Vitamin D and the RNA transcriptome: more than mRNA regulation

Abstract

The GRCh37.p13 primary assembly of the human genome contains 20805 protein coding mRNA, and 37147 non-protein coding genes and pseudogenes that as a result of RNA processing and editing generate 196501 gene transcripts. Given the size and diversity of the human transcriptome, it is timely to revisit what is known of VDR function in the regulation and targeting of transcription. 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. With the discovery of microRNA, investigators also considered VDR regulation of these non-protein coding RNA. Again, cell and time dependency has emerged. 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. As the awareness of the diversity of non-coding RNA increases, it is increasingly likely it will be revealed that VDR actions are mediated through these molecules also. Key knowledge gaps remain over the VDR transcriptome. The causes for the cell and type dependent transcriptional heterogenetiy remain enigmatic. ChIP-Seq approaches have confirmed that VDR binding choices differ very significantly by cell type, but as yet the underlying causes distilling VDR binding choices are unclear. Similarly, it is clear that many of the VDR binding sites are non-canonical in nature but again the mechanisms underlying these interactions are unclear. Finally, although alternative splicing is clearly a very significant process in cellular transcriptional control, the lack of RNA-Seq data centered on VDR function are currently limiting the global assessment of the VDR transcriptome. VDR focused research that complements publically available data (e.g., ENCODE Birney et al., 2007; Birney, 2012), TCGA (Strausberg et al., 2002), GTEx (Consortium, 2013) will enable these questions to be addressed through large-scale data integration efforts.

Keywords: VDR; epigenetic; microRNA; microarray; transcriptome.

Figure 1

An overview of regulation and impact of the transcriptome by the nuclear VDR and the future challenges. The VDR toggles between a gene repressive and activating complex depending on the presence of ligand. Ligand activated gene regulated scenarios are most well understood. In the presense of ligand the VDR complex is associated with both mRNA and miRNA activation and there is clear evidence for co-regulation of these transcriptomes to tightly control final protein coding gene expression and phenotype. Ligand activated VDR also represses a number of miRNA for example including those that control expression of the VDR and components of the repressive complex. The major phenotypes associated with VDR control include cell cycle regulation and an emerging theme is the control of the epigenome. Four major questions remain in understanding VDR transcription. (1) What guides where the VDR binds in the genome? (2) What role does genetic variation in VDR binding sites play in changing the VDR transriptome? (3) What is the total VDR transcriptome? (4) What is the combined effect of the VDR transcriptome on health and disease and how can this be monitored and exploited?