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Proceedings of the 5Th International Symposium on Vitamin D and Analogs in Cancer Prevention and Therapy

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Proceedings of the 5Th International Symposium on Vitamin D and Analogs in Cancer Prevention and Therapy ANTICANCER RESEARCH 35: 1143-1218 (2015) PROCEEDINGS OF THE 5TH INTERNATIONAL SYMPOSIUM ON VITAMIN D AND ANALOGS IN CANCER PREVENTION AND THERAPY 2-3 May, 2014 Krefeld, Germany Local Organizing Committee J. Reichrath1 M. Friedrich2 Th. Vogt1 1Department of Dermatology, Venerology and Allergology, The Saarland University Hospital, Homburg/Saar, Germany; 2Department of Obstetrics and Gynecology, HELIOS Hospital, Krefeld, Germany ANTICANCER RESEARCH 35: 1143-1152 (2015) Review What Do We Learn from the Genome-wide Perspective on Vitamin D3? CARSTEN CARLBERG School of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland Abstract. Vitamin D3 insufficiency is associated with a cell type that sum-up to more than 23,000 non-overlapping number of diseases, such as cancer and autoimmune loci of the receptor. After ligand stimulation VDR associates disorders. This important medical problem leads to the with many new binding loci, of which the most important have question, whether an insight into the genome-wide actions of a higher rate of DR3-type VDR binding sequences than the transcription factor vitamin D receptor (VDR) and its high average sites. On the majority of latter VDR interacts directly affinity ligand 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) can or indirectly with genomic DNA in a presently uncharacterized help in a more global appreciation of the physiological impact fashion. Formaldehyde-assisted isolation of regulatory of vitamin D3. Chromatin immunoprecipitation sequencing elements sequencing (FAIRE-seq) monitors the dynamically (ChIP-seq) studies in 6 human cell culture models opening chromatin regions after 1,25(OH)2D3 stimulation. The demonstrated 1,000 to 10,000 genomic VDR binding sites per integration of ChIP-seq and FAIRE-seq data combined with a screening for DR3-type sequences facilitates the identification of key VDR binding sites and primary 1,25(OH)2D3 target genes. Recent results of the FANTOM5 project strongly Abbreviations: 1,25(OH)2D3: 1α,25-dihydroxyvitamin D3; suggest a shift from in vitro cell culture experiments to 25(OH)D : 25-hydroxyvitamin D ; ASAP2: ArfGAP with SH3 3 3 primary human cells stimulated in vivo. First results suggest domain, ankyrin repeat and PH domain 2; CBS: cystathionine β- synthase; CCNC: cyclin C; CD14: CD14 molecule; CDKN1A: that both the number of genome-wide VDR binding sites and cyclin-dependent kinase inhibitor 1A; ChIA-PET: chromatin the expression of VDR target genes correlate with vitamin D interaction analysis by paired-end tag sequencing; ChIP: chromatin status of the studied human individuals. In conclusion, a immunoprecipitation; ChIP-seq: ChIP sequencing; CTCF: CCCTC- genome-wide overview provides a broader basis for binding factor; CYP: cytochrome P450; DR3: direct repeat spaced addressing vitamin D’s role in health and disease. by 3 nucleotides; DUSP10: dual specificity phosphatase 10; FAIRE- seq: formaldehyde-assisted isolation of regulatory elements Vitamin D is a pleiotropic signaling molecule, which is sequencing; FANTOM: functional annotation of the mammalian 3 genome HOMER: hypergeometric optimization of motif enrichment involved in the regulation of a large number of physiological IGV: Integrative Genomics Viewer; LPS: lipopolysaccharide; LRP5: processes, such as bone formation, immune function and low density lipoprotein receptor-related protein 5; MACS: model- cellular growth and differentiation (6, 8, 26, 54). Via binding based analysis of ChIP-seq data; MYC: v-myc avian to and activation of the transcription factor VDR the myelocytomatosis viral oncogene homolog; NRIP1: nuclear biologically active form of vitamin D3, 1,25(OH)2D3, has a receptor interacting protein 1; PBMC: peripheral blood direct effect on the transcriptional regulation of the genome. mononuclear cell; RXR: retinoid X receptor; TBP: TATA box Since VDR is the only protein that binds 1,25(OH) D with binding protein; TNFSF11: tumor necrosis factor (ligand) 2 3 superfamily, member 11; TRPV6: transient receptor potential cation high-affinity (17), the genomic effects of vitamin D are a channel, subfamily V, member 6; TSS: transcription start site; VDR: subset of those exerted by its nuclear receptor. VDR is one of vitamin D receptor. some 1,900 human transcription factors (55), but within these it plays a special role, since it belongs to the few Correspondence to: Prof. Carsten Carlberg, School of Medicine, dozens proteins that are specifically activated by lipophilic Institute of Biomedicine, University of Eastern Finland, POB 1627, molecules directly reaching the cell nucleus (4). Therefore, FIN-70210 Kuopio. Tel: +358 403553062, e-mail: carsten. the signal transduction by vitamin D /1,25(OH) D is in [email protected] 3 