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

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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