Elsevier

Gene

Volume 561, Issue 2, 1 May 2015, Pages 171-180
Gene

Review
Regulation of the vitamin D receptor gene by environment, genetics and epigenetics

https://doi.org/10.1016/j.gene.2015.02.024Get rights and content

Highlights

  • Role of VDR in physiology and disease necessitates understanding of its regulation.

  • We reviewed the regulation of VDR by environment, genetics and epigenetics.

  • Epigenetic mechanisms regulating VDR: DNA methylation, histone modification, ncRNA.

Abstract

The vitamin D receptor (VDR) plays a pivotal role as a mediator of 1α,25(OH)2D signalling. Besides its role in calcium homeostasis, ligand- bound VDR supports immunity and cell cycle control. While VDR regulates numerous genes across the genome, much remains to be learned about the regulation of the VDR gene itself. Hindered VDR expression and function have a broad impact, contributing to diverse diseases, including cancer, multiple sclerosis, type 1 diabetes and tuberculosis. A better understanding of the three main factors regulating the VDR, namely environment, genetics and epigenetics, may facilitate the development of improved strategies for treatment and prevention of diseases associated with impaired VDR function. This review aims to illuminate the complex interaction and contributions of the three levels of VDR gene regulation to endorse consideration of all three regulatory factors when studying gene regulation.

Introduction

The vitamin D receptor (VDR) is a member of the nuclear receptor superfamily of transcriptional regulators and mediates the diverse biological effects of calcitriol (1α,25(OH)2D3) and its analogues. VDR proposedly originated from duplication of an ancestral gene, along with the pregnane X receptor (PXR — both NR1I subfamily members) (Reschley and Krasowski, 2006). Conservation of 18 of the 22 ligand binding residues in the VDR has been shown across vertebrate species, from the lamprey to humans (Krasowski et al., 2005). The varied roles of vitamin D in immunity, cell proliferation and differentiation (Samuel and Sitrin, 2008), phosphate absorption and calcium homeostasis (DeLuca, 2004) are most likely the cause of VDR abundance across species (Hochberg and Templeton, 2010).

Liganded VDR in complex with retinoid X receptor acts as a promiscuous transcription factor (Haussler et al., 2013). It transactivates or represses numerous target genes by binding to positive or negative vitamin D responsive elements (VDREs and nVDREs, respectively) present in promoters, enhancers or suppressors of these genes (Chen and DeLuca, 1995, Meyer et al., 2014). In this capacity VDR regulates the expression of genes involved in diverse biological functions, including organ development, cell cycle control, calcium and phosphate homeostasis in bone metabolism, and xenobiotic detoxification (Haussler et al., 2013). The VDR also plays a role in both the innate and adaptive arms of the immune system, and has thus been implicated in a range of diseases. Non-communicable diseases associated with vitamin D and VDR include cancer as well as autoimmune disorders such as systemic lupus erythematosus, Crohn's disease, type I diabetes mellitus, multiple sclerosis, and rheumatoid arthritis (Holick, 2004a). VDR-related infectious diseases most notably include HIV, tuberculosis (TB) and leprosy (White, 2008).

A total of six genome-wide VDR-binding ChIP-seq experiments have been performed on six separate cell lines (reviewed in (Carlberg, 2014)). A combined analysis of all six experiments was performed using identical peak calling settings to harmonize the results (Tuoresmäki et al., 2014). When allowing a distance of up to 250 bp between peak summits, the six VDR ChIP-seq datasets specified 21,776 non-overlapping VDR binding sites (Tuoresmäki et al., 2014). Gene ontology (GO) analysis of 11,031 putative VDR target genes revealed that these target genes were involved in a number of diverse functions namely, metabolism (43%), cell and tissue morphology (19%), cell junction and adhesion (10%), differentiation and development (10%), angiogenesis (9%), and epithelial to mesenchymal transition (5%) (Ding et al., 2013). The involvement of VDR in such a large number of diverse diseases and physiological roles makes it a strong focal point for studying the underlying mechanisms of diseases and their possible prevention (Andress, 2006, Wang et al., 2008, Holick, 2004b). Consequently the importance of VDR function, and by extension VDR expression, warrants an understanding of the underlying mechanisms of the regulation of the VDR gene.

