Determining non-genetic risk factors for developing MS

Summary

Despite significant advances in treatment, exactly what triggers MS onset is not known. However, a number of factors have been shown to be associated with the risk of developing MS, including genetics, infection, environmental factors (such as exposure to sunlight), and, most recently, epigenetics. The term “epigenetics” refers to changes in how cells turn genes on or off, without changing the DNA code itself. It is thought that environmental risk factors can influence epigenetic control of gene activity. Associate Professor Lechner-Scott’s study plans to examine the role of epigenetics in MS disease onset.

In a preliminary study, the team isolated immune cells from people with and without MS, and looked for differences in one particular type of epigenetic change, called DNA methylation. They discovered significant changes in the DNA methylation profiles of people with and without MS and determined that the majority of these changes were clustered around a genetic region involved in regulating the immune system. This study aims to further study the changes identified in this region and assess what the outcome of these changes might be for characteristics of MS such as onset, progression, and severity.

A better understanding of the epigenetic profiles of immune cells will provide new insight into the disease mechanisms underlying MS. Additionally, this study may identify epigenetic changes that could be used for predicting prognosis or as new targets for therapy.

Project Outcomes

Associate Professor Lechner-Scott and her team are investigating whether epigenetic changes are associated with the risk of developing MS and whether they are associated with progression, that is, the conversion from relapsing remitting MS to secondary progressive MS. As treatment options for people with secondary progressive MS are limited understanding how this conversion is triggered or comes about is crucial for the development of new medications for this phase of MS.

The first stage of this work compared the DNA methylation changes in people with relapsing remitting MS, people with secondary progressive MS and people without MS. Importantly, the people with MS examined in this study were not on active treatment for their MS, so the medications would not interfere the methylation pattern seen. As DNA methylation can change according to cell type, the researchers looked at the DNA methylation patterns in specific immune cells known to be involved in MS.

Associate Professor Lechner-Scott and her team showed that there were major DNA methylation changes in these cells in people with relapsing remitting MS who were not being treated. When these samples were compared to people with relapsing remitting MS who were on treatment, one of the sites of methylation change was consistent irrespective of whether the people were on treatment or off. The methylation profile of people with secondary progressive MS was different again, and in comparison to people without MS, people with secondary progressive MS were found to have higher levels of methylation in their DNA overall.

This research has resulted in a number of scientific journal papers (please see below) and has been successfully presented at a number of national and international scientific conferences. This work also attracted further funding that allowed the original aims to be expanded and resulted in the completion of one PhD degree.

Ongoing work in this area will integrate information about methylation with other genetic changes and gene activity levels from a single sample to determine the regulatory elements at work in the immune cells of people with MS and determine the cellular pathways involved.

Publications

Groen K, Lea RA, Maltby VE, Scott RJ, Lechner-Scott J. Letter to the editor: blood processing and sample storage have negligible effects on methylation. Clin Epigenetics. 2018 Feb 10:22.
Maltby VE, Lea RA, Sanders KA, White N, Benton MC, Scott RJ, Lechner-Scott J. Differential methylation at MHC in CD4⁺ T cells is associated with multiple sclerosis independently of HLA-DRB1. Clin Epigenetics. 2017 Jul 18;9:71
Sanders KA, Benton MC, Lea RA, Maltby VE, Agland S, Griffin N, Scott RJ, Tajouri L, Lechner-Scott J. Next-generation sequencing reveals broad down-regulation of microRNAs in secondary progressive multiple sclerosis CD4⁺ T cells. Clin Epigenetics. 2016 Aug 27;8(1):87.
Maltby VE, Graves MC, Lea RA, Benton MC, Sanders KA, Tajouri L, Scott RJ, Lechner-Scott J. Genome-wide DNA methylation profiling of CD8+ T cells shows a distinct epigenetic signature to CD4+ T cells in Multiple Sclerosis patients. Clinical Epigenetics. 2015 Nov 5;7
Vicki E Maltby, Rod A Lea, Karen A Ribbons, Katherine Sanders, Daniel Kennedy, Myintzu Min, Rodney J. Scott and Jeannette Lechner-Scott. DNA methylation changes in CD4⁺ T cells isolated from multiple sclerosis patients on dimethyl fumarate. Under review.
Vicki E. Maltby, Rodney A. Lea, Moira C. Graves, Katherine A. Sanders, Miles C. Benton, Lotti Tajouri, Rodney J. Scott and Jeannette Lechner-Scott. A hypermethylated region in the promoter of the lymphotoxin-alpha gene in CD19+ B cells is associated with multiple sclerosis. Under review.
Vicki E Maltby, Rodney A Lea, Katherine A Sanders, Rebecca Seeto, Kira Groen, Rodney J Scott, Lotti Tajouri, Jeannette Lechner-Scott. Interplay of microRNA biogenesis, miR-29b and DNA methylation in CD4⁺ T cells from secondary progressive multiple sclerosis patients. In preparation.