesis, macrophage M1 polarization, tumor stemness, and adipogenesis [PMID:26218741, PMID:31996668, PMID:35254654, PMID:39272040, PMID:32900990, PMID:36845152, PMID:36581217, PMID:35170865]. VDR signaling restrains pathological cardiac remodeling and, when overexpressed in skeletal muscle, drives hypertrophy through mTOR-dependent translational and ribosomal expansion [PMID:26429397, PMID:32771696]. VDR output is further tuned by acidosis-sensitive nuclear export, epigenetic silencing of its own promoter through DNMT3b-mediated CpG methylation, and a non-genomic mode in muscle in which 1α,25(OH)2D3 drives VDR to caveolar plasma-membrane complexes with the TRPC3 channel and Src kinase to activate second-messenger and MAPK cascades [PMID:32900990, PMID:23390308, PMID:21664245]. In vivo humanized-mouse genetics establish that phosphorylation of serine 208 is dispensable for transcriptional and physiological function and that VDR in osteoclast precursors is not required for bone homeostasis [PMID:28602960, PMID:31561003].","teleology":[{"year":2002,"claim":"Establishing the structural basis for how VDR reads distinct response elements and selects its dimerization partner, a prerequisite for understanding target selectivity.","evidence":"X-ray crystallography of the VDR DBD on three response elements plus interface mutagenesis and in vitro heterodimerization assays","pmids":["11980721"],"confidence":"High","gaps":["DBD structures only; full-length receptor on DNA not resolved","Does not address ligand-dependent conformational changes in the LBD"]},{"year":2000,"claim":"Defining the ligand-contact residues that confer high-affinity 1,25(OH)2D3 binding, connecting receptor chemistry to transactivation.","evidence":"Homology modeling/docking of the LBD with site-directed mutagenesis of R274, S237, H397","pmids":["10828304"],"confidence":"Medium","gaps":["Model-based rather than crystallographic confirmation","Single lab"]},{"year":2013,"claim":"Reconstitution with separation-of-function mutants showed both ligand binding and DR3 binding are required for full VDR activity, but residual activity of a DR3-binding mutant revealed non-canonical signaling contributes to anti-cancer effects.","evidence":"Stable expression of WT and mutant hVDR (W286R, R274L, G46D) in VDR-null mammary tumor cells with proliferation and target-gene readouts","pmids":["23681781"],"confidence":"High","gaps":["Mechanism of the non-DR3 residual signaling not defined","Specific to mammary tumor context"]},{"year":2014,"claim":"Genome-wide mapping established DR3 elements as the core determinant of ligand-responsive VDR occupancy while revealing the majority of sites are non-canonical.","evidence":"Unified re-analysis of six ChIP-seq datasets with de novo motif analysis","pmids":["24787735"],"confidence":"High","gaps":["Function of non-DR3 binding sites unresolved","Does not assign individual sites to target genes"]},{"year":2017,"claim":"Identified pioneer-factor and tissue-level control of the VDR cistrome, showing chromatin accessibility, not direct contact, gates VDR regulatory output.","evidence":"PU.1 and VDR ChIP-seq with PU.1 knockdown in monocytes; in vivo tissue ChIP-seq and humanized S208A knock-in mice","pmids":["28232093","28602960"],"confidence":"High","gaps":["No direct PU.1–VDR physical interaction detected","S208A finding is a negative result; other phosphosites not tested"]},{"year":2012,"claim":"Co-repressor biology was defined: NCoR1/NCoR2(SMRT) attenuate VDR activity and VDR-driven NCOR1 recruitment can seed stable epigenetic silencing of target genes.","evidence":"siRNA knockdown/overexpression of co-repressors and ChIP at IGFBP3/G0S2 promoters in prostate and breast cells, with HDAC-inhibitor co-treatment","pmids":["16886664","23098689"],"confidence":"Medium","gaps":["Single lab per study","Causal link from transient co-repressor binding to stable DNA methylation inferred, not directly demonstrated"]},{"year":2011,"claim":"Demonstrated a non-genomic mode in which membrane-localized VDR couples to Ca2+ channels and kinases, expanding VDR beyond transcription.","evidence":"Subcellular fractionation, caveolae isolation, co-IP of VDR with TRPC3 and Src, and second-messenger assays in skeletal muscle cells","pmids":["21664245"],"confidence":"Medium","gaps":["Single lab; reciprocal Co-IP validation limited","Stoichiometry and direct vs. scaffolded interaction with TRPC3/Src unclear"]},{"year":2015,"claim":"Linked VDR to intestinal autophagy and host-microbe homeostasis through direct transcriptional activation of ATG16L1.","evidence":"Reporter assays, VDR knockdown, ChIP, and a mouse colitis model with butyrate modulation","pmids":["26218741"],"confidence":"Medium","gaps":["Single lab","Does not resolve VDRE location specificity at the ATG16L1 locus"]},{"year":2020,"claim":"Established VDR as a regulator of ferroptosis and tumor stemness via opposing transcriptional outputs, and showed acidosis controls VDR localization.","evidence":"Luciferase/ChIP-seq/ATAC-seq with VDR knockout mice, siRNA, and in vivo AKI and CRC models linking VDR to GPX4 