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Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Vitamin D: A Micronutrient Regulating Genes

Author(s): Carsten Carlberg*

Volume 25, Issue 15, 2019

Page: [1740 - 1746] Pages: 7

DOI: 10.2174/1381612825666190705193227

Price: $65

Abstract

Background: At sufficient sun exposure, humans can synthesize vitamin D3 endogenously in their skin, but today’s lifestyle makes the secosteroid a true vitamin that needs to be taken up by diet or supplementation with pills. The vitamin D3 metabolite 1α,25-dihydroxyvitamin D3 acts as a nuclear hormone activating the transcription factor vitamin D receptor (VDR).

Methods: This review discusses the biological effects of micronutrient vitamin D ranging from calcium homeostasis and bone formation to the modulation of innate and adaptive immunity.

Results: Since normal human diet is sufficient in vitamin D, the need for efficient vitamin D3 synthesis in the skin acts as an evolutionary driver for its lightening during the migration out of Africa towards North. Via activating the VDR, vitamin D has direct effects on the epigenome and the expression of more than 1000 genes in most human tissues and cell types.

Conclusions: The pleiotropic action of vitamin D in health and disease prevention is explained through complex gene regulatory events of the transcription factor VDR.

Keywords: Vitamin D, VDR, vitamin D response index, vitamin D supplementation, epigenome, transcriptome, gene regulation, evolution.

