Genome-wide (over)view on the actions of vitamin D

Carsten Carlberg, Carsten Carlberg

Abstract

For a global understanding of the physiological impact of the nuclear hormone 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) the analysis of the genome-wide locations of its high affinity receptor, the transcription factor vitamin D receptor (VDR), is essential. Chromatin immunoprecipitation sequencing (ChIP-seq) in GM10855 and GM10861 lymphoblastoid cells, undifferentiated and lipopolysaccharide-differentiated THP-1 monocytes, LS180 colorectal cancer cells and LX2 hepatic stellate cells revealed between 1000 and 13,000 VDR-specific genomic binding sites. The harmonized analysis of these ChIP-seq datasets indicates that the mechanistic basis for the action of the VDR is independent of the cell type. Formaldehyde-assisted isolation of regulatory elements sequencing (FAIRE-seq) data highlight accessible chromatin regions, which are under control of 1,25(OH)2D3. In addition, public data, such as from the ENCODE project, allow to relate the genome-wide actions of VDR and 1,25(OH)2D3 to those of other proteins within the nucleus. For example, locations of the insulator protein CTCF suggest a segregation of the human genome into chromatin domains, of which more than 1000 contain at least one VDR binding site. The integration of all these genome-wide data facilitates the identification of the most important VDR binding sites and associated primary 1,25(OH)2D3 target genes. Expression changes of these key genes can serve as biomarkers for the actions of vitamin D3 and its metabolites in different tissues and cell types of human individuals. Analysis of primary tissues obtained from vitamin D3 intervention studies using such markers indicated a large inter-individual variation for the efficiency of vitamin D3 supplementation. In conclusion, a genome-wide (over)view on the genomic locations of VDR provides a broader basis for addressing vitamin D's role in health and disease.

Keywords: chromatin; epigenomics; gene regulation; genomics; vitamin D; vitamin D receptor.

Figures

Figure 1
Figure 1
Conserved genomic VDR binding in six cellular models. The Integrative Genomics Viewer (IGV) browser (Robinson et al., 2011) was used to visualize the VDR binding site 15.3 kb downstream of the ZMIZ1 TSS. The peak tracks display data from VDR ChIP-seq datasets from two B cell-like cells (dark and light blue), monocyte-like cells (red), macrophage-like cells (orange), colon cells (gray) and liver cells (violet). The cells were either unstimulated (−) or treated with VDR ligand (+). The gene structures are shown in blue and the sequence of the DR3-type element below the summit of the VDR peak is indicated.
Figure 2
Figure 2
Genomic view of 1,25(OH)2D3-dependent chromatin opening. The IGV browser visualizes the loci of a VDR locus 225 kb downstream of the CHD7 gene (±40 kb of the peak summit). The peak tracks display data from THP-1 cells: a time course of FAIRE-seq data [gray for EtOH-treated controls and turquoise for 1,25(OH)2D3 (1,25D) treatments for the indicated time periods] and a VDR ChIP-seq data [red, from unstimulated cells and after 40 min 1,25(OH)2D3 treatment]. The gene structures are shown in blue and the sequence of the DR3-type element below the summit of the VDR peak is indicated.
Figure 3
Figure 3
Chromatin domain containing VDR binding sites. The IGV browser was used to display the chromatin domain around the CD14 gene. VDR ChIP-seq data from THP-1 cells [unstimulated (−) and treated for 40 min with 1,25(OH)2D3 (+), red] are shown in comparison with CTCF ChIP-seq data from the ENCODE cell lines NHEK, HUVEC and K562 (orange) and CTCF ChIA-PET data from K562 cells in the track view (light blue). The gene structures are shown in blue and the sequence of the DR3-type elements below the summits of the VDR peaks are indicated.

