Vitamin D: An Overview of Gene Regulation, Ranging from Metabolism to Genomic Effects

Abstract

Vitamin D is a pro-hormone characterized by an intricate metabolism and regulation. It is well known for its role in calcium and phosphate metabolism, and in bone health. However, several studies have assessed a huge number of extra-skeletal functions, ranging from cell proliferation in some oncogenic pathways to antioxidant and immunomodulatory functions. Vitamin D exerts its role by binding to VDRs (vitamin D receptors), which are located in many different tissues. Moreover, VDRs are able to bind hundreds of genomic loci, modulating the expression of various primary target genes. Interestingly, plenty of gene polymorphisms regarding VDRs are described, each one carrying a potential influence against gene expression, with relapses in several chronic diseases and metabolic complications. In this review, we provide an overview of the genetic aspects of vitamin D and VDR, emphasizing the gene regulation of vitamin D, and the genetic modulation of VDR target genes. In addition, we briefly summarize the rare genetic disease linked to vitamin D metabolism.

Keywords: RXR; VDR; vitamin D; vitamin D target gene.

Figure 1

Metabolic pathways regarding the production, activation, and effects of vitamin D. The highest amount of vitamin D is produced in the skin, via the conversion of 7-DHC to vitamin D3. Vitamin D2 is mostly assumed through foods. Vitamin D2 and Vitamin D3 are further hydroxylated in carbonium 25 and 1. 1,25(OH)D exerts its genomic effects by binding to VDR and RXR, and translocating to the nucleus, where it interacts with VDRE. Non-genomic effects are mainly involved in calcium–phosphate homeostasis. 7-DHC: 7dehydrocolesterol, vitamin D3: vitamin D3, vitamin D2: vitamin D2, 25(OH)D: 25-hydroxylated vitamin D, 1,25(OH)D: 1,25-hydroxylated vitamin D, VDR: vitamin D receptor, RXR: retinoic acid receptor, VDRE: vitamin D response element.

Figure 2

The main polymorphisms characterizing a vitamin D receptor. Each one is pictured below its corresponding exon (indicated by progressive numbers from 1 to 9) matched via black arrows, and with its known clinical implications. VDR: vitamin D receptor, 25(OH)D: 25-hydroxylated vitamin D, 1,25(OH)D: 1,25-hydroxylated vitamin D.

Figure 3

Describing the multi-complex of the VDR, comprising the receptor, co-receptors, co-repressors, co-activators, and pioneer factors that finally exert genomic effects on gene transcription. VDR: vitamin D receptor, RXR: retinoid acid receptor, PU.1, CEBPα, GABPα, ETS1, RUNX2, BACH2: pioneer factors, KDM1A, KDM6B: chromatin modifiers, BRD7, BRD9: chromatin remodelers, MED1: co-activator, NCOR2, COPS2: co-repressors.