[1]
Tremezaygues L, Sticherling M, Pföhler C, et al. Cutaneous photosynthesis of vitamin D: An evolutionary highly-conserved endocrine system that protects against environmental hazards including UV-radiation and microbial infections. Anticancer Res 2006; 26(4A): 2743-8. [PMID: 16886686].
[2]
Holick MF, Vitamin D. Evolutionary, physiological and health perspectives. Curr Drug Targets 2011; 12(1): 4-18. [http://dx.doi.org/10.2174/138945011793591635]. [PMID: 20795941].
[3]
Holick MF, Vitamin D. A millenium perspective. J Cell Biochem 2003; 88(2): 296-307. [http://dx.doi.org/10.1002/jcb.10338]. [PMID: 12520530].
[4]
McMollum EV, Simmonds N, Becker JE, Shipley PG. Studies on experimental rickets: An experimental demonstration of the existence of a vitamin which promotes calcium deposition. J Biol Chem 1922; 52: 293-8.
[5]
Rajakumar K. Vitamin D, cod-liver oil, sunlight, and rickets: A historical perspective. Pediatrics 2003; 112(2): E132-5. [http://dx.doi.org/10.1542/peds.112.2.e132]. [PMID: 12897318].
[6]
Holick MF. The cutaneous photosynthesis of previtamin D3: A unique photoendocrine system. J Invest Dermatol 1981; 77(1): 51-8. [http://dx.doi.org/10.1111/1523-1747.ep12479237]. [PMID: 6265564].
[7]
Carlberg C. Molecular approaches for optimizing vitamin D supplementation. Vitam Horm 2016; 100: 255-71. [http://dx.doi.org/10.1016/bs.vh.2015.10.001]. [PMID: 26827955].
[8]
Bendik I, Friedel A, Roos FF, Weber P, Eggersdorfer M, Vitamin D. A critical and essential micronutrient for human health. Front Physiol 2014; 5: 248. [http://dx.doi.org/10.3389/fphys.2014.00248]. [PMID: 25071593].
[9]
Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: Implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr 2005; 135(2): 317-22. [http://dx.doi.org/10.1093/jn/135.2.317]. [PMID: 15671234].
[10]
Slominski AT, Kim TK, Takeda Y, et al. RORα and ROR γ are expressed in human skin and serve as receptors for endogenously produced noncalcemic 20-hydroxy- and 20,23-dihydroxyvitamin D. FASEB J 2014; 28(7): 2775-89. [http://dx.doi.org/10.1096/fj.13-242040]. [PMID: 24668754].
[11]
Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: The second decade. Cell 1995; 83(6): 835-9. [http://dx.doi.org/10.1016/0092-8674(95)90199-X]. [PMID: 8521507].
[12]
Turunen MM, Dunlop TW, Carlberg C, Väisänen S. Selective use of multiple vitamin D response elements underlies the 1 α,25-dihydroxyvitamin D3-mediated negative regulation of the human CYP27B1 gene. Nucleic Acids Res 2007; 35(8): 2734-47. [http://dx.doi.org/10.1093/nar/gkm179]. [PMID: 17426122].
[13]
Bouillon R, Suda T, Vitamin D. Calcium and bone homeostasis during evolution. Bonekey Rep 2014; 3: 480. [http://dx.doi.org/10.1038/bonekey.2013.214]. [PMID: 24466411].
[14]
Fleet JC. The role of vitamin D in the endocrinology controlling calcium homeostasis. Mol Cell Endocrinol 2017; 453: 36-45. [http://dx.doi.org/10.1016/j.mce.2017.04.008]. [PMID: 28400273].
[15]
van de Peppel J, van Leeuwen JP. Vitamin D and gene networks in human osteoblasts. Front Physiol 2014; 5: 137. [http://dx.doi.org/10.3389/fphys.2014.00137]. [PMID: 24782782].
[16]
Marks J, Debnam ES, Unwin RJ. Phosphate homeostasis and the renal-gastrointestinal axis. Am J Physiol Renal Physiol 2010; 299(2): F285-96. [http://dx.doi.org/10.1152/ajprenal.00508.2009]. [PMID: 20534868].
[17]
Kim S, Yamazaki M, Zella LA, et al. Multiple enhancer regions located at significant distances upstream of the transcriptional start site mediate RANKL gene expression in response to 1,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol 2007; 103(3-5): 430-4. [http://dx.doi.org/10.1016/j.jsbmb.2006.12.020]. [PMID: 17197168].
[18]
Feldman DJ, Malloy P. Mutations in the vitamin D receptor and hereditary vitamin D-resistant rickets. Bonekey Rep 2014; 3: 510. [http://dx.doi.org/10.1038/bonekey.2014.5]. [PMID: 24818002].
[19]
Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer 2014; 14(5): 342-57. [http://dx.doi.org/10.1038/nrc3691]. [PMID: 24705652].
