Vitamin D and the epigenome

Abstract

Epigenetic mechanisms play a crucial role in regulating gene expression. The main mechanisms involve methylation of DNA and covalent modifications of histones by methylation, acetylation, phosphorylation, or ubiquitination. The complex interplay of different epigenetic mechanisms is mediated by enzymes acting in the nucleus. Modifications in DNA methylation are performed mainly by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins, while a plethora of enzymes, such as histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and histone demethylases (HDMs) regulate covalent histone modifications. In many diseases, such as cancer, the epigenetic regulatory system is often disturbed. Vitamin D interacts with the epigenome on multiple levels. Firstly, critical genes in the vitamin D signaling system, such as those coding for vitamin D receptor (VDR) and the enzymes 25-hydroxylase (CYP2R1), 1α-hydroxylase (CYP27B1), and 24-hydroxylase (CYP24A1) have large CpG islands in their promoter regions and therefore can be silenced by DNA methylation. Secondly, VDR protein physically interacts with coactivator and corepressor proteins, which in turn are in contact with chromatin modifiers, such as HATs, HDACs, HMTs, and with chromatin remodelers. Thirdly, a number of genes encoding for chromatin modifiers and remodelers, such as HDMs of the Jumonji C (JmjC)-domain containing proteins and lysine-specific demethylase (LSD) families are primary targets of VDR and its ligands. Finally, there is evidence that certain VDR ligands have DNA demethylating effects. In this review we will discuss regulation of the vitamin D system by epigenetic modifications and how vitamin D contributes to the maintenance of the epigenome, and evaluate its impact in health and disease.

Neonatal vitamin D status is not associated with later risk of type 1 diabetes: results from two large Danish population-based studies

“…Our studies were based on hypotheses of gestational programming, in this particular case claiming that low levels of 25(OH)D during periods of immune system maturation may cause long-term irreversible effects on immunological health [37]. It can be argued that one 25(OH)D measurement at a specific time-point (i.e.…”

All sites but skin cancer incidences analyzed worldwide by sex, age, and skin type over time (1955-2007), advancing age, and UVB dose reveals important carcinogenic drivers

“…[93] The vitamin D receptor has a large CpG island in its promoter region so that it can be silenced by methylation, which is important because it interacts with coactivator and cosuppressor proteins that are in contact with chromatin modifiers and remodelers and it also has certain ligands that have DNA demethylating effects. [94] We can obtain convincing evidence of an anticancer role for vitamin D 3 in humans from a recent vitamin D 3 , calcium randomized clinical trial using supplements, [95] along with a pooled analysis of randomized trails, [96] and a prospective cohort study [97] because they showed significant reductions in their all-cancers risk. Intriguingly, Neanderthals gave some of the Europeans HPV16A, [98] so that this ancestry population had a "head start" for increasing their incidences of cancer over recent decades from indoor work and decreasing levels of vitamin D 3 .…”

Epigenetics in multiple sclerosis

“…Vitamin D can activate or repress gene expression by recruiting histone acetyltransferases or histone deacetylases, respectively, to the vitamin D target genes. 79 In addition, Vitamin D can affect the expression of enzymes involved in histone demethylation. 79 These effects of vitamin D on histone modification have been demonstrated in several in vitro studies using cancer cell lines.…”

“…79 In addition, Vitamin D can affect the expression of enzymes involved in histone demethylation. 79 These effects of vitamin D on histone modification have been demonstrated in several in vitro studies using cancer cell lines. One study demonstrated that vitamin D suppresses the production of IL-17A, an inflammatory cytokine involved in MS exacerbation, from CD4 + T cells via the recruitment of histone deacetylase and a reduction in histone acetylation at the IL-17A promoter.…”