The regulation of VDR under basal conditions and upon induction is multifaceted; shaped by environment, genetics and epigenetics. Examining the interactions and combined roles of these three facets of gene regulation would facilitate a greater overall understanding of the predisposition and progression of VDR-related diseases such as cancer and TB. This approach to studying gene regulation in relation to disease was put forward as the common disease genetic epigenetic (CDGE) hypothesis by Bjornsson et al. (2004). The principles by which environmental factors influence VDR regulation, as well as the mechanisms of its genetic and epigenetic regulation are illustrated in Fig. 1. Rather than detailing how VDR regulates other genes, this review aims to summarize literature on the regulation of the VDR itself. To the knowledge of the authors, this article is the first to review the VDR as a paradigm of gene-environment interaction through epigenetics. It highlights the inextricable nature of environmental, genetic and epigenetic factors in VDR regulation, and encourages a holistic approach when studying gene regulation to uncover the molecular basis of disease.

Section snippets

Environmental regulation

Diverse environmental factors regulate the VDR, among which are diet (Lamberg-Allardt, 2006), sun exposure (Holick, 2003), age (Hagenau et al., 2009), pollution (Agarwal et al., 2002) and infection (Liu et al., 2006). The majority of these factors exert their effects on VDR regulation by altering levels of vitamin D. Vitamin D is the collective name for cholecalciferol (D3) and ergocalciferol (D2), both of which are precursors of the active VDR ligand, 1α,25(OH)2D. The vitamin D binding protein

Promoters and enhancers

To facilitate the diverse functions of VDR, the complex set of coding and non-coding exons of the VDR are under the control of four promoters (Table 1), some of which are tissue-specific. The gene contains a TATA-less, Sp1-driven primary promoter (GXP_168257; Gene2Promoter, Genomatix) encompassing exon 1a (Miyamoto et al., 1997). Characterization of the structure of the VDR gene revealed constitutive TFBS in the primary promoter, supporting the constitutive expression of VDR from this promoter (

Epigenetic regulation

Broadly, epigenetics refers to heritable and transient changes in gene expression not caused by nucleotide sequence variation, but collectively instigated by epigenetic marks classified as DNA methylation, histone modification and non-coding RNA (O'Neill et al., 2012). However, the definition of this term is still a matter of contention, and many distinct variations exist (Ledford, 2008). Epigenetic regulation of gene function may occur on four levels; DNA methylation, histone modifications,

Concluding remarks

The complex and tight regulation of VDR via environmental, genetic and epigenetic factors supports its important regulatory role in numerous critical physiological systems. Given the important role VDR plays in metabolism, homeostasis and immunity, the understanding of its regulation is of the utmost importance in the fight against infectious diseases and cancer. Although previous studies have excelled in exposing the influence of environmental, genetic and epigenetic components of VDR

Acknowledgements

D. Saccone and F. Asani were supported by the National Research Foundation (NRF) of South Africa. The NRF (Grant No 81774) and the Cancer Association of South Africa (CANSA) support our research through grants to L Bornman. We thank Vanessa O'Neill and Tamsyn Jeffery for the fruitful discussions and editing.

References (87)

  • E.M. Gardiner et al.

    Vitamin D receptor B1 and exon 1d: functional and evolutionary analysis

    J. Steroid Biochem. Mol. Biol.

    (2004)
  • J.A. Halsall et al.

    In silico analysis of the 5′ region of the Vitamin D receptor gene: functional implications of evolutionary conservation

    J. Steroid Biochem. Mol. Biol.

    (2007)
  • R.P. Heaney et al.

    Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol

    Am. J. Clin. Nutr.

    (2003)
  • M.F. Holick

    Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis

    Am. J. Clin. Nutr.

    (2004)
  • M.F. Holick

    Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancer, and cardiovascular disease

    Am. J. Clin. Nutr.

