The Journal of Steroid Biochemistry and Molecular Biology
Emerging regulatory paradigms for control of gene expression by 1,25-dihydroxyvitamin D3☆
Section snippets
Introductory background
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) functions as a systemic endocrine signal in vertebrate organisms to control the expression of genes whose products are vital to the control of cellular growth, differentiation and function and to the maintenance of calcium and phosphorus homeostasis as well [1]. This capability is mediated by the vitamin D receptor (VDR), which binds as a retinoid X receptor (RXR) heterodimer to specific regulatory sequences near target genes where it functions to
The methodologic approach
As outlined above, we have used ChIP analysis [6] coupled to tiled DNA microarray hybridization (ChIP-chip) and/or massively parallel sequencing (ChIP-seq) analyses [13], [16], [17] to explore the actions of 1,25(OH)2D3 and other hormonal regulators at both the genome-wide, targeted genome-wide, and individual gene levels in vitamin D target cells. The results of these studies are then further explored using a number of additional techniques that include enhancer fragment and BAC clone analyses.
Mechanisms of gene regulation by 1,25(OH)2D3
We have used ChIP-chip and ChIP-seq analyses to identify under both basal and 1,25(OH)2D3-treated conditions all VDR and RXR binding sites in the mouse MC3T3-E1 pre-osteoblastic cell genome (termed cistrome analysis) [23]. These techniques have also been used to examine similar activities in human colonic LS180 cells [29]. We have also explored the consequence of this genome-wide binding of VDR and RXR on site-specific coregulator and RNA polymerase II recruitment and changes in levels of
Concluding remarks and future perspectives
The results described above outline new approaches to the exploration of mechanisms that underlie the regulation of gene expression by 1,25(OH)2D3. An advantage of these approaches is that they can provide both a genome-wide as well as an individual gene perspective. With respect to the former, we have defined a new set of overarching principles whereby 1,25(OH)2D3 likely acts to regulate the expression of virtually all genes. At a specific target gene level, we have highlighted several of
Acknowledgements
We thank all members of the Pike laboratory for their contributions to this work and Laura Vanderploeg for preparing the figures. This work was supported by National Institutes of Health grants AR-045173, DK-072281, DK-073995 and DK-074993 to JWP.
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2019, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :The present study was not designed to identify the exact mechanisms through which VitD may prevent lung fibrosis development and progression. Biological actions of VitD are mediated through the ability of the VDR to recruit coregulatory machines to its transactivation domain, including steroid receptor coactivators and thyroid hormone receptor-associated protein 220 (TRAP220) [6,7,50]. Through its ability to recruit steroid receptor coactivators, VitD has been shown to act as a steroid hormone and potentiate the anti-inflammatory effects of steroids [51], upregulate T-regulatory cells [52]and reduce the steroid resistance in patients with asthma [51].
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2016, Vitamins and HormonesCitation Excerpt :Traditional studies over several decades using reporter plasmid analyses facilitated the conclusion that 1,25(OH)2D3 is capable of regulating many vitamin D target genes including osteocalcin (Kerner, Scott, & Pike, 1989; Ozono, Liao, Kerner, Scott, & Pike, 1990), osteopontin (Nilsson et al., 2005), and Cyp24a1 (Ohyama et al., 1994; Zierold, Darwish, & DeLuca, 1995). These studies coupled with the extensive use of electrophoretic mobility shift and other analyses identified key features of the VDR's DNA-binding sites, termed vitamin D response elements or VDREs, and the participation of RXR as a heterodimer partner essential for adequate DNA-binding affinity (Pike & Meyer, 2014; Pike et al., 2010). However, despite the fact that many of these interactions at target genes have been confirmed via the application of chromatin immunoprecipitation analysis (ChIP) (Kim, Shevde, & Pike, 2005), this latter technique was unable to provide sought after confirmation for many gene promoters and more importantly failed to identify mechanisms that mediated regulation for genes such as Tnfsf11 (RANKL), Vdr, and numerous others as well.
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Special issue selected article from the 14th Vitamin D Workshop held at Brugge, Belgium on October 4–8, 2009.