Vitamin D Receptor and RXR in the Post‐Genomic Era

Abstract

Following the elucidation of the human genome and components of the epigenome, it is timely to revisit what is known of vitamin D receptor (VDR) function. Early transcriptomic studies using microarray approaches focused on the protein coding mRNA that were regulated by the VDR, usually following treatment with ligand. These studies quickly established the approximate size and surprising diversity of the VDR transcriptome, revealing it to be highly heterogenous and cell type and time dependent. Investigators also considered VDR regulation of non-protein coding RNA and again, cell and time dependency was observed. Attempts to integrate mRNA and miRNA regulation patterns are beginning to reveal patterns of co-regulation and interaction that allow for greater control of mRNA expression, and the capacity to govern more complex cellular events. Alternative splicing in the trasncriptome has emerged as a critical process in transcriptional control and there is evidence of the VDR interacting with components of the splicesome. ChIP-Seq approaches have proved to be pivotal to reveal the diversity of the VDR binding choices across cell types and following treatment, and have revealed that the majority of these are non-canonical in nature. The underlying causes driving the diversity of VDR binding choices remain enigmatic. Finally, genetic variation has emerged as important to impact the transcription factor affinity towards genomic binding sites, and recently the impact of this on VDR function has begun to be considered.

Vascular Calcification Induced by Chronic Kidney Disease Is Mediated by an Increase of 1α-Hydroxylase Expression in Vascular Smooth Muscle Cells

“…This fact has been shown in the regulation of several proteins. (44,45) Thus, absence of activated VDR in CYP27B1…”

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

“…The vitamin D receptor is found in most human cells including cells of the immune system and beta cells [4]. Inadequate vitamin D status is common among pregnant women and neonates [5], and in the latter may influence disease susceptibility in childhood and adolescence.…”

Vitamin D and Myofibroblasts in Fibrosis and Cancer: At Cross-purposes with TGF-β/SMAD Signaling

“…In Figure 1B) (56,57). Epigenetic changes induce looping of VDR-responsive genomic regions toward the transcription initiation site.…”

“…Acting as a transcription factor, VDR/RXR governs the expression of a large number of genes, and the propensity of VDR to interact with and bind to a vast number of transcription factors to up-regulate or repress gene expression is well-documented (56,57,61). Interacting transcription factors include the potent pro-inflammatory nuclear factor-ĸB (NF-kB) (62) and the growth factor epidermal growth factor (EGF) (63), to name but a few.…”