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.
Highlights
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
WHAT ARE THE PROTEINS, OR PROCESSES THAT GUIDE WHERE THE vitamin D receptor (VDR) BINDS IN THE GENOME? It is unclear what key pioneer factors will be identified and if the VDR is in a strong relationship with a specific family of pioneer factors, in the same that the AR is profoundly influenced by the Forkhead family members
The precise pioneer factor may even be tissue specific as revealed for the AR (Pihlajamaa et al, 2014). This may reflect the fact the ligand activation of the VDR is more associated with re-distribution of the VDR through the genome, rather than triggering movement into the nucleus
Summary
The INTACT database curated by EBI http://www.ebi.ac.uk/intact/ was interrogated for interactions with the VDR. First generation arrays chips, for example from Affymetrix which contained 4500 probes (Akutsu et al, 2001), enabled sufficient genomic coverage to begin to define specific regulated gene networks This particular study from White (Akutsu et al, 2001) and co-workers identified 38 genes that were responsive to 1α,25(OH)2D3 exposure, which represented approximately 1% of the transcriptome studied, and included GADD45A. PROTEIN CODING MRNA Vitamin D effect on bronchial smooth muscle cells Genome-wide analysis of vitamin D receptor (VDR) target genes in THP-1 monocytic leucemia cells Transcriptional effects of 1,25 dihydroxi-vitamin D3 physiological and supra-physiological concentrations in breast cancer organotypic culture Analysis of vitamin D response element binding protein target genes reveals a role for vitamin D in osteoblast mTOR signaling Expression profiling of androgen receptor and vitamin D receptor mediated signaling in prostate cancer cells Understanding vitamin D resistance using expression microarrays Effects of TX527, a hypocalcemic vitamin D analog on human activated T lymphocytes Transcriptome profiling of genes regulated by RXR and its partners in monocyte-derived dendritic cells NON-PROTEIN CODING RNA MicroRNA-22 upregulation by vitamin D mediates its protective action against colon cancer. miRNA profiling of androgen receptor and vitamin D receptor mediated signaling in prostate cancer cells Identification of miRNAs regulated by vitamin D within primary human osteoblasts Vitamin D and microRNA expression
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