• CIP/KIP
• Cancer
• Cyclin-dependent kinase inhibitors
• INK4
• Oncogenic signaling
• Posttranslational modification
• Therapy

• PRIMUS/22/MED/007 Univerzita Karlova v Praze
• National Institute for Cancer Research #LX22NPO5102 European Union - Next Generation EU, Programme EXCELES

• Myopia
• Review
• Serum vitamin D status
• Vitamin D

• Adolescent
• Adult
• Child
• Humans
• Vitamin D
• Vitamins
• Myopia/epidemiology
• Myopia/etiology
• Ciliary Body
• Educational Status

• basal cell carcinoma
• calciferol
• melanoma
• skin cancer
• squamous cell carcinoma
• vitamin D3

The INK4 family is an important family of cyclin-dependent kinase inhibitors (CDKIs) and consists of CDKN2A, CDKN2B, CDKN2, and CDKN2D. Abnormal expression of CDKN2A has been reported in hepatocellular carcinoma (HCC) and is associated with the prognosis of patients and infiltration of immune cells. However, there is a lack of systematic research on the roles of the other INK4 family members in the diagnosis, prognosis, and immune regulation of HCC. Using online public databases and clinical samples, we comprehensively analyzed the INK4 family in HCC. All four INK4 proteins were overexpressed in HCC and correlated with advanced cancer stage and poor prognosis. INK4 expression accurately distinguished tumor from normal tissue, particularly CDKN2A and CDKN2C. The INK4 family participated in cell-cycle regulation and the DNA damage repair pathway, which inhibited genotoxic-induced apoptosis in tumorigenesis. INK4 proteins were positively correlated with the infiltration of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) and immune checkpoints (CTLA-4, PD1, and PD-L1). CDKN2D had the highest correlation (correlation coefficient >0.3) with all the above-mentioned infiltrating immune cells and immune checkpoints, indicating that it may be useful as an immunotherapy target. The INK4 family was valuable for diagnosis and predicting the prognosis of HCC and participated in the occurrence, progression, and immune regulation of HCC, demonstrating its potential as a diagnostic and prognostic biomarker and therapeutic target in HCC.

• Hepatocellular carcinoma
• INK4
• biomarkers
• immune
• prognosis

• children
• myopia
• vitamin d

• Child
• China/epidemiology
• Correlation of Data
• Cross-Sectional Studies
• Diagnostic Techniques, Ophthalmological/statistics & numerical data
• Female
• Health Behavior
• Humans
• Male
• Myopia/blood
• Myopia/diagnosis
• Myopia/epidemiology
• Population
• Risk Factors
• School Health Services
• Vitamin D/analogs & derivatives
• Vitamin D/blood
• Vitamin D Deficiency/blood
• Vitamin D Deficiency/diagnosis
• Vitamin D Deficiency/epidemiology
• Vitamin D Deficiency/psychology

The orbit displays unique vulnerability to inflammatory conditions. The most prevalent of these conditions, thyroid eye disease (TED), occurs in up to 50% of patients with Graves’ disease (GD). Whereas the pathology of both TED and GD is driven by autoantibodies, it is unclear why symptoms manifest specifically in the orbit.

We performed retinoic acid treatment on both normal and TED patient–derived orbital fibroblasts (OFs) followed by mRNA and protein isolation, quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, RNA sequencing, and Western blot analyses.

Both normal and TED patient–derived OFs display robust induction of monocyte chemoattractant protein 1 (MCP-1) upon retinoid treatment; TED OFs secrete significantly more MCP-1 than normal OFs. In addition, pretreatment of OFs with thiophenecarboxamide (TPCA-1) inhibits retinoid-induced MCP-1 induction, suggesting an NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)–dependent mechanism. We also found that treatment with cholecalciferol (vitamin D₃) mitigates MCP-1 induction, likely because of competition between retinoic acid receptors (RARs) and vitamin D receptors (VDR) for their common binding partner retinoid nuclear receptors (RXRs).

Retinoids that naturally accumulate in orbital adipose tissue can act on orbital fibroblasts to induce the expression of inflammation-associated genes. These data suggest a potential role for retinoids in sensitizing the orbit to inflammation.