activation and SOX2 repression","pmids":["31996668","32900990"],"confidence":"High","gaps":["Mechanism of acidosis sensing by the nuclear export signal not detailed","Generalizability of GPX4/SOX2 regulation across tissues untested"]},{"year":2020,"claim":"Showed VDR drives skeletal muscle hypertrophy through mTOR-dependent translational and ribosomal programs, and restrains pathological cardiac remodeling.","evidence":"In vivo VDR electrotransfer overexpression with D2O tracer MPS and RNA-Seq in rat muscle (corroborated in humans); VDR-/- × MHC-DGAT1 cardiac epistasis with echocardiography","pmids":["32771696","26429397"],"confidence":"Medium","gaps":["Direct VDR transcriptional targets driving muscle mTOR signaling not pinpointed","Cardiac protection mechanism inferred from epistasis, not defined molecularly"]},{"year":2023,"claim":"Defined receptor competition for RXR as a layer of VDR regulation, with RAR dominating partner occupancy in an agonist-dependent manner.","evidence":"Fluorescence correlation spectroscopy in live cells co-expressing RAR/VDR/RXR under defined agonist conditions","pmids":["36639026"],"confidence":"Medium","gaps":["No structural or in vitro reconstitution of competition","Single lab"]},{"year":2024,"claim":"Extended VDR's repertoire to immune and metabolic programs, including macrophage M1 polarization (PBLD, JAK1/STAT1), β-cell ferroptosis via FOXO1, steroidogenesis via HSD3B1, NLRP6 inflammasome repression, and adipogenesis via the miR-122/VDR/SREBF1 axis.","evidence":"ChIP/ChIP-seq/ATAC-seq, dual-luciferase, reciprocal siRNA, proteomics, target-engagement assays, and myeloid-specific or global VDR knockout mouse models across multiple tissues","pmids":["39272040","37633235","36581217","35254654","36845152","35170865"],"confidence":"Medium","gaps":["Mostly single-lab studies per target","Whether these targets are conserved direct VDR effectors across human tissues untested"]},{"year":2013,"claim":"Showed VDR expression is itself epigenetically silenced, providing a route for disease (HIV) to suppress VDR-dependent protection.","evidence":"Bisulfite methylation analysis, DNMT3b measurement, and AZA reversal with RAS/ROS/DSB and apoptosis readouts in HIV-infected T cells","pmids":["23390308"],"confidence":"Medium","gaps":["Single lab","Direct DNMT3b recruitment to the VDR promoter not demonstrated"]},{"year":null,"claim":"The function of the predominant non-DR3 VDR binding sites and how ligand-, chromatin-, co-regulator-, and localization-based inputs are integrated into tissue-specific transcriptional outcomes remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No full-length VDR–RXR–DNA structure in the timeline","Functional annotation of non-canonical binding sites missing","Unified model reconciling genomic and non-genomic signaling absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,4,5,12,14,16,21]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,7,11]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,16,17]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,16,17]}],"complexes":["VDR-RXR heterodimer","caveolar VDR-TRPC3-Src membrane complex"],"partners":["RXR","RAR","NCOR1","NCOR2","TRPC3","SRC","PU.1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P11473","full_name":"Vitamin D3 receptor","aliases":["1,25-dihydroxyvitamin D3 receptor","Nuclear receptor subfamily 1 group I member 1"],"length_aa":427,"mass_kda":48.3,"function":"Nuclear receptor for calcitriol, the active form of vitamin D3 which mediates the action of this vitamin on cells (PubMed:10678179, PubMed:15728261, PubMed:16913708, PubMed:28698609, PubMed:37478846). 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The homodimeric protein-protein interface is stabilized by van der Waals interactions and is predominantly non-polar. Structure-based mutations in the asymmetric homodimeric interface created a VDR DBD defective in homodimerization but capable of heterodimerization with the RXR DBD, defining the dimerization interface.\",\n      \"method\": \"X-ray crystallography (2.7–2.8 Å), structure-based site-directed mutagenesis, in vitro heterodimerization assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures at near-atomic resolution combined with mutagenesis to validate functional interface; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"11980721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Homology modeling of the VDR ligand-binding domain (LBD) with docking of 1,25-(OH)2D3 identified specific hydrogen-bond interactions: the 1α-OH group forms a pincer-type hydrogen bond with R274 and S237, and the 25-OH group contacts H397. Mutation analysis confirmed these residues are required for high-affinity ligand binding and transactivation.