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EBNA2 Binds to Genomic Intervals Associated with Multiple Sclerosis and Overlaps with Vitamin D Receptor Occupancy

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EBNA2 Binds to Genomic Intervals Associated with Multiple Sclerosis and Overlaps with Vitamin D Receptor Occupancy RESEARCH ARTICLE 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 Abstract Citation: Ricigliano VAG, Handel AE, Sandve GK, Annibali V, Ristori G, Mechelli R, et al. (2015) EBNA2 Epstein-Barr virus (EBV) is a non-heritable factor that associates with multiple sclerosis Binds to Genomic Intervals Associated with Multiple (MS). However its causal relationship with the disease is still unclear. The virus establishes Sclerosis and Overlaps with Vitamin D Receptor a complex co-existence with the host that includes regulatory influences on gene expres- Occupancy. PLoS ONE 10(4): e0119605. doi:10.1371/journal.pone.0119605 sion. 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 Academic Editor: Makoto Makishima, Nihon University School of Medicine, JAPAN (EBNA2, a protein that recent works by our and other groups have implicated in disease de- velopment) binding inside MS associated genomic intervals. We found that EBNA2 binding Received: October 7, 2014 occurs within MS susceptibility sites more than expected by chance (factor of observed vs Accepted: January 14, 2015 expected overlap [O/E] = 5.392-fold, p < 2.0e-05). This remains significant after controlling Published: April 8, 2015 for multiple genomic confounders. We then asked whether this observation is significant per Copyright: © 2015 Ricigliano et al. This is an open se or should also be viewed in the context of other disease relevant gene-environment inter- access article distributed under the terms of the actions, such as those attributable to vitamin D. We therefore verified the overlap between Creative Commons Attribution License, which permits EBNA2 genomic occupancy and vitamin D receptor (VDR) binding sites. EBNA2 shows a unrestricted use, distribution, and reproduction in any < medium, provided the original author and source are striking overlap with VDR binding sites (O/E = 96.16-fold, p 2.0e-05), even after control- credited. ling for the chromatin accessibility state of shared regions (p <0.001). Furthermore, MS sus- Data Availability Statement: All relevant data are ceptibility regions are preferentially targeted by both EBNA2 and VDR than by EBNA2 within the paper and its Supporting Information files. alone (enrichment difference = 1.722-fold, p = 0.0267). Taken together, these findings dem- Funding: M.Z.C. is supported by Oxford Biomedical onstrate that EBV participates in the gene-environment interactions that predispose to MS. 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. Introduction Competing Interests: The authors have declared Epstein-Barr virus (EBV) is associated with the development of multiple sclerosis (MS), as sup- that no competing interests exist. ported by epidemiological surveys, serological evidences and other experimental laboratory PLOS ONE | DOI:10.1371/journal.pone.0119605 April 8, 2015 1/11 EBNA2 Overlap with MS Associated Regions and VDR Binding Sites based studies [1–6]. However, its exact contribution to the pathogenesis of MS remains unclear. Investigating the possible interplay between EBV and genetic susceptibility factors identified by genome-wide association studies (GWAS) may help clarify its possible causative role. Re- cently, using a "candidate interactome" approach, our group has shown that the interaction be- tween disease-associated genetic variants and EBV proteins is relevant for MS etiology [7]. Viral proteins are able to bind DNA by means of direct [8] or indirect [9] interactions, and lo- calize to promoter and enhancer regions [10] in infected cells, thus affecting transcriptional programs [11]. Among EBV nuclear proteins, Epstein-Barr nuclear antigen 2 (EBNA2) plays a key role in B cell transformation. Furthermore, some evidences suggest its potential implication in MS pa- thology: EBNA2 expressing cells have been observed in affected brains [12] and specific EBNA2 genotypes associate with disease status [13]. However, so far no analyses have been performed to define whether EBNA2 preferentially controls the expression of genes associated with MS susceptibility. To fill this gap, using publicly available ChIP-seq data of lymphoblastoid cell lines (LCLs), we characterized the genomic distribution of EBNA2—and of its cognate factor recombination signal binding protein for immunoglobulin kappa J region (RBPJ)[9]—within