Genomic Effects of the Vitamin D Receptor: Potentially the Link between Vitamin D, Immune Cells, and Multiple Sclerosis

Abstract

Vitamin D has a plethora of functions that are important for the maintenance of general health and in particular, the functional integrity of the immune system, such as promoting an anti-inflammatory cytokine profile and reducing the Treg/Th17 ratio. Multiple sclerosis (MS) is a chronic, inflammatory, and neurodegenerative central nervous system (CNS) disorder of probable autoimmune origin. MS is characterized by recurring or progressive demyelination and degeneration of the CNS due in part to a misguided immune response to as yet undefined (CNS) antigens, potentially including myelin basic protein and proteolipid protein. MS has also been shown to be associated significantly with environmental factors such as the lack of vitamin D. The role of vitamin D in the pathogenesis and progression of MS is complex. Recent genetic studies have shown that various common MS-associated risk-single-nucleotide polymorphisms (SNPs) are located within or in the vicinity of genes associated with the complex metabolism of vitamin D. The functional aspects of these genetic associations may be explained either by a direct SNP-associated loss- or gain-of-function in a vitamin D-associated gene or due to a change in the regulation of gene expression in certain immune cell types. The development of new genetic tools using next-generation sequencing: e.g., chromatin immunoprecipitation sequencing (ChIP-seq) and the accompanying rapid progress of epigenomics has made it possible to recognize that the association between vitamin D and MS could be based on the extensive and characteristic genomic binding of the vitamin D receptor (VDR). Therefore, it is important to analyze comprehensively the spatiotemporal VDR binding patterns that have been identified using ChIP-seq in multiple immune cell types to reveal an integral profile of genomic VDR interaction. In summary, the aim of this review is to connect genomic effects vitamin D has on immune cells with MS and thus, to contribute to a better understanding of the influence of vitamin D on the etiology and the pathogenesis of this complex autoimmune disease.

Keywords: environment; genetics; immune system; multiple sclerosis; vitamin D.

Figure 1

Vitamin D regulates the transcription of target genes. After binding its ligand 1,25(OH)₂D₃ and recruiting its partner retinoid X receptor (RXR), vitamin D receptor (VDR) enters the nucleus and binds to the transcription factor (TF) binding sites of target genes, where causal risk single-nucleotide polymorphism may be located. This induces transcription after the activation of other components of the transcription complex has been completed. A key enhancer can potentially be transcribed into a non-coding enhancer RNA, which regulates gene transcription or orchestrates cohesion-dependent looping to bring target gene promoter and enhancer region into a single-loop domain. The transcription activity of the whole domain is limited and regulated in a 3D loop isolated from other DNA regions by CCCTC-binding factor (CTCF) and cohesin (148), and some of CTCF overlap with binding of VDR (125, 126). Enhancers bound by VDR/RXR especially that in the so-called super-enhancers (SEs) or TF hotspot regions will recruit coregulators that shape chromosome landscapes and cooperate with other TFs. Other genes that are located in the 3D loop but outside the regulatory hub can also be transcribed but at lower rate. Outside the 3D loop, preoccupied VDR or RXR can be detected without vitamin D stimulation showing only low regulatory activity. Some preoccupied basal RXR binding sites can predict VDR binding sites following 1,25(OH)₂D₃ stimulation and could represent storage regions for the VDR in the absence of 1,25(OH)₂D₃. After ligand binding, these “stored” VDR can shift to a DR3 motif in intronic and intergenic regions of regulated genes (120). However, the preoccupied VDR region with DR3 motif plays a master (persistent/mother) enhancer role, persist, and will promote the whole region activation and SE shaping. Secondary VDR binding region without DR3 motif (suggesting it binds DNA via interaction with other pioneer TFs or via non-classic unknown RXR/VDR motifs) will constitute subservient (secondary/daughter) enhancers around master enhancers in SE region (121, 150).