\",\n      \"method\": \"Homology modeling, docking simulation, site-directed mutagenesis\",\n      \"journal\": \"Current pharmaceutical design\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural modeling validated by mutagenesis, but single lab and abstract does not detail full reconstitution or crystallographic confirmation\",\n      \"pmids\": [\"10828304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In skeletal muscle cells, 1α,25(OH)2D3 induces rapid non-genomic signaling via the VDR. Short-term 1α,25(OH)2D3 treatment causes reverse translocation of VDR from nucleus to plasma membranes, where it forms a complex in caveolae with TRPC3 (a capacitative Ca2+ entry channel). VDR also forms complexes with Src kinase, linking it to MAPK cascade activation. These events stimulate adenylyl cyclase/cAMP/PKA, PLC/DAG+IP3/PKC, Ca2+ messenger, and MAPK pathways.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, caveolae isolation, second-messenger assays\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and fractionation showing VDR-TRPC3 and VDR-Src complexes with downstream signaling readouts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21664245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"VDR transcriptionally regulates ATG16L1 as a direct target gene. Low intestinal VDR levels are associated with abnormal Paneth cells, impaired autophagy, and dysbiosis with reduced ATG16L1 expression. Butyrate increases intestinal VDR expression and suppresses inflammation in a colitis model.\",\n      \"method\": \"Transcriptional reporter assays, VDR knockdown, mouse colitis model, ChIP\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays establishing VDR as direct transcriptional activator of ATG16L1, with in vivo validation; single lab\",\n      \"pmids\": [\"26218741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"VDR activation protects against cisplatin-induced acute kidney injury by inhibiting ferroptosis. Mechanistically, VDR transcriptionally activates GPX4 (a key regulator of ferroptosis), as confirmed by luciferase reporter assay. VDR knockout mice showed markedly increased ferroptotic cell death and worse kidney injury. siRNA knockdown of GPX4 largely abolished the protective effect of VDR agonist paricalcitol.\",\n      \"method\": \"Luciferase reporter assay, VDR knockout mouse, siRNA knockdown, ferroptosis phenotype assays (lipid peroxidation, MDA, 4-HNE measurement), in vivo cisplatin AKI model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and pharmacological approaches (KO mouse, VDR agonist, GPX4 siRNA) plus reporter assay confirming VDR→GPX4 direct transcriptional regulation; multiple orthogonal methods\",\n      \"pmids\": [\"31996668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In an acidic tumor microenvironment, VDR is exported from the nucleus (its nuclear export signal is sensitive to acidosis), reducing its transcriptional activity. VDR directly binds to vitamin D response elements (VDREs) in the SOX2 promoter and transcriptionally represses SOX2, as shown by ChIP-seq and ATAC-seq. Loss of nuclear VDR in acidosis allows SOX2 upregulation, increasing colorectal cancer stemness and drug resistance.\",\n      \"method\": \"ChIP-seq, ATAC-seq, nuclear export signal analysis, VDR overexpression, SOX2 reporter assays, in vivo mouse CRC model\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq and ATAC-seq with VDR overexpression and in vivo validation establishing VDR→SOX2 repression; multiple orthogonal methods\",\n      \"pmids\": [\"32900990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Overexpression of VDR in rat tibialis anterior muscle in vivo via electrotransfer increased myofibre area (hypertrophy), total protein and RNA accretion, mTOR signaling (translational efficiency), ribosomal expansion, satellite cell content, and extracellular matrix remodelling gene-sets, with no effects on protein breakdown markers. RNA-Seq identified downstream transcriptional programs. VDR expression correlated with hypertrophy in humans after resistance exercise training.\",\n      \"method\": \"In vivo electrotransfer VDR overexpression in rat muscle, stable isotope tracer (D2O) MPS measurement, RNA-Seq, human resistance exercise training transcriptomics\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo gain-of-function with protein synthesis, signaling, and transcriptomic readouts, corroborated by human data; multiple orthogonal methods\",\n      \"pmids\": [\"32771696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Genome-wide ChIP-seq analysis across six cellular models identified 23,409 non-overlapping VDR binding sites. De novo motif analysis showed that direct repeat sequences spaced by 3 nucleotides (DR3-type) are preferentially enriched at highly ligand-responsive VDR loci across all cell types, indicating that DR3 elements are a core determinant of VDR occupancy and ligand responsiveness. The majority of VDR binding sites do not contain a DR3 sequence, suggesting widespread non-canonical binding.\",\n      \"method\": \"ChIP-seq (six datasets), MACS peak calling, de novo motif analysis, HOMER screening\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — re-analysis of six independent ChIP-seq datasets with unified methodology; replicated across multiple labs' data\",\n      \"pmids\": [\"24787735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The pioneer transcription factor PU.1 modulates VDR signaling genome-wide in human monocytes. 