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

Pike, J. Wesley; Meyer, Mark B.; Lee, Seong-Min; Onal, Melda; Benkusky, Nancy A.

doi:10.1172/jci88887

Cited by 146 publications

(97 citation statements)

References 118 publications

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“…23,[45][46][47] To be active, supplemental vitamin D 3 must undergo 2 hydroxylations, first to 25-OHD and then to the functional metabolite, 1,25(OH) 2 D, which binds to the vitamin D receptor to function as a transcription factor inducing vitamin D-responsive genes. For the principal endocrine functions of vitamin D, bone mineralization, and calcium and phosphate homeostasis, the first hydroxylation takes place using a 25-hydroxylase in the liver, 17,18,48 producing 25-OHD that enters the circulation. The second hydroxylation occurs in the kidney, using the 1-a-hydroxylase CYP27B1 to yield 1,25(OH) 2 D. 17,19 By contrast, for extraskeletal autocrine and paracrine activities, vitamin D 3 , the parent compound, enters cells more easily than 25-OHD, and both hydroxylations may take place intracellularly.…”

Section: Baselinementioning

confidence: 99%

“…11 Vitamin D, in addition to its role in calcium and bone homeostasis, is a multifunctional regulator of innate and adaptive immune responses and of inflammation. [12][13][14][15][16] Vitamin D acts, in part, through its metabolite 1,25-dihydroxyvitamin D [1,25(OH) 2 D], 17,18 which binds to the vitamin D receptor to function as a transcription factor, inducing vitamin D-responsive genes that are present in most, if not all, cells of the immune system. 19 1,25(OH) 2 D mediates the innate immune host response against respiratory tract pathogens by stimulating expression of cathelicidin (hCAP18/LL37), an antimicrobial peptide with activity against viral, bacterial, and fungal pathogens.…”

Section: Introductionmentioning

confidence: 99%

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Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease

Lee¹,

Kattan

Fennoy³

et al. 2018

Blood Advances

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In sickle cell disease, respiratory infection and asthma may lead to respiratory complications that are a leading cause of morbidity and mortality. Vitamin D has anti-infective and immunomodulatory effects that may decrease the risk for respiratory infections, asthma, and acute chest syndrome. We conducted a randomized double-blind active-controlled clinical trial to determine whether monthly oral vitamin D can reduce the rate of respiratory events in children with sickle cell disease. Seventy sickle cell subjects, ages 3-20 years, with baseline records of respiratory events over 1 year before randomization, underwent screening. Sixty-two subjects with 25-hydroxyvitamin D levels of 5-60 ng/mL were randomly assigned to oral vitamin D (100 000 IU or 12 000 IU, n = 31 each) under observed administration once monthly for 2 years. The primary outcome was the annual rate of respiratory events (respiratory infection, asthma exacerbation, or acute chest syndrome) ascertained by the use of a validated questionnaire administered biweekly. Analysis included 62 children (mean age of 9.9 years, 52% female, and predominantly with homozygous HbS disease [87%]) with mean baseline 25-hydroxyvitamin D of 14.3 ng/mL. The annual rates of respiratory events at baseline and intervention years 1 and 2 were 4.34 ± 0.35, 4.28 ± 0.36, and 1.49 ± 0.37 (high dose) and 3.91 ± 0.35, 3.34 ± 0.37, and 1.54 ± 0.37 (standard dose), respectively. In pediatric patients with sickle cell disease, 2-year monthly oral vitamin D was associated with a >50% reduction in the rate of respiratory illness during the second year ( = .0005), with similar decreases associated with high- and standard-dose treatment. This trial was registered at www.clinicaltrials.gov as #NCT01443728.

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Section: Baselinementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease

Lee¹,

Kattan

Fennoy³

et al. 2018

Blood Advances

View full text Add to dashboard Cite

show abstract

“…The active ligand of vitamin D3, 1α,25‐dihydroxy vitamin D 3 (1,25(OH) 2 D 3 ), binds to an intracellular specific vitamin D receptor (VDR) which trans‐locates to the cell nucleus. VDR‐ligand complex interacts with genomic regulatory elements (vitamin D responsive element), particularly at target promoters and regulatory enhancers (Pike & Christakos, 2017; Pike et al, 2016; Pike, Meyer, Lee, Onal, & Benkusky, 2017). VDR can form high molecular weight complexes through specific protein‐protein interactions with transcriptional coactivators and/or corepressors in a ligand‐dependent manner (Herdick & Carlberg, 2000; Meyer & Pike, 2013; Rachez & Freedman, 2000).…”

Section: Introductionmentioning

confidence: 99%

Ezh2‐dependent H3K27me3 modification dynamically regulates vitamin D3‐dependent epigenetic control of CYP24A1 gene expression in osteoblastic cells