References

    1. Bouillon R., Suda T. (2014). Vitamin D: calcium and bone homeostasis during evolution. Bonekey Rep. 3:480 10.1038/bonekey.2013.214
    1. Carlberg C., Bendik I., Wyss A., Meier E., Sturzenbecker L. J., Grippo J. F., Hunziker W. (1993). Two nuclear signalling pathways for vitamin D. Nature 361, 657–660
    1. Carlberg C., Campbell M. J. (2013). Vitamin D receptor signaling mechanisms: integrated actions of a well-defined transcription factor. Steroids 78, 127–136 10.1016/j.steroids.2012.10.019
    1. Carlberg C., Molnár F. (2012). Current status of vitamin D signaling and its therapeutic applications. Curr. Top. Med. Chem. 12, 528–547 10.2174/156802612799436623
    1. Carlberg C., Seuter S., De Mello V. D., Schwab U., Voutilainen S., Pulkki K., et al. (2013). Primary vitamin D target genes allow a categorization of possible benefits of vitamin D3 supplementation. PLoS ONE 8:e71042 10.1371/journal.pone.0071042
    1. Crawford G. E., Holt I. E., Whittle J., Webb B. D., Tai D., Davis S., et al. (2006). Genome-wide mapping of DNase hypersensitive sites using massively parallel signature sequencing (MPSS). Genome Res. 16, 123–131 10.1101/gr.4074106
    1. Deluca H. F. (2004). Overview of general physiologic features and functions of vitamin D. Am. J. Clin. Nutr. 80, 1689S–1696S
    1. Ding N., Yu R. T., Subramaniam N., Sherman M. H., Wilson C., Rao R., et al. (2013). A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 153, 601–613 10.1016/j.cell.2013.03.028
    1. Encode-Project-Consortium. Bernstein B. E., Birney E., Dunham I., Green E. D., Gunter C., Snyder M. (2012). An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 10.1038/nature11247
    1. Engelman C. D., Fingerlin T. E., Langefeld C. D., Hicks P. J., Rich S. S., Wagenknecht L. E., et al. (2008). Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans. J. Clin. Endocrinol. Metab. 93, 3381–3388 10.1210/jc.2007-2702
    1. Fretz J. A., Zella L. A., Kim S., Shevde N. K., Pike J. W. (2007). 1,25-Dihydroxyvitamin D3 induces expression of the Wnt signaling co-regulator LRP5 via regulatory elements located significantly downstream of the gene's transcriptional start site. J. Steroid Biochem. Mol. Biol. 103, 440–445 10.1016/j.jsbmb.2006.11.018
    1. Fullwood M. J., Liu M. H., Pan Y. F., Liu J., Xu H., Mohamed Y. B., et al. (2009). An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 462, 58–64 10.1038/nature08497
    1. Furey T. S. (2012). ChIP-seq and beyond: new and improved methodologies to detect and characterize protein-DNA interactions. Nat. Rev. Genet. 13, 840–852 10.1038/nrg3306
    1. Giresi P. G., Kim J., McDaniell R. M., Iyer V. R., Lieb J. D. (2007). FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements) isolates active regulatory elements from human chromatin. Genome Res. 17, 877–885 10.1101/gr.5533506
    1. Handel A. E., Sandve G. K., Disanto G., Berlanga-Taylor A. J., Gallone G., Hanwell H., et al. (2013). Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease. BMC Med 11:163 10.1186/1741-7015-11-163
    1. Haussler M. R., Haussler C. A., Jurutka P. W., Thompson P. D., Hsieh J. C., Remus L. S., et al. (1997). The vitamin D hormone and its nuclear receptor: molecular actions and disease states. J. Endocrinol. 154(Suppl.), S57–S73
    1. Haussler M. R., Whitfield G. K., Kaneko I., Haussler C. A., Hsieh D., Hsieh J.-C., Jurutka P. W. (2013). Molecular mechanisms of vitamin D action. Calcif. Tissue Int. 92, 77–98 10.1007/s00223-012-9619-0
    1. Heikkinen S., Väisänen S., Pehkonen P., Seuter S., Benes V., Carlberg C. (2011). Nuclear hormone 1α,25-dihydroxyvitamin D3 elicits a genome-wide shift in the locations of VDR chromatin occupancy. Nucleic Acids Res. 39, 9181–9193 10.1093/nar/gkr654
    1. Heinz S., Benner C., Spann N., Bertolino E., Lin Y. C., Laslo P., et al. (2010). Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 10.1016/j.molcel.2010.05.004
