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. 2015 Apr 8;10(4):e0119605.
doi: 10.1371/journal.pone.0119605. eCollection 2015.

EBNA2 binds to genomic intervals associated with multiple sclerosis and overlaps with vitamin D receptor occupancy

Vito A G Ricigliano  1 , Adam E Handel  2 , Geir K Sandve  3 , Viviana Annibali  4 , Giovanni Ristori  4 , Rosella Mechelli  4 , M Zameel Cader  5 , Marco Salvetti  4
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EBNA2 binds to genomic intervals associated with multiple sclerosis and overlaps with vitamin D receptor occupancy

Vito A G Ricigliano et al. PLoS One. .

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 <0.001). Furthermore, MS susceptibility regions are preferentially targeted by both EBNA2 and VDR than by EBNA2 alone (enrichment difference = 1.722-fold, p = 0.0267). Taken together, these findings demonstrate that EBV participates in the gene-environment interactions that predispose to MS.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Histogram plots of VDR, RBPJ and DNase peak distribution centered on EBNA2 peak position.
In similar analyses, when the position of two factors (e.g., co-factors) across the genome tends to coincide, the correspondent graph shows a clear middle-point peak, as seen for the relation between EBNA2 and RBPJ (plot in the middle). Refer to the text for interpretation.
See this image and copyright information in PMC

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Grants and 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.
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