1,25(OH)2D3 significantly increased PU.1 binding at 6,498 genomic loci that overlap with VDR sites. PU.1 knockdown altered transcriptional activation of 1,25(OH)2D3 target genes. Chromatin accessibility at PU.1 sites was the major discriminator of regulatory outcomes. No direct physical interaction between PU.1 and VDR was detected.\",\n      \"method\": \"ChIP-seq (PU.1 and VDR cistrome mapping), PU.1 siRNA knockdown, chromatin accessibility analysis, 1,25(OH)2D3 treatment of THP-1 monocytes\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and knockdown with defined transcriptional readouts; single lab, no physical interaction detected (explicitly negative for direct PU.1-VDR binding)\",\n      \"pmids\": [\"28232093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Elevated co-repressors NCoR2/SMRT (in prostate cancer) and NCoR1 (in breast cancer) attenuate VDR transcriptional and anti-proliferative responses to 1α,25(OH)2D3. siRNA knockdown of NCoR2/SMRT in prostate cancer cells restored VDR transcriptional activity and anti-proliferative responses. Overexpression of NCoR1 in non-malignant breast epithelial cells suppressed VDR actions. Co-treatment with HDAC inhibitors (TSA, NaB) plus 1α,25(OH)2D3 synergistically induced GADD45α and p21waf1/cip1 and inhibited proliferation.\",\n      \"method\": \"siRNA knockdown of co-repressors, NCoR1 overexpression, proliferation assays, gene expression assays, co-treatment experiments in primary tumor material and cell lines\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA and overexpression with defined transcriptional and proliferative readouts; single lab, two orthogonal approaches\",\n      \"pmids\": [\"16886664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In prostate cancer cells (PC-3), VDR inappropriately recruits the co-repressor NCOR1 to the promoter regions of target genes IGFBP3 and G0S2. ChIP assays showed that VDR-induced NCOR1 enrichment at VDR-binding regions correlates with suppressed transcriptional responses and local H3K9 hypoacetylation, proposing a mechanism by which transient co-repressor binding triggers stable DNA methylation-based silencing.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), time-resolved gene expression analysis, comparison between non-malignant RWPE-1 and PC-3 prostate cells\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating VDR-NCOR1 co-occupancy at target gene promoters with transcriptional readouts; single lab, single method type\",\n      \"pmids\": [\"23098689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Stable expression of wild-type human VDR in VDR-knockout murine mammary tumor cells restored 1,25D-induced growth inhibition and target gene regulation (PDGFB, VEGFA, NFKBI). VDR point mutations W286R and R274L (reducing/abolishing ligand binding) abolished responses at physiological doses. VDR mutation G46D (abrogating DR3 binding) provided only partial growth inhibition, demonstrating that non-canonical (non-DR3) genomic or non-genomic VDR signaling contributes to anti-cancer effects.\",\n      \"method\": \"Stable transfection of WT and mutant hVDR into VDR-null cells, proliferation assays, gene expression analysis, site-directed mutagenesis\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with multiple point mutants defining ligand-binding and DNA-binding requirements; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"23681781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"VDR transcriptionally regulates HSD3B1 in mouse Leydig cells by binding to candidate vitamin D response elements (VDREs) in the upstream region of the Hsd3b1 gene, as confirmed by dual-luciferase reporter assay. VDR and HSD3B1 overexpression increased testosterone synthesis. HSD3B1 overexpression downregulated LPL and upregulated ANGPTL4, linking VDR→HSD3B1 to lipid metabolism regulation in Leydig cells.\",\n      \"method\": \"Dual-luciferase reporter assay, VDR deletion (testicular proteome data), VDR and HSD3B1 overexpression, RT-qPCR, western blot, testosterone ELISA\",\n      \"journal\": \"Genes & genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-luciferase confirming VDRE-driven HSD3B1 transcription with functional overexpression readout; single lab\",\n      \"pmids\": [\"35254654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"1,25D/VDR inhibits ferroptosis in pancreatic β cells by downregulating the transcription factor FOXO1. Proteomic sequencing identified FOXO1 as a downstream VDR target. VDR knockdown reversed 1,25D effects on cell viability, ROS, iron, GPX4, and ACSL4. FOXO1 knockdown independently reduced β cell ferroptotic death, phenocopying VDR activation.