2 3 contrast to that of hydrophilic signaling molecules, such as Key Words: Vitamin D insuffiency, genome-wide research, vitamin peptide hormones, growth factors and cytokines, a rather D receptor, 1,25(OH)2D3, ChIP-seq, review straightforward process. In addition, VDR is expressed in 0250-7005/2015 $2.00+.40 1143 ANTICANCER RESEARCH 35: 1143-1152 (2015) Table I. Number of VDR ChIP-seq peaks in human cellular models. The raw data of six publically available VDR ChIP-seq experiments had been re-analyzed under identical settings (49). The resulting number of significant VDR peaks is reported in bold, while the originally reported peaks is indicated in brackets. ND, Not determined. Publication Year Human cell Type Name Unstimulated VDR peaks Ligand-stimulated VDR peaks Ramagopalan et al. (36) 2010 B cells GM10855 3,144 (623) 6,172 (2,776) GM10861 4,072 (623) 12,448 (2,776) Heikkinen et al. (19) 2011 Monocytes THP-1 613 (1,169) 774 (1,820) Meyer et al. (29) 2012 Colon carcinoma LS180 165 (262) 3,777 (2,209) Ding et al. (9) 2013 Hepatic stellate LX2 1,474 (ND) 1,532 (6,281) Tuoresmäki et al. (49) 2014 Macrophages LPS-THP-1 529 955 most human tissues and cell types (57). This suggests that nucleotides, so-called “sequence tags”, of the investigated understanding of the actions of VDR on a genome-wide level genomic regions. However, the length of these tags is will lead to a comprehensive insight on the genomic effects sufficient to locate them back to their origin in the genome of of vitamin D in health and disease. the species, in which the experiment had been originally This review discusses how the understanding of vitamin performed. The accumulation of sequence tags to a genomic D signaling has changed and improved during the last years region looks like a peak, when it is visualized via a genome based on the knowledge of the genome-wide locations of browser, such as the Integrative Genome Viewer (IGV). So- VDR in a number of key human cell types. called “peak calling software”, such as MACS, is then applied to identify those regions within the genome, where Monitoring Genomic VDR Loci the peaks are significantly above the signal of a control, such as the input of the ChIP reaction (Figure 1). The specific ChIP is a method that is used since more than 10 years (33), peaks mark in this way the genomic loci of the investigated in order to monitor the genomic location of transcription nuclear protein (14, 35). It should be noted that ChIP-seq factors. The core of the technique is a physical cross-linking peaks represent in most cases the average of a signal from between nuclear proteins and genomic DNA and a sonication millions of cells. Therefore, the ChIP signal of an individual of chromatin into small fragments in the size of 200-400 bp. cell can differ from the often heterogeneous average. A precipitation step with an antibody specific for a nuclear VDR belongs to those nuclear receptors, for which the protein of choice (for example against VDR) and a reverse complex formation with genomic DNA depends on the cross-linking allows the enrichment for those regions of the absence or presence of their specific ligand. Therefore, the genome that, at the time of the crosslinking, had been in VDR ChIP-seq signal from 1,25(OH)2D3-treated cells differs complex with the chosen nuclear protein (27). from those that were not stimulated. Figure 1 illustrates three The specific enrichment of a chosen genomic region in scenarios, where 1,25(OH)2D3 stimulation either leads to i) a reference to a negative control region can be monitored by strong induction of VDR binding, such as illustrated for the quantitative PCR (ChIP-qPCR). This approach had been locus of the known VDR target gene ASAP2 (45) (Figure successfully used in the past for the study of the regulatory 1A), ii) no significant differences, such as those regions of known primary VDR target genes, such as CYP24A1 demonstrated for the transcription start site (TSS) of the TBP (52), CYP27B1 (50), CCNC (46) and CDKN1A (40, 41). For a gene (Figure 1B) or iii) a down-regulation of VDR binding, short while also the use of tiled microarrays, so-called “chips”, as shown for the VDR site of the MYC gene (Figure 1C). The was popular for the identification of enriched chromatin latter example demonstrates that VDR also acts in the fragments (ChIP-chip) and allowed for identification of VDR absence of its ligand and, in fact, the MYC gene is down- binding sites of the mouse genes Vdr (60), Trpv6 (30), Lrp5 regulated by 1,25(OH)2D3 (48). (12), Tnfsf11 (also known as Rankl) (24), Cyp24a1 (28) and At present (August 2014) VDR ChIP-seq data are Cbs (25). However, PCR and microarrays are based on nucleic publically available for 6 human cellular models. These are acid hybridization, which could cause a bias for certain the immortalized lymphoblastoid cell lines GM10855 and genomic regions, since the efficiency of these methods varies GM10861 (36), THP-1 monocyte-like cells (19), with the investigated sequence.
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