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

Ricigliano VA, Handel AE, Sandve GK, Annibali V, Ristori G, Mechelli R, Cader MZ, Salvetti M - PLoS ONE (2015)

Bottom Line: 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.Taken together, these findings demonstrate that EBV participates in the gene-environment interactions that predispose to MS.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; Neuroimmunology Unit, Fondazione Santa Lucia (I.R.C.C.S.), Rome, Italy.

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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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.
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pone.0119605.g001: 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.

Mentions: We observed that VDR binding sites are strikingly enriched for EBNA2 peaks (O/E = 96.16-fold, p < 2.0e-05;) even after controlling for DHSs track (p = 9.99e-04). EBNA2-VDR propensity to localize in similar genomic regions was confirmed by the analysis of VDR peak distribution around EBNA2 peak position (Fig. 1).


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

Ricigliano VA, Handel AE, Sandve GK, Annibali V, Ristori G, Mechelli R, Cader MZ, Salvetti M - PLoS ONE (2015)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390304&req=5

pone.0119605.g001: 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.
Mentions: We observed that VDR binding sites are strikingly enriched for EBNA2 peaks (O/E = 96.16-fold, p < 2.0e-05;) even after controlling for DHSs track (p = 9.99e-04). EBNA2-VDR propensity to localize in similar genomic regions was confirmed by the analysis of VDR peak distribution around EBNA2 peak position (Fig. 1).

Bottom Line: 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.Taken together, these findings demonstrate that EBV participates in the gene-environment interactions that predispose to MS.

View Article: PubMed Central - PubMed

Affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; Neuroimmunology Unit, Fondazione Santa Lucia (I.R.C.C.S.), Rome, Italy.

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.

Show MeSH
Related in: MedlinePlus