The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights.

The vitamin D receptor (VDR) is the single known regulatory mediator of hormonal 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in higher vertebrates. It acts in the nucleus of vitamin D target cells to regulate the expression of genes whose products control diverse, cell type-specific biological functions that include mineral homeostasis. In this Review we describe progress that has been made in defining new cellular sites of action of this receptor, the mechanisms through which this mediator controls the expression of genes, the biology that ensues, and the translational impact of this receptor on human health and disease. We conclude with a brief discussion of what comes next in understanding vitamin D biology and the mechanisms that underlie its actions.

[1]  J. Pike,et al.  Selective regulation of Mmp13 by 1,25(OH)2D3, PTH, and Osterix through distal enhancers , 2016, The Journal of Steroid Biochemistry and Molecular Biology.

[2]  John H. White,et al.  Species-specific regulation of innate immunity by vitamin D signaling , 2016, The Journal of Steroid Biochemistry and Molecular Biology.

[3]  J. Pike,et al.  The vitamin D receptor functions as a transcription regulator in the absence of 1,25-dihydroxyvitamin D3 , 2016, The Journal of Steroid Biochemistry and Molecular Biology.

[4]  C. Carlberg,et al.  Vitamin D receptor 2016: novel ligands and structural insights , 2016, Expert opinion on therapeutic patents.

[5]  M. Holick,et al.  Targeting the vitamin D endocrine system (VDES) for the management of inflammatory and malignant skin diseases: An historical view and outlook , 2016, Reviews in Endocrine and Metabolic Disorders.

[6]  J. Rubin,et al.  Epigenetic Plasticity Drives Adipogenic and Osteogenic Differentiation of Marrow-derived Mesenchymal Stem Cells* , 2016, The Journal of Biological Chemistry.

[7]  A. Ferrante,et al.  The Non-Genomic Actions of Vitamin D , 2016, Nutrients.

[8]  J. Pike,et al.  Unique Distal Enhancers Linked to the Mouse Tnfsf11 Gene Direct Tissue-Specific and Inflammation-Induced Expression of RANKL. , 2016, Endocrinology.

[9]  J. Pike,et al.  Deletion of the Distal Tnfsf11 RL‐D2 Enhancer That Contributes to PTH‐Mediated RANKL Expression in Osteoblast Lineage Cells Results in a High Bone Mass Phenotype in Mice , 2016, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[10]  R. Koren,et al.  TNF-α increases the expression and activity of vitamin D receptor in keratinocytes: role of c-Jun N-terminal kinase , 2016, Dermato-endocrinology.

[11]  J. Pike,et al.  Epigenetic histone modifications and master regulators as determinants of context dependent nuclear receptor activity in bone cells. , 2015, Bone.

[12]  C. O’Brien,et al.  Mechanisms of Enhancer-mediated Hormonal Control of Vitamin D Receptor Gene Expression in Target Cells* , 2015, The Journal of Biological Chemistry.

[13]  C. Cooper,et al.  Serum 25‐Hydroxyvitamin D Levels: Variability, Knowledge Gaps, and the Concept of a Desirable Range , 2015, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[14]  P. Jurutka,et al.  1,25‐Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes: implication for behavioral influences of vitamin D , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  R. Bouillon,et al.  Physiological functions of vitamin D: what we have learned from global and conditional VDR knockout mouse studies. , 2015, Current opinion in pharmacology.

[16]  J. Pike,et al.  Selective Distal Enhancer Control of the Mmp13 Gene Identified through Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) Genomic Deletions* , 2015, The Journal of Biological Chemistry.

[17]  D. Moras,et al.  A vitamin D receptor selectively activated by gemini analogs reveals ligand dependent and independent effects. , 2015, Cell reports.

[18]  Sneha S. Joshi,et al.  Novel Mechanism of Negative Regulation of 1,25-Dihydroxyvitamin D3-induced 25-Hydroxyvitamin D3 24-Hydroxylase (Cyp24a1) Transcription , 2014, The Journal of Biological Chemistry.

[19]  J. Adams,et al.  Regulation of the extrarenal CYP27B1-hydroxylase , 2014, The Journal of Steroid Biochemistry and Molecular Biology.

[20]  J. Goellner,et al.  A humanized mouse model of hereditary 1,25-dihydroxyvitamin D-resistant rickets without alopecia. , 2014, Endocrinology.

[21]  R. Mason,et al.  The Vitamin D Receptor (VDR) Is Expressed in Skeletal Muscle of Male Mice and Modulates 25-Hydroxyvitamin D (25OHD) Uptake in Myofibers , 2014, Endocrinology.

[22]  J. Pike,et al.  Genomic Determinants of Gene Regulation by 1,25-Dihydroxyvitamin D3 during Osteoblast-lineage Cell Differentiation*♦ , 2014, The Journal of Biological Chemistry.

[23]  Ning Leng,et al.  The osteoblast to osteocyte transition: epigenetic changes and response to the vitamin D3 hormone. , 2014, Molecular endocrinology.

[24]  P. Liu,et al.  Intracellular distribution of the vitamin D receptor in the brain: Comparison with classic target tissues and redistribution with development , 2014, Neuroscience.

[25]  J. Goellner,et al.  Mouse and human BAC transgenes recapitulate tissue-specific expression of the vitamin D receptor in mice and rescue the VDR-null phenotype. , 2014, Endocrinology.

[26]  D. Bikle Vitamin D metabolism, mechanism of action, and clinical applications. , 2014, Chemistry & biology.

[27]  D. Feldman,et al.  Mutations in the vitamin D receptor and hereditary vitamin D-resistant rickets. , 2014, BoneKEy reports.

[28]  N. Turner,et al.  Effects of vitamin D in skeletal muscle: falls, strength, athletic performance and insulin sensitivity , 2014, Clinical endocrinology.

[29]  J. Pike,et al.  Regulation of gene expression by 1,25-dihydroxyvitamin D3 in bone cells: exploiting new approaches and defining new mechanisms. , 2014, BoneKEy reports.

[30]  Glenville Jones,et al.  Cytochrome P450-mediated metabolism of vitamin D , 2014, Journal of Lipid Research.

[31]  R. Evans,et al.  Hepatic actions of vitamin D receptor ligands: a sunshine option for chronic liver disease? , 2013, Expert review of clinical pharmacology.

[32]  M. Meyer,et al.  Corepressors (NCoR and SMRT) as well as coactivators are recruited to positively regulated 1α,25-dihydroxyvitamin D3-responsive genes , 2013, The Journal of Steroid Biochemistry and Molecular Biology.

[33]  R. Evans,et al.  A Vitamin D Receptor/SMAD Genomic Circuit Gates Hepatic Fibrotic Response , 2013, Cell.

[34]  D. Eyles,et al.  The vitamin D receptor in dopamine neurons; its presence in human substantia nigra and its ontogenesis in rat midbrain , 2013, Neuroscience.

[35]  M. Holick,et al.  The roles of vitamin D in skeletal muscle: form, function, and metabolism. , 2013, Endocrine reviews.

[36]  Le Cong,et al.  Multiplex Genome Engineering Using CRISPR/Cas Systems , 2013, Science.

[37]  Raymond K. Auerbach,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[38]  M. Demay The hair cycle and Vitamin D receptor. , 2012, Archives of biochemistry and biophysics.

[39]  R. Koren,et al.  The inflammatory response of keratinocytes and its modulation by vitamin D: The role of MAPK signaling pathways , 2012, Journal of cellular physiology.

[40]  D. Moras,et al.  Structure of the full human RXR/VDR nuclear receptor heterodimer complex with its DR3 target DNA , 2012, The EMBO journal.

[41]  V. Beneš,et al.  Nuclear hormone 1α,25-dihydroxyvitamin D3 elicits a genome-wide shift in the locations of VDR chromatin occupancy , 2011, Nucleic acids research.