• Lung cancer
• PI3K/AKT/mTOR
• Vitamin D

• A549 Cells
• Animals
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/metabolism
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Cisplatin/administration & dosage
• Cisplatin/pharmacology
• Drug Resistance, Neoplasm/drug effects
• Drug Synergism
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Lung Neoplasms/drug therapy
• Lung Neoplasms/metabolism
• Mice
• Mice, Nude
• Phosphatidylinositol 3-Kinases/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction/drug effects
• Vitamin D/administration & dosage
• Vitamin D/pharmacology
• Xenograft Model Antitumor Assays

• carcinogenesis
• cell death
• inflammation immunomodulation
• signaling pathways
• therapeutic implications
• vitamin D

• APL
• Cell cycle
• Differentiation
• NLS-RARα
• Target diagnosis

Maximizing vaccine efficacy is critical, but previous research has failed to provide a one-size-fits-all solution. Although vitamin A and vitamin D supplementation studies have been designed to improve vaccine efficacy, experimental results have been inconclusive. Information is urgently needed to explain study discrepancies and to provide guidance for the future use of vitamin supplements at the time of vaccination. We conducted a randomized, blinded, placebo-controlled study of influenza virus vaccination and vitamin supplementation among 2 to 8 (inclusive) year old children over three seasons, including 2015–2016 (n = 9), 2016–2017 (n = 44), and 2017–2018 (n = 26). Baseline measurements of vitamins A and D were obtained from all participants. Measurements were of serum retinol, retinol-binding protein (RBP, a surrogate for retinol), and 25-hydroxyvitamin D (25(OH)D). Participants were stratified into two groups based on high and low incoming levels of RBP. Children received two doses of the seasonal influenza virus vaccine on days 0 and 28, either with an oral vitamin supplement (termed A&D; 20,000 IU retinyl palmitate and 2000 IU cholecalciferol) or a matched placebo. Hemagglutination inhibition (HAI) antibody responses were evaluated toward all four components of the influenza virus vaccines on days 0, 28, and 56. Our primary data were from season 2016–2017, as enrollment was highest in this season and all children exhibited homogeneous and negative HAI responses toward the Phuket vaccine at study entry. Responses among children who entered the study with insufficient or deficient levels of RBP and 25(OH)D benefited from the A&D supplement (p < 0.001 for the day 28 Phuket response), whereas responses among children with replete levels of RBP and 25(OH)D at baseline were unaffected or weakened (p = 0.02 for the day 28 Phuket response). High baseline RBP levels associated with high HAI titers, particularly for children in the placebo group (baseline RBP correlated positively with Phuket HAI titers on day 28, r = 0.6, p = 0.003). In contrast, high baseline 25(OH)D levels associated with weak HAI titers, particularly for children in the A&D group (baseline 25(OH)D correlated negatively with Phuket HAI titers on day 28, r = −0.5, p = 0.02). Overall, our study demonstrates that vitamin A&D supplementation can improve immune responses to vaccines when children are vitamin A and D-insufficient at baseline. Results provide guidance for the appropriate use of vitamins A and D in future clinical vaccine studies.

• antibody response
• baseline
• influenza virus vaccine
• pediatric
• supplement
• vitamins A and D

• Active vitamin D
• Akt
• Autophagy
• Beclin-1
• Biochemistry
• Cancer research
• Endocrinology
• Endothelial cells
• Molecular biology
• vGPCR

• immune response
• pneumococcus
• supplementation
• vaccines
• vitamin A

• Animals
• Dietary Supplements
• Female
• Immunogenicity, Vaccine/immunology
• Male
• Mice
• Mice, Inbred C57BL
• Pneumococcal Vaccines/immunology
• Pregnancy
• Vaccination/methods
• Vitamin A/administration & dosage
• Vitamin A/immunology
• Vitamin A Deficiency/immunology

• P30 CA021765 NCI NIH HHS

• Adult
• Age Factors
• Cross-Sectional Studies
• Female
• Humans
• Leukocyte Count
• Male
• Middle Aged
• Myopia/epidemiology
• Nutrition Surveys
• Parents
• Prevalence
• Republic of Korea/epidemiology
• Risk Factors
• Vitamin D/blood
• Young Adult

• National Research Foundation of Korea
• Ministry of Education (KR)

• Adult
• Autophagy
• Beclin-1/blood
• Beclin-1/metabolism
• Case-Control Studies
• Cell Differentiation
• Cell Survival
• Female
• Fetal Growth Retardation/blood
• Fetal Growth Retardation/metabolism
• Fetal Growth Retardation/pathology
• Humans
• Microtubule-Associated Proteins/blood
• Microtubule-Associated Proteins/metabolism
• Placenta/metabolism
• Placenta/pathology
• Placentation
• Pre-Eclampsia/blood
• Pre-Eclampsia/metabolism
• Pre-Eclampsia/pathology
• Pregnancy
• Receptors, Calcitriol/blood
• Receptors, Calcitriol/metabolism
• Trophoblasts/metabolism
• Trophoblasts/pathology
• Vitamin D/analogs & derivatives
• Vitamin D/blood
• Vitamin D/metabolism
• Young Adult

