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.

Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis ‬

“…Thus, we could confirm that vitamin D supplementation induces a decrease in DNA methylation at numerous regions in the genome, although the sample size was too small to reliably establish all DMRs. The impact of vitamin D on DNA methylation is rather unique, with several studies in cancer starting to reveal this link, although the underlying mechanisms are still unknown (21,22). Changes in leukocyte DNA methylation between vitamin D-deficient and -sufficient healthy adolescent males of African-American origin have recently been reported using 27,000 CpG methylation arrays (38).…”

“…The cellular epigenetic state comprises highly interconnected mechanisms such as DNA methylation, histone modifications, and expression of noncoding RNAs (ncRNAs), which is critical for cell survival and its physiological function. Although the impact of vitamin D on histone modifications is well documented, because of VDR/RXR associations with histone acetyltransferases, deacetylases, and histone methyltransferases, its impact on DNA methylation is just beginning to emerge (21,22). Additionally, recent studies in cancer suggest that ncRNAs, including long ncRNAs and microRNAs (miRNA), may be involved in mediating VDR signaling (22).…”

Actions of 1,25(OH)2-vitamin D3 on the cellular cycle depend on VDR and p38 MAPK in skeletal muscle cells

“…VDR bound to 1,25D and retinoid X receptor interacts with vitamin D-response elements (VDREs) in the promoters of vitamin D target genes (Aslam et al 1999). In this regard, it is known that the VDR interacts with co-repressors as part of the transcriptional mechanisms by which myoblast arrest is induced (Campbell 2014). However, it is uncertain whether the binding of an agonist to the VDR allows RXR to bind the co-repressors.…”

A Combined Bioinformatics and Literature Based Approach for Identification of Long Non-coding RNAs That Modulate Vitamin D Receptor Signaling in Breast Cancer

“…Animal studies have shown the effect of VDR on lncRNA expression in a way that in VDR null mouse epidermis, mHOTAIR, MALAT1 and SRA are up-regulated while Foxn2-as, Gtl2-as and H19-as are down-regulated [55]. However, VDR transcriptome puzzle has many gaps which is mostly originated from the scarcity of RNA-Seq data focused on VDR function [54]. With the purpose of filling such knowledge gap, in the present study, we aimed at identification of the complex network between lncRNA expression, VDR signal ing and BC using a novel bio informatics approach.…”

“…Several patterns of co-expression, co-regulation and interactions have been revealed through integrated analyses of mRNA, miRNAs and lncRNAs [54]. Animal studies have shown the effect of VDR on lncRNA expression in a way that in VDR null mouse epidermis, mHOTAIR, MALAT1 and SRA are up-regulated while Foxn2-as, Gtl2-as and H19-as are down-regulated [55].…”