[20]
Chun RF, Liu PT, Modlin RL, Adams JS, Hewison M. Impact of vitamin D on immune function: Lessons learned from genome-wide analysis. Front Physiol 2014; 5: 151. [http://dx.doi.org/10.3389/fphys.2014.00151]. [PMID: 24795646].
[21]
Luxwolda MF, Kuipers RS, Kema IP, Dijck-Brouwer DA, Muskiet FA. Traditionally living populations in East Africa have a mean serum 25-hydroxyvitamin D concentration of 115 nmol/l. Br J Nutr 2012; 108(9): 1557-61. [http://dx.doi.org/10.1017/S0007114511007161]. [PMID: 22264449].
[22]
Hochberg Z, Templeton AR. Evolutionary perspective in skin color, vitamin D and its receptor. Hormones (Athens) 2010; 9(4): 307-11. [http://dx.doi.org/10.14310/horm.2002.1281]. [PMID: 21112861].
[23]
Jablonski NG, Chaplin G. The roles of vitamin D and cutaneous vitamin D production in human evolution and health. Int J Paleopathol 2018; 23: 54-9. [http://dx.doi.org/10.1016/j.ijpp.2018.01.005]. [PMID: 29606375].
[24]
Carlberg C. The physiology of vitamin D-far more than calcium and bone. Front Physiol 2014; 5: 335. [http://dx.doi.org/10.3389/fphys.2014.00335]. [PMID: 25228886].
[25]
Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3): 266-81. [http://dx.doi.org/10.1056/NEJMra070553]. [PMID: 17634462].
[26]
Schwartz GG. Multiple sclerosis and prostate cancer: What do their similar geographies suggest? Neuroepidemiology 1992; 11(4-6): 244-54. [http://dx.doi.org/10.1159/000110937]. [PMID: 1291888].
[27]
Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press 2011.
[28]
Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: Consequences for bone loss and fractures and therapeutic implications. Endocr Rev 2001; 22(4): 477-501. [http://dx.doi.org/10.1210/edrv.22.4.0437]. [PMID: 11493580].
[29]
Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96(7): 1911-30. [http://dx.doi.org/10.1210/jc.2011-0385]. [PMID: 21646368].
[30]
Vieth R. Critique of the considerations for establishing the tolerable upper intake level for vitamin D: Critical need for revision upwards. J Nutr 2006; 136(4): 1117-22. [http://dx.doi.org/10.1093/jn/136.4.1117]. [PMID: 16549491].
[31]
Carlberg C, Seuter S, de Mello VD, et al. Primary vitamin D target genes allow a categorization of possible benefits of vitamin D3 supplementation. PLoS One 2013; 8(7)e71042 [http://dx.doi.org/10.1371/journal.pone.0071042]. [PMID: 23923049].
[32]
Wilfinger J, Seuter S, Tuomainen T-P, et al. Primary vitamin D receptor target genes as biomarkers for the vitamin D3 status in the hematopoietic system. J Nutr Biochem 2014; 25(8): 875-84. [http://dx.doi.org/10.1016/j.jnutbio.2014.04.002]. [PMID: 24854954].
[33]
Ryynänen J, Neme A, Tuomainen TP, et al. Changes in vitamin D target gene expression in adipose tissue monitor the vitamin D response of human individuals. Mol Nutr Food Res 2014; 58(10): 2036-45. [http://dx.doi.org/10.1002/mnfr.201400291]. [PMID: 24975273].
[34]
Saksa N, Neme A, Ryynänen J, et al. Dissecting high from low responders in a vitamin D3 intervention study. J Steroid Biochem Mol Biol 2015; 148: 275-82. [http://dx.doi.org/10.1016/j.jsbmb.2014.11.012]. [PMID: 25448738].
[35]
Vukić M, Neme A, Seuter S, et al. Relevance of vitamin D receptor target genes for monitoring the vitamin D responsiveness of primary human cells. PLoS One 2015; 10(4)e0124339 [http://dx.doi.org/10.1371/journal.pone.0124339]. [PMID: 25875760].
[36]
Seuter S, Virtanen JK, Nurmi T, et al. Molecular evaluation of vitamin D responsiveness of healthy young adults. J Steroid Biochem Mol Biol 2017; 174: 314-21. [http://dx.doi.org/10.1016/j.jsbmb.2016.06.003]. [PMID: 27282116].
[37]
Carlberg C, Haq A. The concept of the personal vitamin D response index. J Steroid Biochem Mol Biol 2018; 175: 12-7. [http://dx.doi.org/10.1016/j.jsbmb.2016.12.011]. [PMID: 28034764].
[38]
Haussler MR, Jurutka PW, Mizwicki M, Norman AW. Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)2 vitamin D3: Genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab 2011; 25(4): 543-59. [http://dx.doi.org/10.1016/j.beem.2011.05.010]. [PMID: 21872797].