• Animals
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Antioxidants/pharmacology
• Antioxidants/therapeutic use
• Gene Expression Regulation, Neoplastic/drug effects
• Hormones/metabolism
• Humans
• Metabolic Networks and Pathways/drug effects
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Receptors, Calcitriol/metabolism
• Vitamin D/metabolism
• Vitamin D/pharmacology
• Vitamin D/therapeutic use

• apoptosis
• autophagy
• hcc
• hcv
• vitamin d
• vitamin d receptor

• Apoptosis/physiology
• Autophagy/physiology
• Biomarkers/blood
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/complications
• Caspase 3/blood
• Cholecalciferol/blood
• Cross-Sectional Studies
• Hepacivirus
• Hepatitis C/blood
• Hepatitis C/complications
• Humans
• Liver/metabolism
• Liver Neoplasms/blood
• Liver Neoplasms/complications
• Microtubule-Associated Proteins/blood
• Receptors, Calcitriol/blood
• Serum Albumin/metabolism
• Vitamin D Deficiency/blood
• Vitamin D Deficiency/complications

Epidemiological studies have demonstrated a relationship between cancer incidence and dietary habits. Especially intake of certain essential nutrients like vitamins has been shown to be beneficial in experimental studies and some clinical trials. Vitamin K (VK) is an essential nutrient involved in the blood clotting cascade, and there are considerable experimental data demonstrating its potential anticancer activity in several cancer types including prostate cancer. Previous in vitro and in vivo studies have focused mainly on anti-oxidative effects as the underlying anticancer mechanism of VK. However, recent studies reveal that VK inhibits the growth of cancer cells through other mechanisms, including apoptosis, cell cycle arrest, autophagy, and modulation of various transcription factors such as Myc and Fos. In the present review, we focus on the anticancer effect of dietary VK and its analogs on prostate cancer, with an emphasis on the signaling pathways that are activated following exposure to these compounds. This review also highlights the potential of VK and its derivatives as an adjuvant treatment in combination with other vitamins or with chemotherapeutic drugs. Based on our recent results and a review of the existing literature, we present evidence that VK and its derivatives can potentially be explored as cancer therapy, especially for prostate cancer.

• Vitamin K
• apoptosis and autophagy
• dietary constituents
• prostate cancer

Epidemiological evidence suggests that vitamin D can protect women from developing breast cancer (BC). This study reveals that vitamin D and its receptor regulate autophagy in both normal mammary epithelial cells and luminal BCs, and suggests a potential mechanism underlying the link between vitamin D levels and BC risk. In addition, this work suggests that vitamin D receptor ligands could be exploited therapeutically for the treatment of a significant subset of BCs.

Women in North America have a one in eight lifetime risk of developing breast cancer (BC), and a significant proportion of these individuals will develop recurrent BC and will eventually succumb to the disease. Metastatic, therapy-resistant BC cells are refractory to cell death induced by multiple stresses. Here, we document that the vitamin D receptor (VDR) acts as a master transcriptional regulator of autophagy. Activation of the VDR by vitamin D induces autophagy and an autophagic transcriptional signature in BC cells that correlates with increased survival in patients; strikingly, this signature is present in the normal mammary gland and is progressively lost in patients with metastatic BC. A number of epidemiological studies have shown that sufficient vitamin D serum levels might be protective against BC. We observed that dietary vitamin D supplementation in mice increases basal levels of autophagy in the normal mammary gland, highlighting the potential of vitamin D as a cancer-preventive agent. These findings point to a role of vitamin D and the VDR in modulating autophagy and cell death in both the normal mammary gland and BC cells.

• autophagy
• breast cancer
• oncology
• vitamin D
• vitamin D signaling

Myopia is a major public health concern throughout the world but whether vitamin D played a role in myopia development remains unknown.

