2.1. Vitamin D regulation of epigenetic mechanism
In keeping with its proposed role as a custodian of phenotypic
stability, Vitamin D regulates epigenetic mechanisms that maintain
the transcription of its target genes that contribute to its regulatory
network (Fig. 2) [10]. For example, the VDR/RXR dimer recruits
histone acetyltransferases (HATs) such as p300/CBP and steroid
receptor coactivators 1 and 2 (SRC-1 and SRC-2) that carry out the
acetylation reactions that opens up the chromatin structure to
facilitate transcription.
Vitamin D also regulates the methylation state of its gene promotors.
Methylation of the CpG islands located in such promotor
regions can silence many of the genes that are regulated by Vitamin
D. For example, the decline in SERCA2a activity in cardiovascular
disease may be caused by hypermethylation of its promotor region
[11]. Another example is the expression of Klotho, which is another
significant custodian of phenotypic stability that is silenced by
methylation [12,13]. In cervical cancer, such epigenetic silencing
enhances tumorigenesis due to the activation of Wnt signalling that
is normally inhibited by Klotho [13]. Such hypermethylation of
promotor regions increases during ageing and has been linked to the
onset of many diseases such as cancer, cardiovascular and neurodegenerative
diseases [14]. For example, hypermethylation of promotors
in GABAergic neurons may contribute to the phenotypic
remodelling responsible for schizophrenia and bipolar disorder [15].
Given thatmany of these diseases have also been linked to VitaminD
deficiency, it isnot surprising tofind that VitaminDcanmodulate the
epigenetic landscape and this may contribute to its ability to maintain
phenotypic stability. This regulation of the epigenome by
VitaminDdependsonits ability to induce the expressionof anumber
of key DNA demethylases such as JMJD3, LSD1 and LSD2 [16].