[39]
Ordóñez-Morán P, Larriba MJ, Pálmer HG, et al. RhoA-ROCK and p38MAPK-MSK1 mediate vitamin D effects on gene expression, phenotype, and Wnt pathway in colon cancer cells. J Cell Biol 2008; 183(4): 697-710. [http://dx.doi.org/10.1083/jcb.200803020]. [PMID: 19015318].
[40]
Haussler MR, Haussler CA, Jurutka PW, et al. The vitamin D hormone and its nuclear receptor: Molecular actions and disease states. J Endocrinol 1997; 154(Suppl.): S57-73. [PMID: 9379138].
[41]
Vaquerizas JM, Kummerfeld SK, Teichmann SA, Luscombe NM. A census of human transcription factors: Function, expression and evolution. Nat Rev Genet 2009; 10(4): 252-63. [http://dx.doi.org/10.1038/nrg2538]. [PMID: 19274049].
[42]
Molnár F, Peräkylä M, Carlberg C. Vitamin D receptor agonists specifically modulate the volume of the ligand-binding pocket. J Biol Chem 2006; 281(15): 10516-26. [http://dx.doi.org/10.1074/jbc.M513609200]. [PMID: 16478719].
[43]
Herdick M, Carlberg C. Agonist-triggered modulation of the activated and silent state of the vitamin D(3) receptor by interaction with co-repressors and co-activators. J Mol Biol 2000; 304(5): 793-801. [http://dx.doi.org/10.1006/jmbi.2000.4267]. [PMID: 11124027].
[44]
Polly P, Herdick M, Moehren U, Baniahmad A, Heinzel T, Carlberg C. VDR-Alien: A novel, DNA-selective vitamin D(3) receptor-corepressor partnership. FASEB J 2000; 14(10): 1455-63. [http://dx.doi.org/10.1096/fasebj.14.10.1455]. [PMID: 10877839].
[45]
Pereira F, Barbáchano A, Singh PK, Campbell MJ, Muñoz A, Larriba MJ. Vitamin D has wide regulatory effects on histone demethylase genes. Cell Cycle 2012; 11(6): 1081-9. [http://dx.doi.org/10.4161/cc.11.6.19508]. [PMID: 22370479].
[46]
Molnár F. Structural considerations of vitamin D signaling. Front Physiol 2014; 5: 191. [http://dx.doi.org/10.3389/fphys.2014.00191]. [PMID: 24936188].
[47]
Wei Z, Yoshihara E, He N, et al. Vitamin D switches BAF complexes to protect beta cells. Cell 2018; 173: 1135-49 e15.
[48]
Pereira F, Barbáchano A, Silva J, et al. KDM6B/JMJD3 histone demethylase is induced by vitamin D and modulates its effects in colon cancer cells. Hum Mol Genet 2011; 20(23): 4655-65. [http://dx.doi.org/10.1093/hmg/ddr399]. [PMID: 21890490].
[49]
Carlberg C, Bendik I, Wyss A, et al. Two nuclear signalling pathways for vitamin D. Nature 1993; 361(6413): 657-60. [http://dx.doi.org/10.1038/361657a0]. [PMID: 8382345].
[50]
Ramagopalan SV, Heger A, Berlanga AJ, et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution. Genome Res 2010; 20(10): 1352-60. [http://dx.doi.org/10.1101/gr.107920.110]. [PMID: 20736230].
[51]
Heikkinen S, Väisänen S, Pehkonen P, Seuter S, Benes V, Carlberg C. Nuclear hormone 1α,25-dihydroxyvitamin D3 elicits a genome-wide shift in the locations of VDR chromatin occupancy. Nucleic Acids Res 2011; 39(21): 9181-93. [http://dx.doi.org/10.1093/nar/gkr654]. [PMID: 21846776].
[52]
Tuoresmäki P, Väisänen S, Neme A, Heikkinen S, Carlberg C. Patterns of genome-wide VDR locations. PLoS One 2014; 9(4)e96105 [http://dx.doi.org/10.1371/journal.pone.0096105]. [PMID: 24787735].
[53]
Meyer MB, Goetsch PD, Pike JW. VDR/RXR and TCF4/β-catenin cistromes in colonic cells of colorectal tumor origin: Impact on c-FOS and c-MYC gene expression. Mol Endocrinol 2012; 26(1): 37-51. [http://dx.doi.org/10.1210/me.2011-1109]. [PMID: 22108803].
[54]
Ding N, Yu RT, Subramaniam N, et al. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 2013; 153(3): 601-13. [http://dx.doi.org/10.1016/j.cell.2013.03.028]. [PMID: 23622244].
[55]
Carlberg C. Genome-wide (over)view on the actions of vitamin D. Front Physiol 2014; 5: 167. [http://dx.doi.org/10.3389/fphys.2014.00167]. [PMID: 24808867].
[56]
Neme A, Seuter S, Carlberg C. Selective regulation of biological processes by vitamin D based on the spatio-temporal cistrome of its receptor. Biochim Biophys Acta Gene Regul Mech 2017; 1860(9): 952-61. [http://dx.doi.org/10.1016/j.bbagrm.2017.07.002]. [PMID: 28712921].