    1. Hochberg Z., Templeton A. R. (2010). Evolutionary perspective in skin color, vitamin D and its receptor. Hormones (Athens) 9, 307–311 10.14310/horm.2002.1281
    1. Holick M. F. (2004). Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am. J. Clin. Nutr. 80, 1678S–1688S
    1. Holick M. F. (2007). Vitamin D deficiency. N. Engl. J. Med. 357, 266–281 10.1056/NEJMra070553
    1. Holick M. F. (2011). Vitamin D: evolutionary, physiological and health perspectives. Curr. Drug Targets 12, 4–18 10.2174/138945011793591635
    1. Hollis B. W. (2005). Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J. Nutr. 135, 317–322
    1. Institute-of-Medicine. (2011). Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press
    1. Jones G., Strugnell S. A., Deluca H. F. (1998). Current understanding of the molecular actions of vitamin D. Physiol. Rev. 78, 1193–1231
    1. Kadauke S., Blobel G. A. (2009). Chromatin loops in gene regulation. Biochim. Biophys. Acta 1789, 17–25 10.1016/j.bbagrm.2008.07.002
    1. Kim S., Yamazaki M., Zella L. A., Shevde N. K., Pike J. W. (2006). Activation of receptor activator of NF-kappaB ligand gene expression by 1,25-dihydroxyvitamin D3 is mediated through multiple long-range enhancers. Mol. Cell Biol. 26, 6469–6486 10.1128/MCB.00353-06
    1. Kriebitzsch C., Verlinden L., Eelen G., Van Schoor N. M., Swart K., Lips P., et al. (2011). 1,25-dihydroxyvitamin D3 influences cellular homocysteine levels in murine preosteoblastic MC3T3-E1 cells by direct regulation of cystathionine beta-synthase. J. Bone Miner. Res. 26, 2991–3000 10.1002/jbmr.493
    1. Mangelsdorf D. J., Thummel C., Beato M., Herrlich P., Schütz G., Umesono K., et al. (1995). The nuclear receptor superfamily: the second decade. Cell 83, 835–839
    1. Maston G. A., Landt S. G., Snyder M., Green M. R. (2012). Characterization of enhancer function from genome-wide analyses. Annu. Rev. Genomics Hum. Genet. 13, 29–57 10.1146/annurev-genom-090711-163723
    1. Meyer M. B., Goetsch P. D., Pike J. W. (2010). A downstream intergenic cluster of regulatory enhancers contributes to the induction of CYP24A1 expression by 1α,25-dihydroxyvitamin D3. J. Biol. Chem. 285, 15599–15610 10.1074/jbc.M110.119958
    1. Meyer M. B., Goetsch P. D., Pike J. W. (2012). VDR/RXR and TCF4/beta-catenin cistromes in colonic cells of colorectal tumor origin: impact on c-FOS and c-MYC gene expression. Mol. Endocrinol. 26, 37–51 10.1210/me.2011-1109
    1. Meyer M. B., Watanuki M., Kim S., Shevde N. K., Pike J. W. (2006). The human transient receptor potential vanilloid type 6 distal promoter contains multiple vitamin D receptor binding sites that mediate activation by 1,25-dihydroxyvitamin D3 in intestinal cells. Mol. Endocrinol. 20, 1447–1461 10.1210/me.2006-0031
    1. Misteli T. (2007). Beyond the sequence: cellular organization of genome function. Cell 128, 787–800 10.1016/j.cell.2007.01.028
    1. Mohn F., Schubeler D. (2009). Genetics and epigenetics: stability and plasticity during cellular differentiation. Trends Genet. 25, 129–136 10.1016/j.tig.2008.12.005
    1. Molnár F., Peräkylä M., Carlberg C. (2006). Vitamin D receptor agonists specifically modulate the volume of the ligand-binding pocket. J. Biol. Chem. 281, 10516–10526 10.1074/jbc.M513609200
    1. Moras D., Gronemeyer H. (1998). The nuclear receptor ligand-binding domain: structure and function. Curr. Opin. Cell Biol. 10, 384–391
    1. Narlikar G. J., Fan H. Y., Kingston R. E. (2002). Cooperation between complexes that regulate chromatin structure and transcription. Cell 108, 475–487 10.1016/S0092-8674(02)00654-2
    1. Norman A. W. (2008). From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. Am. J. Clin. Nutr. 88, 491S–499S
    1. Orlando V. (2000). Mapping chromosomal proteins in vivo by formaldehyde-crosslinked-chromatin immunoprecipitation. Trends Biochem. Sci. 25, 99–104 10.1016/S0968-0004(99)01535-2