[42]  H. Takayanagi,et al.  [RANKL signal and osteoimmunology]. , 2011, Clinical calcium.

[43]  Dmitri I Svergun,et al.  Common architecture of nuclear receptor heterodimers on DNA direct repeat elements with different spacings , 2011, Nature Structural &Molecular Biology.

[44]  V. Corces,et al.  Enhancer function: new insights into the regulation of tissue-specific gene expression , 2011, Nature Reviews Genetics.

[45]  Raymond K. Auerbach,et al.  A User's Guide to the Encyclopedia of DNA Elements (ENCODE) , 2011, PLoS biology.

[46]  H. DeLuca,et al.  Vitamin D, disease and therapeutic opportunities , 2010, Nature Reviews Drug Discovery.

[47]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[48]  J. Pike,et al.  A Downstream Intergenic Cluster of Regulatory Enhancers Contributes to the Induction of CYP24A1 Expression by 1α,25-Dihydroxyvitamin D3* , 2010, The Journal of Biological Chemistry.

[49]  P. Dhawan,et al.  CCAAT Enhancer-binding Protein α Is a Molecular Target of 1,25-Dihydroxyvitamin D3 in MCF-7 Breast Cancer Cells* , 2009, Journal of Biological Chemistry.

[50]  W. Willett,et al.  Vitamin D and Health: Perspectives From Mice and Man , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[51]  C. Mathieu,et al.  Vitamin D and human health: lessons from vitamin D receptor null mice. , 2008, Endocrine reviews.

[52]  C. Carlberg,et al.  The vitamin D receptor. , 2007, Dermatologic clinics.

[53]  J. Adams,et al.  Extra-renal 25-hydroxyvitamin D3-1α-hydroxylase in human health and disease , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[54]  K. Skorija,et al.  Role of the vitamin D receptor in hair follicle biology , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[55]  Sungtae Kim,et al.  The human transient receptor potential vanilloid type 6 distal promoter contains multiple vitamin D receptor binding sites that mediate activation by 1,25-dihydroxyvitamin D3 in intestinal cells. , 2006, Molecular endocrinology.

[56]  Sungtae Kim,et al.  Enhancers located within two introns of the vitamin D receptor gene mediate transcriptional autoregulation by 1,25-dihydroxyvitamin D3. , 2006, Molecular endocrinology.

[57]  R. Kumar,et al.  Multiple potential clinical benefits for 1α,25-dihydroxyvitamin D3 analogs in kidney transplant recipients , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[58]  Clifford A. Meyer,et al.  Chromosome-Wide Mapping of Estrogen Receptor Binding Reveals Long-Range Regulation Requiring the Forkhead Protein FoxA1 , 2005, Cell.

[59]  Mahboob Rahman,et al.  Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[60]  T. Suda Vitamin D and bone , 2004, Proceedings of the Japan Academy. Series B, Physical and Biological Sciences.

[61]  D. Miao,et al.  Inactivation of the 25-Hydroxyvitamin D 1α-Hydroxylase and Vitamin D Receptor Demonstrates Independent and Interdependent Effects of Calcium and Vitamin D on Skeletal and Mineral Homeostasis* , 2004, Journal of Biological Chemistry.

[62]  Y. Takeuchi,et al.  FGF‐23 Is a Potent Regulator of Vitamin D Metabolism and Phosphate Homeostasis , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[63]  G. Yehia,et al.  Evidence for a regulatory role of inducible cAMP early repressor in protein kinase a-mediated enhancement of vitamin D receptor expression and modulation of hormone action. , 2002, Molecular endocrinology.

[64]  Olivier Dardenne,et al.  Targeted Inactivation of the 25-Hydroxyvitamin D3-1α-Hydroxylase Gene (CYP27B1) Creates an Animal Model of Pseudovitamin D-Deficiency Rickets. , 2001, Endocrinology.