\",\n      \"method\": \"Proteomic sequencing (identifying FOXO1 as VDR target), VDR siRNA knockdown, FOXO1 siRNA knockdown, ROS and iron assays, western blot for GPX4/ACSL4, STZ-induced T2DM rat model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic target identification plus reciprocal knockdown experiments with defined ferroptosis phenotype; single lab\",\n      \"pmids\": [\"36581217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VDR transcriptionally represses NLRP6 in intestinal epithelial cells by binding to VDREs in the NLRP6 promoter, as demonstrated by ChIP and ATAC-seq. VD3-mediated VDR activation abolished NLRP6 inflammasome assembly (suppressing NLRP6, ASC, and Caspase-1), with protective effects against ulcerative colitis confirmed in NLRP6-/- mice and siRNA-NLRP6 cells.\",\n      \"method\": \"ChIP assay, ATAC-seq, VDR agonist treatment, NLRP6 knockout mice, siRNA knockdown, RNA-seq, colitis mouse model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP and ATAC-seq establishing direct VDR→NLRP6 repression, validated in both genetic knockout and siRNA models in vivo and in vitro; multiple orthogonal methods\",\n      \"pmids\": [\"36845152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RAR and VDR compete for heterodimerization with their shared partner RXR in live cells in an agonist-dependent manner, and this competition is manifested in their DNA binding. Fluorescence correlation spectroscopy showed that coexpression of RAR and VDR with RXR leads to reduced DNA-bound fraction of each receptor when the other's agonist is present. RAR dominates over VDR for RXR binding in the absence of agonist or when both agonists are present. RXR agonist increases RAR DNA binding at the expense of VDR.\",\n      \"method\": \"Fluorescence correlation spectroscopy (FCS) in live cells, agonist treatment, co-expression of RAR/VDR/RXR\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell FCS is a rigorous direct measurement; single lab with systematic agonist conditions, but no structural or in vitro reconstitution\",\n      \"pmids\": [\"36639026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Vitexin directly binds the VDR protein and facilitates VDR nuclear translocation to exert transcriptional activity. ChIP-seq and dual-luciferase reporter assays established that VDR transcriptionally activates PBLD (phenazine biosynthesis-like domain protein) via VDREs in its promoter. VDR/PBLD signaling promotes M1 macrophage polarization. In myeloid-specific VDR knockout mice, the protective effects of vitexin on colitis-associated colorectal cancer were abolished.\",\n      \"method\": \"Molecular docking, co-culture macrophage/cancer cell model, ChIP-seq, dual-luciferase reporter assay, VDR nuclear translocation imaging, myeloid-specific VDR KO mouse model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq plus dual-luciferase confirming VDR→PBLD direct transcription, validated with myeloid-specific knockout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"39272040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Monotropein binds the VDR protein directly (confirmed by molecular docking, biolayer interferometry BLI, CESTA, and DARTS). VDR nuclear translocation is reduced in tumor-conditioned macrophages, and monotropein treatment restores nuclear VDR, activates VDR signaling, and promotes M1 macrophage polarization via the VDR/JAK1/STAT1 pathway. Normal and myeloid VDR knockout mice confirmed JAK1 upregulation and M1 polarization downstream of VDR.\",\n      \"method\": \"Molecular docking, BLI, CESTA, DARTS (target engagement), immunofluorescence for VDR localization, VDR knockout animals, western blot for JAK1/STAT1, macrophage polarization assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple target engagement methods plus KO animal validation; single lab\",\n      \"pmids\": [\"37633235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In vivo ChIP-seq from mouse tissues identified tissue-specific regulatory regions controlling Vdr gene expression. A humanized VDR mouse expressing hVDR with a S208A mutation (serine 208 → alanine, abolishing phosphorylation at that site) showed unchanged target gene expression, normal serum calcium and PTH, and no alopecia, establishing that phosphorylation of hVDR at serine 208 is NOT required for transcriptional activity or in vivo function.\",\n      \"method\": \"ChIP-seq in mouse tissues, transgenic humanized VDR mouse models (mini-gene), hVDR-S208A knock-in mice, target gene expression, serum biochemistry\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo humanized mouse models with rigorous physiological readouts, ChIP-seq for regulatory region mapping; multiple orthogonal methods in one study (negative finding on S208 phosphorylation is mechanistically informative)\",\n      \"pmids\": [\"28602960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Conditional deletion of Vdr specifically in myeloid cells (osteoclast precursors, monocytes, macrophages) did not alter bone or calcium homeostasis under normal or low-calcium diet conditions, and osteoclastogenesis from Vdr-null myeloid cells was equivalent to wildtype. This establishes that VDR signaling in osteoclast precursors is NOT required for bone homeostasis.