ReviewRegulation of the vitamin D receptor gene by environment, genetics and epigenetics
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.
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