Vitamin D Regulates Genes Associated with Susceptibility to Autoimmune Diseases

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Vitamin D is, at this point, probably one of the trendiest vitamins around. Everyone suddenly seems to be getting their vitamin D level tested (specifically vitamin D3 or 25(OH)D, also called calcidiol) and, when levels are found to be deficient, taking supplements. In November 2010, the Institute of Medicine tripled its daily recommendations for vitamin D from 200 International Units to 600 [1]. Severe vitamin D deficiency causes rickets, which leads to a softening and weakening of the bones, so milk has been fortified with vitamin D to prevent rickets. Less dramatic vitamin D deficiency has been implicated in ailments ranging from cancer to heart disease to schizophrenia to autoimmune diseases to colds and the flu. But how does vitamin D act in the body — how can it contribute to so many different physiological processes?

The vitamin D receptor (VDR) belongs to a large family of proteins, the nuclear receptors. Upon binding to its substrate — in this case calcitriol, or 1,25(OH)2D vitamin D, the biologically active form of the vitamin — the VDR moves from the cytoplasm of the cell into the nucleus, where it binds to specific DNA sequences called vitamin D response elements (VDREs). By binding to these sites, the VDR can affect the expression of nearby genes, either turning them on so they make more of the protein they encode or off so they make less. In a recent study reported in the journal Genome Research, a team of scientists based at the University of Oxford scanned the genome for such VDREs to catalog all of the genes they can impact [2].

They used a technique called Chromatin Immunoprecipitation followed by massively parallel DNA sequencing, known more colloquially as ChIP-Seq. This entails using an antibody generated against the VDR to find it at all of the sites along the chromatin to which it is bound — all of the VDREs. They performed their analysis on white blood cells in the presence and absence of calcitriol. Once the antibody pulled down all of the VDREs, the researchers used DNA sequencing to determine which genes the sites were closest to, and therefore most likely to regulate.

They found 2776 VDREs occupied by VDR after stimulation with calcitriol, compared to 623 before stimulation — a 4.5 fold increase. They found 226 genes that were significantly upregulated by calcitriol treatment and three genes that were significantly downregulated. Many of these differently expressed genes were associated with immune function, and new VDREs were identified near genes associated with susceptibility to autoimmune disease. When they looked to see if VDREs were enriched in loci known through Genome Wide Association Studies to be associated with various diseases, they found that VDREs were found preferentially at regions of the genome associated with Type I diabetes, Crohn’s disease, lupus, colorectal cancer, chronic lymphocytic leukemia, rheumatoid arthritis and multiple sclerosis. Gene regulation by vitamin D had not previously been suggested to play a role in multiple sclerosis but they supported this finding with their observation that VDR binding was enriched in genes known to be differentially expressed in multiple sclerosis, including those encoding proteins involved in translational regulation, oxidative phosphorylation and antigen presentation pathways. The enrichment they found of VDREs near genes associated with cancer and autoimmune diseases is consistent with epidemiological data.

The authors note that further work is required in other cell types to establish the tissue specificity of VDR binding to different VDREs, and how quickly the VDRs can get to the nucleus once exposed to calcitriol. But this study provides a first map of VDR binding across the human genome, and identified thousands of new VDREs. Hopefully, these will begin to explain the diversity of biological and clinical activities ascribed to vitamin D.

References

1. IOM Report Sets New Dietary Intake Levels for Calcium and Vitamin D To Maintain Health and Avoid Risks Associated With Excess. Institute of Medicine. 2010 Nov 30.
2. Ramagopalan et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res. 2010 Oct;20(10):1352-60. Epub 2010 Aug 24.
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