    1. Orton S. M., Morris A. P., Herrera B. M., Ramagopalan S. V., Lincoln M. R., Chao M. J., et al. (2008). Evidence for genetic regulation of vitamin D status in twins with multiple sclerosis. Am. J. Clin. Nutr. 88, 441–447
    1. Park P. J. (2009). ChIP-seq: advantages and challenges of a maturing technology. Nat. Rev. Genet. 10, 669–680 10.1038/nrg2641
    1. Perissi V., Jepsen K., Glass C. K., Rosenfeld M. G. (2010). Deconstructing repression: evolving models of co-repressor action. Nat. Rev. Genet. 11, 109–123 10.1038/nrg2736
    1. Polly P., Herdick M., Moehren U., Baniahmad A., Heinzel T., Carlberg C. (2000). VDR-Alien: a novel, DNA-selective vitamin D3 receptor-corepressor partnership. FASEB J. 14, 1455–1463 10.1096/fj.14.10.1455
    1. Ramagopalan S. V., Heger A., Berlanga A. J., Maugeri N. J., Lincoln M. R., Burrell A., et al. (2010). A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res. 20, 1352–1360 10.1101/gr.107920.110
    1. Razin A. (1998). CpG methylation, chromatin structure and gene silencing-a three-way connection. EMBO J. 17, 4905–4908
    1. Robinson J. T., Thorvaldsdottir H., Winckler W., Guttman M., Lander E. S., Getz G., Mesirov J. P. (2011). Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 10.1038/nbt.1754
    1. Ryynänen J., Seuter S., Campbell M. J., Carlberg C. (2013). Gene regulatory scenarios of primary 1,25-dihydroxyvitamin D3 target genes in a human myeloid leukemia cell line. Cancers 5, 1221–1241 10.3390/cancers5041221
    1. Saramäki A., Banwell C. M., Campbell M. J., Carlberg C. (2006). Regulation of the human p21(waf1/cip1) gene promoter via multiple binding sites for p53 and the vitamin D3 receptor. Nucleic Acids Res. 34, 543–554 10.1093/nar/gkj460
    1. Saramäki A., Diermeier S., Kellner R., Laitinen H., Väisänen S., Carlberg C. (2009). Cyclical chromatin looping and transcription factor association on the regulatory regions of the p21 (CDKN1A) gene in response to 1α,25-dihydroxyvitamin D3. J. Biol. Chem. 284, 8073–8082 10.1074/jbc.M808090200
    1. Schmidt D., Schwalie P. C., Wilson M. D., Ballester B., Gonçalves A., Kutter C., et al. (2012). Waves of retrotransposon expansion remodel genome organization and CTCF binding in multiple mammalian lineages. Cell 148, 335–348 10.1016/j.cell.2011.11.058
    1. Schüle R., Umesono K., Mangelsdorf D. J., Bolado J., Pike J. W., Evans R. M. (1990). Jun-Fos and receptors for vitamins A and D recognize a common response element in the human osteocalcin gene. Cell 61, 497–504
    1. Seuter S., Neme A., Carlberg C. (2014). Characterization of genomic vitamin D receptor binding sites through chromatin looping and opening. PLoS ONE 9 10.1371/journal.pone.0096184
    1. Seuter S., Pehkonen P., Heikkinen S., Carlberg C. (2013). Dynamics of 1α,25-dihydroxyvitamin D-dependent chromatin accessibility of early vitamin D receptor target genes. Biochim. Biophys. Acta 1829, 1266–1275 10.1016/j.bbagrm.2013.10.003
    1. Seuter S., Väisänen S., Radmark O., Carlberg C., Steinhilber D. (2007). Functional characterization of vitamin D responding regions in the human 5-lipoxygenase gene. Biochim. Biophys. Acta 1771, 864–872 10.1016/j.bbalip.2007.04.007
    1. Shaffer P. L., Gewirth D. T. (2002). Structural basis of VDR-DNA interactions on direct repeat response elements. EMBO J. 21, 2242–2252 10.1093/emboj/21.9.2242
    1. Shaffer P. L., Gewirth D. T. (2004). Structural analysis of RXR-VDR interactions on DR3 DNA. J. Steroid Biochem. Mol. Biol. 89–90, 215–219 10.1016/j.jsbmb.2004.03.084
    1. Sierra J., Villagra A., Paredes R., Cruzat F., Gutierrez S., Javed A., et al. (2003). Regulation of the bone-specific osteocalcin gene by p300 requires Runx2/Cbfa1 and the vitamin D3 receptor but not p300 intrinsic histone acetyltransferase activity. Mol. Cell Biol. 23, 3339–3351 10.1128/MCB.23.9.3339-3351.2003