• knhanes
• myopia
• outdoor acitivity
• vitamin d

• Adult
• Cross-Sectional Studies
• Female
• Humans
• Male
• Middle Aged
• Myopia/blood
• Myopia/epidemiology
• Myopia/etiology
• Nutrition Surveys
• Prevalence
• Republic of Korea/epidemiology
• Sunlight
• Vitamin D/analogs & derivatives
• Vitamin D/blood

Effective adaptive immune responses rely upon appropriate activation of T cells by antigenic peptide-major histocompatibility complex on the surface of antigen presenting cells (APCs). Activation relies on additional signals including co-stimulatory molecules on the surface of the APCs that promote T cell expansion. The immune response is further sculpted by the cytokine environment. However, T cells also respond to other environmental signals including hormones, neurotransmitters, and vitamins. In this review, we summarize the mechanisms through which vitamins A and D impact immune responses, particularly in the context of T cell responses.

• Vitamin D
• Retinoic acid
• T helper cells
• Cytokines
• Transcription factors
• Allergy
• Autoimmune diseases

• Animals
• Calcitriol/metabolism
• Cholestanetriol 26-Monooxygenase/metabolism
• Cytochrome P450 Family 2
• Dietary Supplements
• Disease Models, Animal
• Genetic Predisposition to Disease
• Humans
• Mice, Transgenic
• Phenotype
• Protein Conformation
• Receptors, Calcitriol/agonists
• Receptors, Calcitriol/chemistry
• Receptors, Calcitriol/genetics
• Receptors, Calcitriol/metabolism
• Signal Transduction/drug effects
• Structure-Activity Relationship
• Vitamin D/analogs & derivatives
• Vitamin D/chemistry
• Vitamin D/metabolism
• Vitamin D/therapeutic use
• Vitamin D Deficiency/drug therapy
• Vitamin D Deficiency/epidemiology
• Vitamin D Deficiency/metabolism
• Vitamin D3 24-Hydroxylase/metabolism

• DK38961-22 NIDDK NIH HHS
• AI100379 NIAID NIH HHS
• R21 AG044552 NIA NIH HHS
• AG044552 NIA NIH HHS
• R01 DK038961 NIDDK NIH HHS

• Autophagy
• Bone
• Osteoporosis

• Aging/psychology
• Animals
• Autophagy/physiology
• Bone Remodeling/physiology
• Bone and Bones/pathology
• Bone and Bones/physiology
• Bone and Bones/physiopathology
• Disease Models, Animal
• Humans
• Mice

• Calcitriol
• Vitamin D analogues
• cancer prevention

• Animals
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/therapeutic use
• Breast Neoplasms/diagnosis
• Breast Neoplasms/epidemiology
• Breast Neoplasms/prevention & control
• Chemoprevention/trends
• Clinical Trials as Topic
• Colorectal Neoplasms/diagnosis
• Colorectal Neoplasms/epidemiology
• Colorectal Neoplasms/prevention & control
• Female
• Growth Inhibitors/chemistry
• Growth Inhibitors/therapeutic use
• Humans
• Immunologic Factors/chemistry
• Immunologic Factors/therapeutic use
• Male
• Neoplasms/diagnosis
• Neoplasms/epidemiology
• Neoplasms/prevention & control
• Prostatic Neoplasms/diagnosis
• Prostatic Neoplasms/epidemiology
• Prostatic Neoplasms/prevention & control
• Vitamin D/analogs & derivatives
• Vitamin D/therapeutic use

Cell proliferation and differentiation are highly coordinated processes. These two processes are disrupted during leukemogenesis, resulting in differentiation block and uncontrolled proliferation in leukemia. To understand the mechanisms disrupting the coordination between the two processes in acute promyelocytic leukemia (APL), we investigated the regulatory mechanism of the negative cell cycle regulator CDKN2D by the promyelocytic leukemia/retinoic acid receptor α (PML/RARα) fusion protein and the role of CDKN2D in cell differentiation and proliferation. We found that CDKN2D expression in APL cells was significantly lower than that in normal promyelocytes. By chromatin immunoprecipitation and luciferase reporter assays, we showed that PML/RARα directly bound to and inhibited the transactivation of the CDKN2D promoter. Further evidence by the truncated and mutated CDKN2D promoters revealed that the everted repeat 8 (ER8) motif on the promoter was the binding site of PML/RARα. Forced expression of CDKN2D induced G0/G1 phase arrest and partial granulocytic differentiation in APL-derived NB4 cells, suggesting the function of CDKN2D in regulating both cell proliferation and granulocytic differentiation. Furthermore, all-trans retinoic acid (ATRA) significantly induced CDKN2D expression in APL cells and knockdown of CDKN2D expression during ATRA treatment partially blocked the ATRA-induced differentiation and cell cycle arrest. Collectively, our data indicate that CDKN2D repression by PML/RARα disrupts both cell proliferation and differentiation in the pathogenesis of APL, and induced expression of CDKN2D by ATRA alleviates the disruption of both processes to ensure treatment efficiency. This study provides a mechanism for coupling proliferation and differentiation in leukemic cells through the action of CDKN2D.