\",\n      \"method\": \"Myeloid-specific Vdr conditional knockout (M-lysozyme-Cre), bone densitometry, calcium homeostasis measurements, in vitro osteoclastogenesis assay (M-CSF/RANKL, osteoblast co-culture), dietary calcium restriction challenge\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with multiple in vivo and in vitro readouts; clean negative result mechanistically placing VDR as dispensable in osteoclast precursors for bone homeostasis\",\n      \"pmids\": [\"31561003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In C. elegans, the VDR ortholog DAF-12 acts cell-autonomously in specific cell types to control anatomical, molecular, and behavioral remodeling during dauer entry. Conditional alleles showed that DAF-12/VDR is required continuously both to initiate and maintain tissue remodeling (not only at entry). DAF-12/VDR also exhibits non-cell-autonomous function in nervous system remodeling, indicating interorgan signaling.\",\n      \"method\": \"Conditional genetic alleles (spatial and temporal control), tissue-specific rescue experiments, behavioral and anatomical phenotyping in C. elegans dauer model\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — C. elegans ortholog, conditional genetics establishing cell-autonomous and non-autonomous roles; single lab but rigorous genetic dissection (ortholog, not human VDR)\",\n      \"pmids\": [\"33891586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-122 directly targets VDR mRNA (confirmed by dual-luciferase reporter assay). VDR in turn binds to the BS1 region of the SREBF1 promoter and inhibits SREBF1 expression (confirmed by ChIP). The miR-122/VDR/SREBF1 axis regulates adipogenesis: VDR overexpression inhibits adipogenesis, while exosomal miR-122 reverses this inhibition by suppressing VDR, thereby derepressing SREBF1 and promoting lipid accumulation.\",\n      \"method\": \"Dual-luciferase reporter assay (miR-122 targeting VDR 3'UTR), ChIP (VDR binding SREBF1 promoter), VDR overexpression, miR-122 inhibition, high-fat diet mouse model\",\n      \"journal\": \"Obesity (Silver Spring, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual-luciferase and ChIP confirming direct miR-122→VDR and VDR→SREBF1 regulatory links with in vivo validation; single lab\",\n      \"pmids\": [\"35170865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In a murine model of cardiac steatosis (MHC-DGAT1 transgenic mice), VDR deficiency (VDR-/- background) synergistically worsened cardiomyopathy: double-mutant mice showed greater myocyte hypertrophy, increased interstitial fibrosis (collagen 1a1, collagen 3a1, osteopontin, MMP2 upregulation), and severely reduced ejection fraction (37% reduction) and fractional shortening (55% reduction) compared to either single mutant alone, establishing that VDR signaling restrains pathological cardiac remodeling.\",\n      \"method\": \"VDR-/- × MHC-DGAT1 Tg genetic cross, echocardiography (ejection fraction, fractional shortening), histology (fibrosis), gene expression (collagen, natriuretic peptide, ECM genes)\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (double KO/Tg) with quantitative cardiac phenotyping; single lab\",\n      \"pmids\": [\"26429397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HIV infection of T cells induces VDR promoter CpG methylation via upregulation of DNMT3b, resulting in attenuated VDR expression. This epigenetic silencing activates RAS, increases ROS generation, and induces DNA double-strand breaks, leading to T cell apoptosis. Demethylating agent 5-azacytidine (AZA) reversed VDR hypermethylation and blocked HIV-induced T cell apoptosis.\",\n      \"method\": \"Bisulfite methylation analysis, DNMT3b expression measurement, demethylating agent (AZA) treatment, RAS activation assay, ROS/DSB quantification, apoptosis assays\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epigenetic writer (DNMT3b) identified with pharmacological reversal and downstream phenotypic readouts; single lab\",\n      \"pmids\": [\"23390308\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VDR is a ligand-activated nuclear receptor that, upon binding 1,25(OH)2D3, heterodimerizes with RXR and binds DR3-type vitamin D response elements (VDREs) to transcriptionally activate or repress target genes including GPX4, ATG16L1, NLRP6, SOX2, PBLD, HSD3B1, and FOXO1; its activity is modulated by co-repressors (NCoR1, SMRT), pioneer factors (PU.1), competition with RAR for RXR, epigenetic silencing of its own promoter (by DNMT3b or HDACs), and context-dependent rapid non-genomic signaling through plasma-membrane complexes with TRPC3 and Src kinase in muscle cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VDR is a ligand-activated nuclear receptor that, upon binding 1,25(OH)2D3, regulates transcriptional programs governing tissue homeostasis, cell-fate, metabolism, and immunity [#11, #7]. Crystal structures of its DNA-binding domain bound to distinct response elements define an asymmetric, predominantly non-polar dimerization interface, and interface mutations generate a VDR DBD defective in homodimerization yet still able to heterodimerize, while homology modeling and mutagenesis of the ligand-binding domain identify the pincer hydrogen bonds (R274/S237 to the 1\\u03b1-OH, H397 to the 25-OH) required