    1. Sinkkonen L., Malinen M., Saavalainen K., Väisänen S., Carlberg C. (2005). Regulation of the human cyclin C gene via multiple vitamin D3-responsive regions in its promoter. Nucleic Acids Res. 33, 2440–2451 10.1093/nar/gki502
    1. Snellman G., Melhus H., Gedeborg R., Olofsson S., Wolk A., Pedersen N. L., et al. (2009). Seasonal genetic influence on serum 25-hydroxyvitamin D levels: a twin study. PLoS ONE 4:e7747 10.1371/journal.pone.0007747
    1. Sone T., Ozono K., Pike J. W. (1991). A 55-kilodalton accessory factor facilitates vitamin D receptor DNA binding. Mol Endocrinol 5, 1578–1586
    1. Standahl Olsen K., Rylander C., Brustad M., Aksnes L., Lund E. (2013). Plasma 25 hydroxyvitamin D level and blood gene expression profiles: a cross-sectional study of the Norwegian women and cancer post-genome cohort. Eur. J. Clin. Nutr. 67, 773–778 10.1038/ejcn.2013.53
    1. Talbert P. B., Henikoff S. (2006). Spreading of silent chromatin: inaction at a distance. Nat. Rev. Genet. 7, 793–803 10.1038/nrg1920
    1. Tolon R. M., Castillo A. I., Jimenez-Lara A. M., Aranda A. (2000). Association with ets-1 causes ligand- and AF2-independent activation of nuclear receptors. Mol. Cell Biol. 20, 8793–8802 10.1128/MCB.20.23.8793-8802.2000
    1. Toropainen S., Väisänen S., Heikkinen S., Carlberg C. (2010). The down-regulation of the human MYC gene by the nuclear hormone 1α,25-dihydroxyvitamin D3 is associated with cycling of corepressors and histone deacetylases. J. Mol. Biol. 400, 284–294 10.1016/j.jmb.2010.05.031
    1. Tuoresmäki P., Väisänen S., Neme A., Heikkinen S., Carlberg C. (2014). Patterns of genome-wide VDR locations. PLoS ONE 9 10.1371/journal.pone.0096105
    1. Turunen M. M., Dunlop T. W., Carlberg C., Väisänen S. (2007). Selective use of multiple vitamin D response elements underlies the 1α,25-dihydroxyvitamin D3-mediated negative regulation of the human CYP27B1 gene. Nucleic Acids Res 35, 2734–2747 10.1093/nar/gkm179
    1. Umesono K., Murakami K. K., Thompson C. C., Evans R. M. (1991). Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell 65, 1255–1266
    1. Väisänen S., Dunlop T. W., Sinkkonen L., Frank C., Carlberg C. (2005). Spatio-temporal activation of chromatin on the human CYP24 gene promoter in the presence of 1α,25-dihydroxyvitamin D3. J. Mol. Biol. 350, 65–77 10.1016/j.jmb.2005.04.057
    1. Van Bortle K., Corces V. G. (2013). The role of chromatin insulators in nuclear architecture and genome function. Curr. Opin. Genet. Dev. 23, 212–218 10.1016/j.gde.2012.11.003
    1. Vaquerizas J. M., Kummerfeld S. K., Teichmann S. A., Luscombe N. M. (2009). A census of human transcription factors: function, expression and evolution. Nat. Rev. Genet. 10, 252–263 10.1038/nrg2538
    1. Virtanen J. K., Nurmi T., Voutilainen S., Mursu J., Tuomainen T. P. (2011). Association of serum 25-hydroxyvitamin D with the risk of death in a general older population in Finland. Eur. J. Nutr. 50, 305–312 10.1007/s00394-010-0138-3
    1. Wang Y., Zhu J., Deluca H. F. (2012). Where is the vitamin D receptor? Arch. Biochem. Biophys. 523, 123–133 10.1016/j.abb.2012.04.001
    1. Zaret K. S., Carroll J. S. (2011). Pioneer transcription factors: establishing competence for gene expression. Gen. Dev. 25, 2227–2241 10.1101/gad.176826.111
    1. Zella L. A., Kim S., Shevde N. K., Pike J. W. (2006). Enhancers located within two introns of the vitamin D receptor gene mediate transcriptional autoregulation by 1,25-dihydroxyvitamin D3. Mol. Endocrinol. 20, 1231–1247 10.1210/me.2006-0015
    1. Zella L. A., Meyer M. B., Nerenz R. D., Lee S. M., Martowicz M. L., Pike J. W. (2010). Multifunctional enhancers regulate mouse and human vitamin D receptor gene transcription. Mol. Endocrinol. 24, 128–147 10.1210/me.2009-0140

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