• Apoptosis
• Beta amyloid peptide
• DNA damage
• Learning and memory
• Neocarzinostatin
• Neurodegeneration

• Aging
• CDK inhibitor
• Cellular senescence
• DNA damage
• Heterochromatin

Many studies in different biological systems have revealed that 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃) modulates signaling pathways triggered at the plasma membrane by agents such as Wnt, transforming growth factor (TGF)-β, epidermal growth factor (EGF), and others. In addition, 1α,25(OH)₂D₃ may affect gene expression by paracrine mechanisms that involve the regulation of cytokine or growth factor secretion by neighboring cells. Moreover, post-transcriptional and post-translational effects of 1α,25(OH)₂D₃ add to or overlap with its classical modulation of gene transcription rate. Together, these findings show that vitamin D receptor (VDR) cannot be considered only as a nuclear-acting, ligand-modulated transcription factor that binds to and controls the transcription of target genes. Instead, available data support the view that much of the complex biological activity of 1α,25(OH)₂D₃ resides in its capacity to interact with membrane-based signaling pathways and to modulate the expression and secretion of paracrine factors. Therefore, we propose that future research in the vitamin D field should focus on the interplay between 1α,25(OH)₂D₃ and agents that act at the plasma membrane, and on the analysis of intercellular communication. Global analyses such as RNA-Seq, transcriptomic arrays, and genome-wide ChIP are expected to dissect the interactions at the gene and molecular levels.

• 1α,25(OH)2D3
• VDR
• Wnt
• cytokines
• growth factors
• membrane-based signaling
• paracrine effects

The unfolded protein response (UPR) is an endoplasmic reticulum (ER)-based cytoprotective mechanism acting to prevent pathologies accompanying protein aggregation. It is frequently active in tumors, but relatively unstudied in gliomas. We hypothesized that UPR stress effects on glioma cells might protect tumors from additional exogenous stress (ie, chemotherapeutics), postulating that protection was concurrent with altered tumor cell metabolism. Using human brain tumor cell lines, xenograft tumors, human samples and gene expression databases, we determined molecular features of glioma cell UPR induction/activation, and here report a detailed analysis of UPR transcriptional/translational/metabolic responses. Immunohistochemistry, Western and Northern blots identified elevated levels of UPR transcription factors and downstream ER chaperone targets in gliomas. Microarray profiling revealed distinct regulation of stress responses between xenograft tumors and parent cell lines, with gene ontology and network analyses linking gene expression to cell survival and metabolic processes. Human glioma samples were examined for levels of the ER chaperone GRP94 by immunohistochemistry and for other UPR components by Western blotting. Gene and protein expression data from patient gliomas correlated poor patient prognoses with increased expression of ER chaperones, UPR target genes, and metabolic enzymes (glycolysis and lipogenesis). NMR-based metabolomic studies revealed increased metabolic outputs in glucose uptake with elevated glycolytic activity as well as increased phospholipid turnover. Elevated levels of amino acids, antioxidants, and cholesterol were also evident upon UPR stress; in particular, recurrent tumors had overall higher lipid outputs and elevated specific UPR arms. Clonogenicity studies following temozolomide treatment of stressed or unstressed cells demonstrated UPR-induced chemoresistance. Our data characterize the UPR in glioma cells and human tumors, and link the UPR to chemoresistance possibly via enhanced metabolism. Given the role of the UPR in the balance between cell survival and apoptosis, targeting the UPR and/or controlling metabolic activity may prove beneficial for malignant glioma therapeutics.