for high-affinity ligand binding and transactivation [#0, #1]. Reconstitution with point mutants confirms that both ligand binding (W286R, R274L) and DR3 element binding (G46D) are needed for full activity, although the partial activity of the DR3-binding mutant indicates non-canonical genomic and non-genomic signaling also contributes [#11]. Genome-wide, VDR occupies tens of thousands of sites with DR3-type direct repeats enriched at the most ligand-responsive loci, and its cistrome and outputs are shaped by chromatin accessibility set by the pioneer factor PU.1, by co-repressor recruitment (NCoR1, NCoR2/SMRT) that drives histone hypoacetylation and stable silencing of target genes, and by agonist-dependent competition with RAR for the shared partner RXR [#7, #8, #9, #10, #15]. As a transcription factor VDR both activates targets (ATG16L1, GPX4, HSD3B1, PBLD) and represses others (SOX2, NLRP6, FOXO1, SREBF1), thereby controlling intestinal autophagy and inflammation, ferroptosis resistance, steroidogenesis, macrophage M1 polarization, tumor stemness, and adipogenesis [#3, #4, #12, #16, #5, #14, #13, #21]. VDR signaling restrains pathological cardiac remodeling and, when overexpressed in skeletal muscle, drives hypertrophy through mTOR-dependent translational and ribosomal expansion [#22, #6]. VDR output is further tuned by acidosis-sensitive nuclear export, epigenetic silencing of its own promoter through DNMT3b-mediated CpG methylation, and a non-genomic mode in muscle in which 1\\u03b1,25(OH)2D3 drives VDR to caveolar plasma-membrane complexes with the TRPC3 channel and Src kinase to activate second-messenger and MAPK cascades [#5, #23, #2]. In vivo humanized-mouse genetics establish that phosphorylation of serine 208 is dispensable for transcriptional and physiological function and that VDR in osteoclast precursors is not required for bone homeostasis [#18, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing the structural basis for how VDR reads distinct response elements and selects its dimerization partner, a prerequisite for understanding target selectivity.\",\n      \"evidence\": \"X-ray crystallography of the VDR DBD on three response elements plus interface mutagenesis and in vitro heterodimerization assays\",\n      \"pmids\": [\"11980721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DBD structures only; full-length receptor on DNA not resolved\", \"Does not address ligand-dependent conformational changes in the LBD\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defining the ligand-contact residues that confer high-affinity 1,25(OH)2D3 binding, connecting receptor chemistry to transactivation.\",\n      \"evidence\": \"Homology modeling/docking of the LBD with site-directed mutagenesis of R274, S237, H397\",\n      \"pmids\": [\"10828304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Model-based rather than crystallographic confirmation\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Reconstitution with separation-of-function mutants showed both ligand binding and DR3 binding are required for full VDR activity, but residual activity of a DR3-binding mutant revealed non-canonical signaling contributes to anti-cancer effects.\",\n      \"evidence\": \"Stable expression of WT and mutant hVDR (W286R, R274L, G46D) in VDR-null mammary tumor cells with proliferation and target-gene readouts\",\n      \"pmids\": [\"23681781\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of the non-DR3 residual signaling not defined\", \"Specific to mammary tumor context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genome-wide mapping established DR3 elements as the core determinant of ligand-responsive VDR occupancy while revealing the majority of sites are non-canonical.\",\n      \"evidence\": \"Unified re-analysis of six ChIP-seq datasets with de novo motif analysis\",\n      \"pmids\": [\"24787735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of non-DR3 binding sites unresolved\", \"Does not assign individual sites to target genes\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified pioneer-factor and tissue-level control of the VDR cistrome, showing chromatin accessibility, not direct contact, gates VDR regulatory output.\",\n      \"evidence\": \"PU.1 and VDR ChIP-seq with PU.1 knockdown in monocytes; in vivo tissue ChIP-seq and humanized S208A knock-in mice\",\n      \"pmids\": [\"28232093\", \"28602960\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct PU.1\\u2013VDR physical interaction detected\", \"S208A finding is a negative result; other phosphosites not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Co-repressor biology was defined: NCoR1/NCoR2(SMRT) attenuate VDR activity and VDR-driven NCOR1 recruitment can seed stable epigenetic silencing of target genes.\",\n      \"evidence\": \"siRNA knockdown/overexpression of co-repressors and ChIP at IGFBP3/G0S2 promoters in prostate and breast cells, with HDAC-inhibitor co-treatment\",\n      \"pmids\": [\"16886664\", \"23098689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab per study\", \"Causal link from transient co-repressor binding to stable DNA methylation inferred, not directly demonstrated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated a non-genomic mode in which membrane-localized VDR couples to Ca2+ channels and kinases, expanding VDR beyond transcription.