Moena

Nardocci

Acevedo

et al. 2020

Journal Cellular Physiology

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Epigenetic control is critical for the regulation of gene transcription in mammalian cells. Among the most important epigenetic mechanisms are those associated with posttranslational modifications of chromosomal histone proteins, which modulate chromatin structure and increased accessibility of promoter regulatory elements for competency to support transcription. A critical histone mark is trimethylation of histone H3 at lysine residue 27 (H3K27me3), which is mediated by Ezh2, the catalytic subunit of the polycomb group complex PRC2 to repress transcription. Treatment of cells with the active vitamin D metabolite 1,25(OH)2D3, results in transcriptional activation of the CYP24A1 gene, which encodes a 24‐hydroxylase enzyme, that is, essential for physiological control of vitamin D3 levels. We report that the Ezh2‐mediated deposition of H3K27me3 at the CYP24A1 gene promoter is a requisite regulatory component during transcriptional silencing of this gene in osteoblastic cells in the absence of 1,25(OH)2D3. 1,25(OH)2D3 dependent transcriptional activation of the CYP24A1 gene is accompanied by a rapid release of Ezh2 from the promoter, together with the binding of the H3K27me3‐specific demethylase Utx/Kdm6a and thereby subsequent erasing of the H3K27me3 mark. Importantly, we find that these changes in H3K27me3 enrichment at the CYP24A1 gene promoter are highly dynamic, as this modification is rapidly reacquired following the withdrawal of 1,25(OH)2D3.

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“…VDR is a member of the superfamily of nuclear receptors that form ligand‐dependent high molecular weight complexes that include transcription factors and coregulators (Montecino et al, ; Pike et al, ). Tissue specific transcription factors (Christakos et al, ; Paredes et al, ) and epigenetic regulators (Meyer & Pike, ; Seth‐Vollenweider, Joshi, Dhawan, Sif, & Christakos, ; Sierra et al, ; Zella, Kim, Shevde, & Pike, ) together modify the epigenetic landscape at specific genomic domains, change local chromatin structure and modulate 1,25(OH) 2 D 3 ‐responsive transcriptional activity (Pike, Meyer, John, & Benkusky, ).…”

Section: Introductionmentioning

confidence: 99%

Switches in histone modifications epigenetically control vitamin D3‐dependent transcriptional upregulation of the CYP24A1 gene in osteoblastic cells

Moena

Merino

Lian

et al. 2019

Journal Cellular Physiology

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In bone cells vitamin D dependent regulation of gene expression principally occurs through modulation of gene transcription. Binding of the active vitamin D metabolite, 1,25‐dihydroxy vitamin D3 (1,25(OH)2D3) to the vitamin D receptor (VDR) induces conformational changes in its C‐terminal domain enabling competency for interaction with physiologically relevant coactivators, including SRC‐1. Consequently, regulatory complexes can be assembled that support intrinsic enzymatic activities with competency to posttranslationally modify chromatin histones at target genomic sequences to epigenetically alter transcription. Here we examine specific transitions in representation and/or enrichment of epigenetic histone marks during 1,25(OH)2D3 mediated upregulation of CYP24A1 gene expression in osteoblastic cells. This gene encodes the 24‐hydroxylase enzyme, essential for biological control of vitamin D levels. We demonstrate that as the CYP24A1 gene promoter remains transcriptionally silent, there is enrichment of H4R3me2s together with its “writing” enzyme PRMT5 and decreased abundance of the istone H3 and H4 acetylation, H3R17me2a, and H4R3me2a marks as well as of their corresponding “writers.” Exposure of osteoblastic cells to 1,25(OH)2D3 stimulates the recruitment of a VDR/SRC‐1 containing complex to the CYP24A1 promoter to mediate increased H3/H4 acetylation. VDR/SRC‐1 binding occurs concomitant with the release of PRMT5 and the recruitment of the arginine methyltransferases CARM1 and PRMT1 to catalyze the deposition of the H3R17me2a and H4R3me2a marks, respectively. Our results indicate that these dynamic transitions of histone marks at the CYP24A1 promoter, provide a “chromatin context” that is transcriptionally competent for activation of the CYP24A1 gene in osteoblastic cells in response to 1,25(OH)2D3.

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

Cited by 146 publications

References 118 publications

Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease

Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease

Ezh2‐dependent H3K27me3 modification dynamically regulates vitamin D3‐dependent epigenetic control of CYP24A1 gene expression in osteoblastic cells

Switches in histone modifications epigenetically control vitamin D3‐dependent transcriptional upregulation of the CYP24A1 gene in osteoblastic cells

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