[65]  M. Tremblay,et al.  Targeted ablation of the 25-hydroxyvitamin D 1α-hydroxylase enzyme: Evidence for skeletal, reproductive, and immune dysfunction , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[66]  S. Takeda,et al.  Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[67]  M. Galligan,et al.  The polymorphic N terminus in human vitamin D receptor isoforms influences transcriptional activity by modulating interaction with transcription factor IIB. , 2000, Molecular endocrinology.

[68]  J. Pike,et al.  The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. , 1999, Endocrine reviews.

[69]  S. Nomura,et al.  Maturational disturbance of chondrocytes in Cbfa1‐deficient mice , 1999, Developmental dynamics : an official publication of the American Association of Anatomists.

[70]  E. Takeda,et al.  The Caudal‐Related Homeodomain Protein Cdx‐2 Regulates Vitamin D Receptor Gene Expression in the Small Intestine , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[71]  David A. Agard,et al.  The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen , 1998, Cell.

[72]  P. Malloy,et al.  The Vitamin D Receptor Gene Start Codon Polymorphism: A Functional Analysis of FokI Variants , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[73]  C. López-Otín,et al.  Collagenase-3 (MMP-13) expression in chondrosarcoma cells and its regulation by basic fibroblast growth factor. , 1998, The American journal of pathology.

[74]  H. Gronemeyer,et al.  The nuclear receptor ligand-binding domain: structure and function. , 1998, Current opinion in cell biology.

[75]  P. Puigserver,et al.  A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis , 1998, Cell.

[76]  H. DeLuca,et al.  Parathyroid hormone activation of the 25-hydroxyvitamin D3-1alpha-hydroxylase gene promoter. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[77]  F. Glorieux,et al.  The 25‐Hydroxyvitamin D 1‐Alpha‐Hydroxylase Gene Maps to the Pseudovitamin D‐Deficiency Rickets (PDDR) Disease Locus , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[78]  R. Baron,et al.  Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[79]  H. Yamamoto,et al.  Structural organization of the human vitamin D receptor chromosomal gene and its promoter. , 1997, Molecular endocrinology.

[80]  R. Marcus,et al.  The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal mexican‐American women , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[81]  J. Pike,et al.  Transcriptional activation and dimerization functions in the human vitamin D receptor. , 1996, Molecular endocrinology.

[82]  R. Evans,et al.  The RXR heterodimers and orphan receptors , 1995, Cell.

[83]  K. Umesono,et al.  The nuclear receptor superfamily: The second decade , 1995, Cell.

[84]  M. Haussler,et al.  New understanding of the molecular mechanism of receptor-mediated genomic actions of the vitamin D hormone. , 1995, Bone.

[85]  H. DeLuca,et al.  Two Vitamin D Response Elements Function in the Rat 1,25-Dihydroxyvitamin D 24-Hydroxylase Promoter (*) , 1995, The Journal of Biological Chemistry.

[86]  H. DeLuca,et al.  Identification of a DNA sequence responsible for binding of the 1,25-dihydroxyvitamin D3 receptor and 1,25-dihydroxyvitamin D3 enhancement of mouse secreted phosphoprotein 1 (SPP-1 or osteopontin) gene expression. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[87]  H. DeLuca,et al.  The vitamin D system: 1990. , 1990, Kidney international. Supplement.

[88]  B. O’Malley,et al.  Mutant vitamin D receptors which confer hereditary resistance to 1,25-dihydroxyvitamin D3 in humans are transcriptionally inactive in vitro. , 1989, The Journal of biological chemistry.

[89]  B. O’Malley,et al.  An ochre mutation in the vitamin D receptor gene causes hereditary 1,25-dihydroxyvitamin D3-resistant rickets in three families. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[90]  J. Pike,et al.  Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[91]  B. O’Malley,et al.  Point mutations in the human vitamin D receptor gene associated with hypocalcemic rickets. , 1988, Science.

[92]  R. Evans,et al.  The steroid and thyroid hormone receptor superfamily. , 1988, Science.