\",\n      \"evidence\": \"Subcellular fractionation, caveolae isolation, co-IP of VDR with TRPC3 and Src, and second-messenger assays in skeletal muscle cells\",\n      \"pmids\": [\"21664245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; reciprocal Co-IP validation limited\", \"Stoichiometry and direct vs. scaffolded interaction with TRPC3/Src unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked VDR to intestinal autophagy and host-microbe homeostasis through direct transcriptional activation of ATG16L1.\",\n      \"evidence\": \"Reporter assays, VDR knockdown, ChIP, and a mouse colitis model with butyrate modulation\",\n      \"pmids\": [\"26218741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Does not resolve VDRE location specificity at the ATG16L1 locus\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established VDR as a regulator of ferroptosis and tumor stemness via opposing transcriptional outputs, and showed acidosis controls VDR localization.\",\n      \"evidence\": \"Luciferase/ChIP-seq/ATAC-seq with VDR knockout mice, siRNA, and in vivo AKI and CRC models linking VDR to GPX4 activation and SOX2 repression\",\n      \"pmids\": [\"31996668\", \"32900990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of acidosis sensing by the nuclear export signal not detailed\", \"Generalizability of GPX4/SOX2 regulation across tissues untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed VDR drives skeletal muscle hypertrophy through mTOR-dependent translational and ribosomal programs, and restrains pathological cardiac remodeling.\",\n      \"evidence\": \"In vivo VDR electrotransfer overexpression with D2O tracer MPS and RNA-Seq in rat muscle (corroborated in humans); VDR-/- \\u00d7 MHC-DGAT1 cardiac epistasis with echocardiography\",\n      \"pmids\": [\"32771696\", \"26429397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct VDR transcriptional targets driving muscle mTOR signaling not pinpointed\", \"Cardiac protection mechanism inferred from epistasis, not defined molecularly\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined receptor competition for RXR as a layer of VDR regulation, with RAR dominating partner occupancy in an agonist-dependent manner.\",\n      \"evidence\": \"Fluorescence correlation spectroscopy in live cells co-expressing RAR/VDR/RXR under defined agonist conditions\",\n      \"pmids\": [\"36639026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural or in vitro reconstitution of competition\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended VDR's repertoire to immune and metabolic programs, including macrophage M1 polarization (PBLD, JAK1/STAT1), \\u03b2-cell ferroptosis via FOXO1, steroidogenesis via HSD3B1, NLRP6 inflammasome repression, and adipogenesis via the miR-122/VDR/SREBF1 axis.\",\n      \"evidence\": \"ChIP/ChIP-seq/ATAC-seq, dual-luciferase, reciprocal siRNA, proteomics, target-engagement assays, and myeloid-specific or global VDR knockout mouse models across multiple tissues\",\n      \"pmids\": [\"39272040\", \"37633235\", \"36581217\", \"35254654\", \"36845152\", \"35170865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mostly single-lab studies per target\", \"Whether these targets are conserved direct VDR effectors across human tissues untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed VDR expression is itself epigenetically silenced, providing a route for disease (HIV) to suppress VDR-dependent protection.\",\n      \"evidence\": \"Bisulfite methylation analysis, DNMT3b measurement, and AZA reversal with RAS/ROS/DSB and apoptosis readouts in HIV-infected T cells\",\n      \"pmids\": [\"23390308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct DNMT3b recruitment to the VDR promoter not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The function of the predominant non-DR3 VDR binding sites and how ligand-, chromatin-, co-regulator-, and localization-based inputs are integrated into tissue-specific transcriptional outcomes remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length VDR\\u2013RXR\\u2013DNA structure in the timeline\", \"Functional annotation of non-canonical binding sites missing\", \"Unified model reconciling genomic and non-genomic signaling absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 4, 5, 12, 14, 16, 21]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 7, 11]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 16, 17]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 16, 17]}\n    ],\n    \"complexes\": [\n      \"VDR-RXR heterodimer\",\n      \"caveolar VDR-TRPC3-Src membrane complex\"\n    ],\n    \"partners\": [\n      \"RXR\",\n      \"RAR\",\n      \"NCOR1\",\n      \"NCOR2\",\n      \"TRPC3\",\n      \"SRC\",\n      \"PU.1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}