    (2004)
  • T. Kouzarides

    Chromatin modifications and their function

    Cell

    (2007)
  • C. Lamberg-Allardt

    Vitamin D in foods and as supplements

    Prog. Biophys. Mol. Biol.

    (2006)
  • M.B. Meyer et al.

    Genomic determinants of gene regulation by 1,25-dihydroxyvitamin D3 during osteoblast-lineage cell differentiation

    J. Biol. Chem.

    (2014)
  • A.W. Norman

    Sunlight, season, skin pigmentation, vitamin D, and 25-hydroxyvitamin D: integral components of the vitamin D endocrine system

    Am. J. Clin. Nutr.

    (1998)
  • A. Nykjaer et al.

    An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3

    Cell

    (1999)
  • C.P. Ponting et al.

    Evolution and functions of long noncoding RNAs

    Cell

    (2009)
  • M. Sinotte et al.

    Genetic polymorphisms of the vitamin D binding protein and plasma concentrations of 25-hydroxyvitamin D in premenopausal women

    Am. J. Clin. Nutr.

    (2009)
  • R. Vieth et al.

    Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level

    Am. J. Clin. Nutr.

    (2001)
  • T.J. Wang et al.

    Common genetic determinants of vitamin D insufficiency: a genome-wide association study

    Lancet

    (2010)
  • R.J. Wiese et al.

    Up-regulation of the vitamin D receptor in response to 1,25-dihydroxyvitamin D3 results from ligand-induced stabilization

    J. Biol. Chem.

    (1992)
  • R.J. Wilkinson et al.

    Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in West London: a case-control study

    Lancet

    (2000)
  • L.A. Zella et al.

    Enhancers located in the vitamin D receptor gene mediate transcriptional autoregulation by 1,25-dihydroxyvitamin D3

    J. Steroid Biochem. Mol. Biol.

    (2007)
  • K.S. Agarwal et al.

    The impact of atmospheric pollution on vitamin D status of infants and toddlers in Delhi, India

    Arch. Dis. Child.

    (2002)
  • J. Ahn et al.

    Genome-wide association study of circulating vitamin D levels

    Hum. Mol. Genet.

    (2010)
  • H. Arai et al.

    A vitamin D receptor gene polymorphism in the translation initiation codon: effect on protein activity and relation to bone mineral density in Japanese women

    J. Bone Miner. Res.

    (1997)
  • H. Arai et al.

    The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene

    J. Bone Miner. Res.

    (2001)
  • M. Baker

    Long noncoding RNAs: the search for function

    Nat. Methods

    (2011)
  • C. Bock et al.

    CpG island mapping by epigenome prediction

    PLoS Comput. Biol.

    (2007)
  • C. Carlberg

    Genome-wide (over)view on the actions of vitamin D

    Front. Physiol.

    (2014)
  • N. Chandel et al.

    VDR hypermethylation and HIV-induced T-cell loss

    J. Leukoc. Biol.

    (2013)
  • J.B. Cheng et al.

    Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • M.P. Creyghton et al.

    Histone H3K27ac separates active from poised enhancers and predicts developmental state

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • L.A. Crofts et al.

    Multiple promoters direct the tissue-specific expression of novel N-terminal variant human vitamin D receptor gene transcripts

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • S. Essa et al.

    Signature of VDR miRNAs and epigenetic modulation of vitamin D signaling in melanoma cell lines

    Anticancer Res.

    (2012)
  • I.S. Fetahu et al.

    Vitamin D and the epigenome

    Front. Physiol.

    (2014)
  • T.B. Fitzpatrick

    The validity and practicality of sun-reactive skin types I through VI

    Arch. Dermatol.

    (1988)
  • B. Fu et al.

    Epigenetic regulation of BMP2 by 1,25-dihydroxyvitamin D3 through DNA methylation and histone modification

    PLoS One

    (2013)
  • X. Gu et al.

    Effect of narrow-band ultraviolet B phototherapy on p63 and microRNA (miR-21 and miR-125b) expression in psoriatic epidermis

    Acta Derm. Venereol.

    (2011)
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