A ChIP-seq defined genome-wide map of vitamin D receptor binding: Associations with disease and evolution

  1. Julian C. Knight1,7
  1. 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Headington, Oxford OX3 7BN, United Kingdom;
  2. 2 Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom;
  3. 3 Blizard Institute of Cell and Molecular Science, Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London E1 2AT, United Kingdom;
  4. 4 MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, United Kingdom;
  5. 5 Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada
    1. 6 These authors contributed equally to this work.

    Abstract

    Initially thought to play a restricted role in calcium homeostasis, the pleiotropic actions of vitamin D in biology and their clinical significance are only now becoming apparent. However, the mode of action of vitamin D, through its cognate nuclear vitamin D receptor (VDR), and its contribution to diverse disorders, remain poorly understood. We determined VDR binding throughout the human genome using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq). After calcitriol stimulation, we identified 2776 genomic positions occupied by the VDR and 229 genes with significant changes in expression in response to vitamin D. VDR binding sites were significantly enriched near autoimmune and cancer associated genes identified from genome-wide association (GWA) studies. Notable genes with VDR binding included IRF8, associated with MS, and PTPN2 associated with Crohn's disease and T1D. Furthermore, a number of single nucleotide polymorphism associations from GWA were located directly within VDR binding intervals, for example, rs13385731 associated with SLE and rs947474 associated with T1D. We also observed significant enrichment of VDR intervals within regions of positive selection among individuals of Asian and European descent. ChIP-seq determination of transcription factor binding, in combination with GWA data, provides a powerful approach to further understanding the molecular bases of complex diseases.

    Footnotes

    • 7 Corresponding authors.

      E-mail sreeramr{at}well.ox.ac.uk; fax 44-1865-287501.

      E-mail george.ebers{at}clneuro.ox.ac.uk; fax 44-1865-231914.

      E-mail julian{at}well.ox.ac.uk; fax 44-1865-231914.

    • [Supplemental material is available online at http://www.genome.org. The sequence data from this study have been submitted to the NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under series accession nos. GSE22484 and GSE22176, respectively.]

    • Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.107920.110.

    • Received March 16, 2010.
    • Accepted July 13, 2010.

    Freely available online through the Genome Research Open Access option.

    | Table of Contents
    OPEN ACCESS ARTICLE

    Preprint Server