[57]
Campbell MJ. Vitamin D and the RNA transcriptome: More than mRNA regulation. Front Physiol 2014; 5: 181. [http://dx.doi.org/10.3389/fphys.2014.00181]. [PMID: 24860511].
[58]
Waddington CH. Canalization of development and the inheritance of acquired characters. Nature 1942; 150: 563-5. [http://dx.doi.org/10.1038/150563a0].
[59]
Wu Ct, Morris JR. Genes, genetics, and epigenetics: A correspondence. Science 2001; 293(5532): 1103-5. [http://dx.doi.org/10.1126/science.293.5532.1103]. [PMID: 11498582].
[60]
Beisel C, Paro R. Silencing chromatin: Comparing modes and mechanisms. Nat Rev Genet 2011; 12(2): 123-35. [http://dx.doi.org/10.1038/nrg2932]. [PMID: 21221116].
[61]
Carlberg C, Molnár F. The epigenome Mechanisms of Gene Regulation. 2nd ed. Springer 2016; pp. 159-72.
[62]
Dawson MA, Kouzarides T. Cancer epigenetics: From mechanism to therapy. Cell 2012; 150(1): 12-27. [http://dx.doi.org/10.1016/j.cell.2012.06.013]. [PMID: 22770212].
[63]
Carlberg C, Molnár F. The Impact of Chromatin Mechanisms of Gene Regulation. 2nd ed. Springer 2016; pp. 17-34.
[64]
Zentner GE, Henikoff S. Regulation of nucleosome dynamics by histone modifications. Nat Struct Mol Biol 2013; 20(3): 259-66. [http://dx.doi.org/10.1038/nsmb.2470]. [PMID: 23463310].
[65]
Deans C, Maggert KA. What do you mean, “epigenetic”? Genetics 2015; 199(4): 887-96. [http://dx.doi.org/10.1534/genetics.114.173492]. [PMID: 25855649].
[66]
Carlberg C, Campbell MJ. Vitamin D receptor signaling mechanisms: Integrated actions of a well-defined transcription factor. Steroids 2013; 78(2): 127-36. [http://dx.doi.org/10.1016/j.steroids.2012.10.019]. [PMID: 23178257].
[67]
Nurminen V, Neme A, Seuter S, Carlberg C. The impact of the vitamin D-modulated epigenome on VDR target gene regulation. Biochim Biophys Acta Gene Regul Mech 2018; 1861(8): 697-705. [http://dx.doi.org/10.1016/j.bbagrm.2018.05.006]. [PMID: 30018005].
[68]
An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489(7414): 57-74. [http://dx.doi.org/10.1038/nature11247]. [PMID: 22955616].
[69]
Seuter S, Neme A, Carlberg C. Epigenome-wide effects of vitamin D and their impact on the transcriptome of human monocytes involve CTCF. Nucleic Acids Res 2016; 44(9): 4090-104. [PMID: 26715761].
[70]
Carlberg C, Seuter S, Nurmi T, Tuomainen TP, Virtanen JK, Neme A. In vivo response of the human epigenome to vitamin D: A Proof-of-principle study. J Steroid Biochem Mol Biol 2018; 180: 142-8. [http://dx.doi.org/10.1016/j.jsbmb.2018.01.002]. [PMID: 29317287].
[71]
Neme A, Seuter S, Carlberg C. Vitamin D-dependent chromatin association of CTCF in human monocytes. Biochim Biophys Acta 2016; 1859(11): 1380-8. [http://dx.doi.org/10.1016/j.bbagrm.2016.08.008]. [PMID: 27569350].
[72]
Seuter S, Neme A, Carlberg C. Epigenomic PU.1-VDR crosstalk modulates vitamin D signaling. Biochim Biophys Acta Gene Regul Mech 2017; 1860(4): 405-15. [http://dx.doi.org/10.1016/j.bbagrm.2017.02.005]. [PMID: 28232093].
[73]
Seuter S, Neme A, Carlberg C. Epigenome-wide effects of vitamin D and their impact on the transcriptome of human monocytes involve CTCF. Nucleic Acids Res 2016; 44(9): 4090-104. [http://dx.doi.org/10.1093/nar/gkv1519]. [PMID: 26715761].
[74]
Dixon JR, Selvaraj S, Yue F, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 2012; 485(7398): 376-80. [http://dx.doi.org/10.1038/nature11082]. [PMID: 22495300].
[75]
Ali T, Renkawitz R, Bartkuhn M. Insulators and domains of gene expression. Curr Opin Genet Dev 2016; 37: 17-26. [http://dx.doi.org/10.1016/j.gde.2015.11.009]. [PMID: 26802288].
[76]
Carlberg C. Molecular endocrinology of vitamin D on the epigenome level. Mol Cell Endocrinol 2017; 453: 14-21. [http://dx.doi.org/10.1016/j.mce.2017.03.016]. [PMID: 28315703].
[77]
Verstuyf A, Carmeliet G, Bouillon R, Mathieu C, Vitamin D. A pleiotropic hormone. Kidney Int 2010; 78(2): 140-5. [http://dx.doi.org/10.1038/ki.2010.17]. [PMID: 20182414].

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