[93]  J. Shine,et al.  Cloning and expression of full-length cDNA encoding human vitamin D receptor. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[94]  M. Haussler,et al.  Molecular cloning of complementary DNA encoding the avian receptor for vitamin D. , 1987, Science.

[95]  H. Sakagami,et al.  Differentiation of mouse myeloid leukemia cells induced by 1 alpha,25-dihydroxyvitamin D3. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[96]  D. Feldman,et al.  Organ distribution of the cytoplasmic 1,25-dihydroxycholecalciferol receptor in various mouse tissues. , 1980, Endocrinology.

[97]  M. Haussler,et al.  Biochemical evidence for 1,25-dihydroxyvitamin D receptor macromolecules in parathyroid, pancreatic, pituitary, and placental tissues. , 1980, Life sciences.

[98]  H. DeLuca,et al.  A specific high-affinity binding macromolecule for 1,25-dihydroxyvitamin D3 in fetal bone. , 1977, Science.

[99]  M. Haussler,et al.  1 Alpha,25-dihydroxycholecalciferol receptors in intestine. II. Temperature-dependent transfer of the hormone to chromatin via a specific cytosol receptor. , 1974, The Journal of biological chemistry.

[100]  M. Haussler,et al.  1α,25-Dihydroxycholecalciferol Receptors in Intestine I. ASSOCIATION OF 1α,25-DIHYDROXYCHOLECALCIFEROL WITH INTESTINAL MUCOSA CHROMATIN , 1974 .

[101]  H. DeLuca,et al.  Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[102]  D. Trump,et al.  Vitamin D Signaling Modulators in Cancer Therapy. , 2016, Vitamins and hormones.

[103]  Zainab N. Khan,et al.  1,25-Dihydroxyvitamin D and Klotho: A Tale of Two Renal Hormones Coming of Age. , 2016, Vitamins and hormones.

[104]  P. Dhawan,et al.  Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. , 2016, Physiological reviews.

[105]  J. Pike,et al.  Genomic Determinants of Vitamin D-Regulated Gene Expression. , 2016, Vitamins and hormones.

[106]  V. Tasic,et al.  Vitamin D receptor mutations in patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets. , 2014, Molecular genetics and metabolism.

[107]  J. Pike,et al.  The RUNX2 Cistrome in Osteoblasts: Characterization, Downregulation Following Differentiation and Relationship to Gene Expression* , 2014 .

[108]  J. Pike,et al.  VDR/RXR and TCF4/β-catenin cistromes in colonic cells of colorectal tumor origin: impact on c-FOS and c-MYC gene expression. , 2012, Molecular endocrinology.

[109]  L. Quarles,et al.  Regulation and function of the FGF23/klotho endocrine pathways. , 2012, Physiological reviews.

[110]  B. Bernstein,et al.  Charting histone modifications and the functional organization of mammalian genomes , 2011, Nature Reviews Genetics.

[111]  D. Bikle Vitamin D regulation of immune function. , 2011, Vitamins and hormones.

[112]  R. D. Nerenz,et al.  Multifunctional enhancers regulate mouse and human vitamin D receptor gene transcription. , 2010, Molecular endocrinology.

[113]  R. Weinstein,et al.  Targeted deletion of a distant transcriptional enhancer of the receptor activator of nuclear factor-kappaB ligand gene reduces bone remodeling and increases bone mass. , 2008, Endocrinology.

[114]  D. Kleinjan,et al.  Long-range control of gene expression: emerging mechanisms and disruption in disease. , 2005, American journal of human genetics.

[115]  A. Uitterlinden,et al.  CHAPTER 68 – Genetic Vitamin D Receptor Polymorphisms and Risk of Disease , 2005 .

[116]  D. Moras,et al.  The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. , 2000, Molecular cell.

[117]  M. Noda Identification of a RNA sequence responsible for binding of the 1,25-dihydroxyvitamin D3 enhancement of mouse secreted phosphoprotein 1 (Spp-1 or osteopontin) gene expression , 1990 .

[118]  J. S. Hayden,et al.  "Systematic" , 1966, Comput. J..