Epigenetics & immune dysfunction

A Scientific Illustration of How Epigenetic Mechanisms Can Affect Health (National Institutes of Health, USA)
A Scientific Illustration of How Epigenetic Mechanisms Can Affect Health (National Institutes of Health, USA)

We have all become accustomed to the idea that diseases can have either environmental or heritable causes – in fact, this dichotomy is now hard-wired into our views of the world. However, a relatively new field of endeavour – epigenetics – is beginning to challenge these assumptions.

Conventional genetics is concerned with changes to sequences of DNA (the genotype) which are then inherited, but epigenetics postulates that changes in gene expression (the way information from a gene is used to make products, usually proteins) can be affected by other factors and processes, including childhood development, drugs, diet, environmental chemicals, and even the aging process itself. In particular, epigenetic modifications (through, for example, DNA methylation) can have effects on the function of genes over the long term, and may be involved in a range of illnesses, such as diabetes or cancer (See NIH’s How Epigenetic Mechanisms Can Affect Health)

In ME/CFS, a variety of studies have examined gene regulation; these have shown alterations in gene function in the immune system of patients, supporting other evidence of immune system abnormalities and dysregulation. Since epigenetic modifications could well be involved, researchers at University of Toronto decided to test for these in the DNA of 12 female ME/CFS patients (who all reported sudden infectious onset of their illness) and 12 matched healthy controls, all recruited through the SolveCFS BioBank in the USA. There are many techniques for identifying epigenetic modifications of DNA, and the researchers chose to examine the occurrence of ‘DNA methylation’ in white blood cells using a specific BeadChip array and complex analysis techniques, including gene ontology (GO) analysis, to identify the biological pathways in which changes in DNA methylation might be involved.

The results (published in PlosOne 2014) make interesting if complicated reading. The researchers found a range of specific regions of DNA (methylated CpG dinucleotide sites) which differed between ME/CFS patients and controls. After GO analysis, four cluster groups, consisting of a total of 57 GO terms, were identified – a cellular processes group, a positive metabolic regulation group, a enzyme kinase activity group, and an immune cell regulation group. Within the four cluster groups, 511 unique genes containing a total of 637 CpG sites were significantly ‘hypermethylated’ in ME/CFS patients compared with healthy people, and 184 unique genes containing 237 CpGs were significantly ‘hypomethylated’. The immune cell regulation cluster, with 22 GO terms, had the largest “enrichment of differentially methylated gene pathways” (indicating alterations in gene expression in ME/CFS patients compared with healthy people), and there were clear indications of a shift towards ‘hypomethylated’ immune genes in the patient group.

Overall, the epigenetic analysis found evidence that immune cell regulation differs between ME/CFS patients and controls, a result that accords with what we already know about functional changes in immune profiles in the illness. The other differences noted by the researchers in gene set-enrichment – linked to differences in cellular processes, enzyme kinase activity and positive metabolic activity – also support current understanding about the role of dysregulation of cellular metabolism and oxidative stress in ME/CFS.

The importance of these findings (at least at present, until further epigenetic investigations are done) is that they confirm, using very different methodologies from studies in the past, that multisystem dysregulation is a feature of ME/CFS. However, they also implicate the involvement of specific DNA modifications in the causes or consequences of the disease, a potentially important finding in itself. While the reasons for these epigenetic modifications (environmental agents? infections?) in patients remain unknown, the researchers point out that “epigenetic changes can exert long-term effects on gene expression and are potentially amenable to therapeutic intervention”, citing the example of cancer in which therapeutic interventions targeting epigenetic mechanisms have had some success in altering inflammatory pathways.

Although it is still too early to tell whether or not the new ‘epigenetic perspective’ will revolutionise the investigation and treatment of complex chronic diseases, this novel report from the University of Toronto has presented valuable evidence to an international audience that epigenetic alterations can have a role in the pathophysiology of ME/CFS.

Further reading
DNA Methylation Modifications Associated with Chronic Fatigue Syndrome. de Vega WC, et al. PLoS One, 11 August 2014. 
A Scientific Illustration of How Epigenetic Mechanisms Can Affect Health. National Institutes of Health, USA.
The emerging role of epigenetics in cardiovascular disease. Review in Therapeutic Advances in Chronic Disease, July 2014.
Next-generation sequencing and epigenomics research: a hammer in search of nails. Review in Genomics Informatics, March 2014.
A gene signature for post-infectious chronic fatigue syndrome. ME Research UK-funded investigation.
Study of single nucleotide polymorphisms (SNPs) in CFS/ME and CFS/ME subtypes. ME Research UK-funded investigation.

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