• Animals
• Antineoplastic Agents, Alkylating/pharmacology
• Cell Line, Tumor
• Dacarbazine/analogs & derivatives
• Dacarbazine/pharmacology
• Disease Models, Animal
• Drug Resistance, Neoplasm/genetics
• Endoplasmic Reticulum Stress/genetics
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Glioma/genetics
• Glioma/metabolism
• Glioma/mortality
• Glioma/pathology
• Humans
• Lipogenesis
• Mice
• Molecular Chaperones/metabolism
• Neoplasm Grading
• Prognosis
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Signal Transduction
• Temozolomide
• Transcription Factors/metabolism
• Transcription, Genetic
• Unfolded Protein Response/genetics
• Xenograft Model Antitumor Assays

• P30 CA046934 NCI NIH HHS
• R25 GM083333 NIGMS NIH HHS
• UL1 RR025780 NCRR NIH HHS
• R25GM083333 NIGMS NIH HHS

• Animals
• Antineoplastic Agents/therapeutic use
• Breast Neoplasms/drug therapy
• Colorectal Neoplasms/drug therapy
• Female
• Humans
• Male
• Prostatic Neoplasms/drug therapy
• Vitamin D/analogs & derivatives
• Vitamin D/therapeutic use

• hepatic stellate cell
• interleukin-6
• regulatory t cell
• retinoic acid

• 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism
• Adaptive Immunity/physiology
• Animals
• Humans
• Immune System/metabolism
• Immunity, Innate/physiology
• Receptors, Calcitriol/metabolism
• Vitamin D/metabolism

• Cell Cycle
• Cells, Cultured
• DNA Damage
• Humans
• Nutritional Requirements
• Oxidative Stress/drug effects
• Skin/radiation effects
• Ultraviolet Rays/adverse effects
• Vitamin D/pharmacology
• Vitamin D/physiology

A global understanding of the actions of the nuclear hormone 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃) and its vitamin D receptor (VDR) requires a genome-wide analysis of VDR binding sites. In THP-1 human monocytic leukemia cells we identified by ChIP-seq 2340 VDR binding locations, of which 1171 and 520 occurred uniquely with and without 1α,25(OH)₂D₃ treatment, respectively, while 649 were common. De novo identified direct repeat spaced by 3 nucleotides (DR3)-type response elements (REs) were strongly associated with the ligand-responsiveness of VDR occupation. Only 20% of the VDR peaks diminishing most after ligand treatment have a DR3-type RE, in contrast to 90% for the most growing peaks. Ligand treatment revealed 638 1α,25(OH)₂D₃ target genes enriched in gene ontology categories associated with immunity and signaling. From the 408 upregulated genes, 72% showed VDR binding within 400 kb of their transcription start sites (TSSs), while this applied only for 43% of the 230 downregulated genes. The VDR loci showed considerable variation in gene regulatory scenarios ranging from a single VDR location near the target gene TSS to very complex clusters of multiple VDR locations and target genes. In conclusion, ligand binding shifts the locations of VDR occupation to DR3-type REs that surround its target genes and occur in a large variety of regulatory constellations.

• Animals
• Autophagy
• Cholecalciferol/metabolism
• Communicable Diseases/metabolism
• Communicable Diseases/pathology
• Homeostasis
• Humans
• Inflammation/metabolism
• Inflammation/pathology
• Receptors, Calcitriol/metabolism

• R03 DK089010-01 NIDDK NIH HHS
• K01 DK075386 NIDDK NIH HHS
• R03 DK089010 NIDDK NIH HHS
• R03DK089010-01 NIDDK NIH HHS
• DK075386-0251 NIDDK NIH HHS
• K01 DK075386-05 NIDDK NIH HHS

• vitamin d
• myopia
• refractive error

• Adolescent
• Adult
• Age Factors
• Chromatography, Liquid
• Diet
• Dietary Sucrose/pharmacology
• Female
• Folic Acid/administration & dosage
• Humans
• Male
• Mass Spectrometry
• Myopia/blood
• Sunlight
• Time Factors
• Vitamin D/blood
• Young Adult

• U10 EY008893 NEI NIH HHS
• U10 EY008893-20 NEI NIH HHS
• UL1 RR025755 NCRR NIH HHS
• U10-EY08893 NEI NIH HHS

• cell differentiation
• cytokine
• inflammation
• protein synthesis
• vitamin d

• Animals
• CCAAT-Enhancer-Binding Proteins/metabolism
• CD4-Positive T-Lymphocytes/cytology
• CD4-Positive T-Lymphocytes/metabolism
• Calcitriol/metabolism
• Gene Expression Regulation
• Hyaluronan Receptors/biosynthesis
• Interleukin-2 Receptor alpha Subunit/biosynthesis
• L-Selectin/biosynthesis
• Mice
• Mice, Inbred C57BL
• RNA, Messenger/metabolism
• Receptors, Calcitriol/metabolism
• Th17 Cells/metabolism
• Transcription Factor CHOP/biosynthesis
• Vitamin D/metabolism

• R01 AR050772 NIAMS NIH HHS
• 5R01AR050772-09 NIAMS NIH HHS