Schibeci, S. D. | Search bioRxiv

bioRxiv2020

Age-dependent VDR peak DNA methylation as a mechanism for latitude-dependent MS risk

BackgroundThe mechanisms linking UV radiation and vitamin D exposure to the risk of acquiring the latitude and critical period dependent autoimmune disease, multiple sclerosis, is unclear. We examined the effect of vitamin D on DNA methylation as well as DNA methylation at vitamin D receptor binding sites in adult and paediatric myeloid cells. ResultsVery few DNA methylation changes occurred in adult and paediatric cells treated with calcitriol. However, several VDR binding sites across the genome demonstrated increased DNA methylation in cells of adult origin. Genes associated with these VDR binding sites were enriched for intracellular signalling and cell activation pathways, suggesting that age-dependent potential for myeloid cell differentiation and adaptive immune system regulation may be encoded for by DNA methylation. ConclusionsThese results suggest vitamin D exposure at critical periods in immune system development may contribute to the well characterised latitude related differences in autoimmune disease incidence.

genetics↗

bioRxiv2018

Genetic evidence that the latency III stage of Epstein-Barr Virus infection is a therapeutic target for Multiple Sclerosis

Genome wide association studies have identified >200 susceptibility loci accounting for much of the heritability of Multiple Sclerosis (MS). Epstein Barr virus (EBV), a memory B cell tropic virus, has been identified as necessary but not sufficient for development of MS, with evidence for disease causation. The molecular and immunological basis for this has not been established. LCL proliferation is driven by signalling through the EBV produced cell surface protein LMP1, a homologue of the MS risk gene CD40. We show that the CD40 ligand, CD40L, potentially through competitive signalling with LMP1, reduces LCL proliferation (p<0.001). The MS risk variants of the LMP1 signalling inhibitor, TRAF3, had altered expression in B cells and LCLs. Both CD40 and TRAF3 risk SNPs are in binding sites for the EBV transcription factor EBNA2. We have investigated transcriptomes of B cells and EBV infected B cells at Latency III (LCLs) and identified 47 MS risk genes with altered expression, associated with the risk genotype. Overall these MS risk SNPs were overrepresented in target loci of the EBV transcription factor EBNA2 (p<10-16), in genes dysregulated between B and LCLs (p<10-5), and as targets for EBV miRNAs (p<10-4). The risk gene ZC3HAV1 is the putative target for multiple EBV miRNAs. It amplifies the interferon response, and was shown to have reduced expression in LCLs for the risk allele. These data indicate targeting EBV EBNA2, miRNAs, and MS risk genes on the LMP1/LMP2 pathways, and the pathways themselves, may be of therapeutic benefit in MS.

genomics↗