disease-specific regions. We then investigated its potential interplay with vitamin D, another major environ- mental risk factor for MS, whose receptor (VDR) preferentially interacts with disease suscepti- bility regions in LCLs [14] and other immune cell types [15]. To study their relation on a genomic scale, we looked at the overlap between EBNA2 distribution and VDR occupancy both inside and outside of MS associated regions. Methods MS without major histocompatibility complex (MHC) single nucleotide polymorphisms (SNPs) were obtained from the latest published list of GWAS variants [16]; MS MHC SNPs in- cluded 2 Class II SNPs (rs3135388 and rs3135391) and 20 Class I SNPs contributing to MS risk independently of the HLA-DRB1Ã15:01 [17]. For the other disorders (obesity, UC, RA and SLE), we collected disease-associated SNPs from the ‘Catalog of Published Genome-Wide As- sociation Studies’ (http://www.genome.gov/gwastudies/)[18]. Only associations reported from GWAS with replication cohort were selected. Associated regions were defined as the genomic intervals of 25, 50, 100 and 150 kb centered on the MS associated SNPs. Genomic interval of 100 kb were considered for other disease- associated SNPs. GM12878 DNase I hypersensitive sites (DHSs) track and immune response gene track were extracted from ENCODE data [19] and the HyperBrowser track repository [20]. EBNA2 and RBPJ ChIP-seq raw data were obtained from a previous publication [9] and processed on the Lifeportal platform (https://lifeportal.uio.no). We used BWA [21] for Illu- mina to map sequences to the reference genome hg19 and MACS (Model-based analysis of ChIP-Seq) [22] for peak-calling. MACS parameters were defined as follows: default genome size, 26 bp tag size, 300 bp band width and a p-value cutoff for peak detection of 1e-05. Peaks with a false discovery rate (FDR) of <1% were selected. VDR genomic distribution was re- trieved from the literature [23]. All the analyses on processed ChIP-seq data and disease re- gions were performed using the Genomic HyperBrowser (http://hyperbrowser.uio.no/hb/) [20]. Enrichment between two different tracks was determined accordingly to what has been described elsewhere [14] and was expressed as the factor of observed vs expected overlap (O/E), which calculates the degree of coverage by track A inside track B segments vs outside them. PLOS ONE | DOI:10.1371/journal.pone.0119605 April 8, 2015 2/11 EBNA2 Overlap with MS Associated Regions and VDR Binding Sites In order to assess statistical significance, we defined a null model where the location of track A intervals varied randomly, while preserving inter-segment gaps distribution and segment lengths. Track B intervals were kept fixed. Overlap analysis between the tracks was measured on real data, as well as on 50.000 Monte Carlo samples from the null model. Statistical signifi- cance was taken at p<0.05. To estimate the overlap of ChIP-seq sites (EBNA2 or RBPJ) and MS associated regions rela- tive to that measured for other disorder-associated regions or for immune response gene re- gions, we generated case–control tracks for each disease pair (MS track-non MS track) and for the MS-immune response gene pair by discarding the overlapping segments between tracks and marking the remaining intervals as case (MS specific intervals) or control (other disorder specific intervals, immune response gene specific intervals). We then calculated the fold enrich- ment difference for the overlap with ChIP-seq regions between MS associated intervals vs control intervals. To control for any confounding effects of chromatin state (‘open’ vs ‘closed’)on EBNA2-MS, EBNA2-VDR and RBPJ-MS relations, we adjusted for confounding track GM12878 DHSs, using the strategy for confounder handling previously described [24]. In the statistical hypothesis testing, MS regions (or VDR segments, for the EBNA2-VDR relations) were kept fixed. Plots of VDR, RBPJ and DHSs peak distribution around EBNA2 peak position were drawn using Homer (http://homer.salk.edu/homer/ngs/quantification.html). Prediction of function of cis-regulatory regions for EBNA2, VDR and the joint overlap track EBNA2-VDR was performed using GREAT [25]. For binding motif analysis, we first enlarged the SNP position track (including both con- firmed MS SNPs and those in LD [r2 0.8] with them, obtained from SNAP [26] on CEU indi- viduals) of 100 bp on each side, in order to intersect it with RBPJ ChIP-seq peaks. We then used MEME and FIMO tools (http://meme.nbcr.net/meme/intro.html) to screen for potential disruptive effects of MS variants on the RBPJ motif.
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