Changes in human genes have been associated with an increased risk of developing multiple sclerosis (MS). Our investigations indicate that a small genetic change in a gene which plays a role in immune regulation may actually have a large effect on the way in which the gene is expressed, and they way it functions in different tissues of the body. In this project I will investigate the relevance of these changes to determine how the expression of genes is influenced, leading to greater understanding of MS and the potential for a more directed approach to the treatment of disease.
Identification of strongly MS-associated single nucleotide polymorphism (SNP) located in the IL2RA gene and subsequent replication of this association in other populations, including Australians leads us to the investigation of the functional consequences of this association and its role in the development of MS.
IL2RA is an immune related protein expressed by T cells and regulatory T cells which have been shown to play a role in MS. A consequence of the associated SNP is the disruption of a site of DNA methylation (CpG dinucleotide). DNA methylation is a mechanism of gene expression regulation. This led to our preliminary investigations showing that IL2RA is tissue-differentially methylated in the brain compared to peripheral blood cells. This suggests a role for DNA methylation in the control of IL2RA expression. Investigation of the methylation status of IL2RA in MS patients compared to controls, in combination with the effect of the associated IL2RA SNP on IL2RA expression will allow us to determine the differences in the epigenetic regulation of IL2RA in MS and ultimately give clues as to why this disease may develop in some individuals and not others. This will lead to a better targeted approach to the development of treatment for MS patients.
With the discovery of novel MS susceptibility genes, MS researchers are now in a better position than ever before to dissect the genetic basis of this debilitating disease. To date, we and others have determined that certain DNA sequence variations are associated with risk of disease, however much work will be required to decipher their functional significance. Epigenetic mechanisms if gene regulation, while heritable, are not detectable as DNA sequence changes, but can have profound effects on gene function. Here we have provided strong preliminary evidence that IL2RA, a bone fife MS susceptibility gene, is epigenetically regulated and I am now seeking support to continue this important work. To our knowledge no group has yet shown an MS susceptibility gene to be epigenetically regulated, or formally implicated epigenetics in the development of MS. This work has, therefore, the potential to shed light on the involvement of this fundamentally important mechanism in disease pathogenesis.
Changes in human genes have been associated with an increased risk of developing MS. Dr Judith Field, from the Florey Neuroscience Institutes in Melbourne, has been researching the effect of small genetic changes in genes which play a role in immune regulation. She has discovered that these small changes may actually have a large effect on the way in which genes are expressed, and they way they function in different tissues of the body.
During her fellowship, Dr Field has been focusing on the relevance of these changes to the expression of genes, leading to greater understanding of MS and the potential for a more directed approach to the treatment of disease.
Dr Field has been investigating an immune related protein called IL2RA. IL2RA is found on T cells and regulatory T cells, both of which have been shown to play a role in MS. In IL2RA a small change in one of the building blocks of DNA, called a single nucleotide polymorphism or SNP, can occur. This change has been found to disrupt DNA methylation, an important regulator of gene expression.
This finding led to Dr Field’s preliminary investigations showing that IL2RA is differently methylated in different regions of the brain compared to circulating blood cells. This suggests a role for DNA methylation in the control of IL2RA expression. Investigation of the methylation status of IL2RA in MS patients compared to controls, in combination with the effect of the associated IL2RA SNP on IL2RA expression is now underway. This will allow the researchers to determine differences in the regulation of IL2RA in MS and ultimately give clues as to why this disease develops in some individuals and not others.
The research has shown that there are significant differences in the levels of DNA methylation in a part of the gene that is known to control levels of expression. Furthermore, treatment of cells with a chemical that reduces methylation leads to an increase in IL2RA expression. These results and further investigation of the potential differences in DNA methylation of the gene in MS will lead to a better targeted approach to the development of treatment for MS patients.
CD40 is another gene recently identified as being associated with the risk of MS. It is also an immune related protein, and is expressed by B cells, monocytes and dendritic cells of the immune system. The genetic change in CD40 that is associated with MS is a decrease in expression in healthy individuals. Dr Field has investigated whether this is also true in cells from MS patients and which immune cell subtype shows the most significant change in expression. The aim is to be able to target the precise cell population where this change in expression is important so as to better target therapeutic approaches in individuals with MS.
Ma, G. Z., J. Stankovich, Kilpatrick, T.K., Binder, M.D., Field, J. (2011). Polymorphisms in the Receptor Tyrosine Kinase MERTK Gene Are Associated with Multiple Sclerosis Susceptibility. PLoS One 6(2): e16964.
Field, J., S. R. Browning, Johnson, L. J., Danoy, P., Varney, M. D., Tait, B.D., Gandhi, K. S., Charlesworth, J. C., Heard, R. N., Stewart, G. J., Kilpatrick, T. J., Foote, S. J., Bahlo, M., Butzkueven, H., Wiley, J., Booth, D. R., Taylor, B. V., Brown, M. A., Rubio, J. P., Stankovich, J. (2010). A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis. PLoS One 5(10): e13454
Updated: 05 January, 2009