MS risk loci are underrepresented in EBV induced DNA hypomethylation
ECTRIMS Online Library. Ong L. 09/12/19; 279501; 221
Lawrence Ong
Lawrence Ong
Contributions
Abstract

Abstract: 221

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics

L. Ong, G. Parnell, G. Stewart, D. Booth

Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia

Introduction: EBV infection causes widespread dysregulation of DNA methylation in human immune cells and is also a risk factor for autoimmune diseases including multiple sclerosis. Genome wide association studies in MS have found >200 loci associated with increased risk of disease. A large proportion are known to be associated with immune function. A subset of these are also known to be associated with gene expression in B cells latently infected with EBV (resulting in immortalised lymphoblastoid cell lines, LCLs). We therefore hypothesised that these loci would demonstrate marked changes in DNA methylation in LCLs when compared to activated B cells.
Aims & Objectives: To determine whether EBV induced DNA methylation changes are over-represented in loci associated with multiple sclerosis.
Methods: We reanalysed extant whole genome bisulfite sequencing data from cells derived from three individuals, namely lymphoblastoid cell lines, CD40L activated B cells and resting B cells. We calculated average methylation values across 1kb tiles centred upon immune, B cell and control loci and compared these across cell subsets. Regions with a methylation difference of >0.2 were considered to be differentially methylated.
Results: We confirmed that EBV infection results in widespread DNA hypomethylation relative to resting B cells and CD40L activated B cells. Differentially methylated regions were found to be underrepresented at loci important in immune and particularly B cell function compared to genome wide 1kb tiles or a control set of loci not specifically associated with immune disease. This underrepresentation was independent of the B cell activation state. Gene promoters did not appear to be affected by dysregulation of DNA methylation.
Conclusions: The role of DNA methylation dysregulation in LCLs is unclear, but this phenomenon appears to be biased against loci important in B cell and immune function. Given the rapid proliferation of LCLs, one would expect precisely these loci to demonstrate greater degrees of dysregulation. DNA methylation dysregulation at MS GWAS risk loci in response to latent EBV infection does not appear to play a role in the pathogenesis of multiple sclerosis.
Disclosure:
Lawrence Ong: Nothing to disclose
Grant Parnell: Nothing to disclose
Graeme Stewart: Nothing to disclose
David Booth: Nothing to disclose

Abstract: 221

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - Genetics/Epigenetics

L. Ong, G. Parnell, G. Stewart, D. Booth

Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia

Introduction: EBV infection causes widespread dysregulation of DNA methylation in human immune cells and is also a risk factor for autoimmune diseases including multiple sclerosis. Genome wide association studies in MS have found >200 loci associated with increased risk of disease. A large proportion are known to be associated with immune function. A subset of these are also known to be associated with gene expression in B cells latently infected with EBV (resulting in immortalised lymphoblastoid cell lines, LCLs). We therefore hypothesised that these loci would demonstrate marked changes in DNA methylation in LCLs when compared to activated B cells.
Aims & Objectives: To determine whether EBV induced DNA methylation changes are over-represented in loci associated with multiple sclerosis.
Methods: We reanalysed extant whole genome bisulfite sequencing data from cells derived from three individuals, namely lymphoblastoid cell lines, CD40L activated B cells and resting B cells. We calculated average methylation values across 1kb tiles centred upon immune, B cell and control loci and compared these across cell subsets. Regions with a methylation difference of >0.2 were considered to be differentially methylated.
Results: We confirmed that EBV infection results in widespread DNA hypomethylation relative to resting B cells and CD40L activated B cells. Differentially methylated regions were found to be underrepresented at loci important in immune and particularly B cell function compared to genome wide 1kb tiles or a control set of loci not specifically associated with immune disease. This underrepresentation was independent of the B cell activation state. Gene promoters did not appear to be affected by dysregulation of DNA methylation.
Conclusions: The role of DNA methylation dysregulation in LCLs is unclear, but this phenomenon appears to be biased against loci important in B cell and immune function. Given the rapid proliferation of LCLs, one would expect precisely these loci to demonstrate greater degrees of dysregulation. DNA methylation dysregulation at MS GWAS risk loci in response to latent EBV infection does not appear to play a role in the pathogenesis of multiple sclerosis.
Disclosure:
Lawrence Ong: Nothing to disclose
Grant Parnell: Nothing to disclose
Graeme Stewart: Nothing to disclose
David Booth: Nothing to disclose

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies