EBNA2 Binds to Genomic Intervals Associated with Multiple Sclerosis and Overlaps with Vitamin D Receptor Occupancy Vito A. G. Ricigliano1,2, Adam E. Handel3,4, Geir K. Sandve5, Viviana Annibali6, Giovanni Ristori6, Rosella Mechelli6*, M. Zameel Cader1, Marco Salvetti6 1 Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom, 2 Neuroimmunology Unit, Fondazione Santa Lucia (I.R.C.C.S.), Rome, Italy, 3 Medical Research Council Functional Genomics Unit and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, United Kingdom, 4 Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom, 5 Department of Informatics, University of Oslo, Blindern, Norway, 6 Centre for Experimental Neurological Therapies (CENTERS), Neurology and Department of Neuroscience, Mental Health and Sensory Organs, Faculty of Medicine and Psychology, “Sapienza” University of Rome, Rome, Italy * [email protected]
OPEN ACCESS Citation: Ricigliano VAG, Handel AE, Sandve GK, Annibali V, Ristori G, Mechelli R, et al. (2015) EBNA2 Binds to Genomic Intervals Associated with Multiple Sclerosis and Overlaps with Vitamin D Receptor Occupancy. PLoS ONE 10(4): e0119605. doi:10.1371/journal.pone.0119605 Academic Editor: Makoto Makishima, Nihon University School of Medicine, JAPAN Received: October 7, 2014 Accepted: January 14, 2015 Published: April 8, 2015 Copyright: © 2015 Ricigliano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: M.Z.C. is supported by Oxford Biomedical Research Centre; M.S. is supported by Fondazione Italiana Sclerosi Multipla (grant number 2011/R/31). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.
Abstract Epstein-Barr virus (EBV) is a non-heritable factor that associates with multiple sclerosis (MS). However its causal relationship with the disease is still unclear. The virus establishes a complex co-existence with the host that includes regulatory influences on gene expression. Hence, if EBV contributes to the pathogenesis of MS it may do so by interacting with disease predisposing genes. To verify this hypothesis we evaluated EBV nuclear antigen 2 (EBNA2, a protein that recent works by our and other groups have implicated in disease development) binding inside MS associated genomic intervals. We found that EBNA2 binding occurs within MS susceptibility sites more than expected by chance (factor of observed vs expected overlap [O/E] = 5.392-fold, p < 2.0e-05). This remains significant after controlling for multiple genomic confounders. We then asked whether this observation is significant per se or should also be viewed in the context of other disease relevant gene-environment interactions, such as those attributable to vitamin D. We therefore verified the overlap between EBNA2 genomic occupancy and vitamin D receptor (VDR) binding sites. EBNA2 shows a striking overlap with VDR binding sites (O/E = 96.16-fold, p < 2.0e-05), even after controlling for the chromatin accessibility state of shared regions (p