Resetting ME/CFS with epigenetics? Part 1

This month at ME Research UK we are focusing on the exciting world of epigenetics, ahead of a new study announcement in a couple of weeks.

To kick off, here is the first part of an article by Cort Johnson, who writes the excellent Health Rising blog on ME/CFS research news. Here, Cort introduces the world of epigenetics, and looks at how it might be relevant for ME/CFS.

Is there any subject riper with promise for ME/CFS than epigenetics?

In simple terms, genetics (without the ‘epi’) is how a person’s characteristics (including their susceptibility to illnesses) are passed on from one generation to another via their genes.

Using this model, a person may be more likely to develop an illness such as ME/CFS because they have inherited some genetic weakness from their parents. However, we now know that the genes we are born with simply provide a template for a lot of action to come.

Epigenetics (meaning ‘on or above genetics’) refers to the multiple ways our body has of turning our genes on or off in a cell. How important is this process? Very important. It is by epigenetically turning genes on or off that a cell becomes an eye, a muscle or a kidney cell.

Those changes in gene expression don’t stop as we grow up. If we change our diet, or if we encounter a pathogen or toxin, our cells can respond by changing which genes are expressed. Because the epigenetic changes to our DNA are preserved when our cells divide, they can be long-lasting. Some can even be passed down through generations.

The longer we’re alive, therefore, the more genetically different we become at the level that really matters – the level of our gene expression. Some researchers believe that epigenetics will ultimately prove to be more powerful than genetics as a driver of health and illness. 

The question is whether an infection or toxin – or whatever it was that initiated ME/CFS – can generate a new genetic us? Could an infection, for instance, turn on or off immune, metabolic or other genes that produce the symptoms of ME/CFS?

Take neuroinflammation – currently a hot topic in ME/CFS. Epigenetic modifications appear to play a major role in the microglial activation that produces neuroinflammation. Microglia are even believed to contain an ‘epigenetic memory’ which causes them to revert to certain states when exposed to similar challenges.

Ten years ago, a review of the genetics and epigenetics of fatigue noted that no epigenetic studies had been done in ME, but since then epigenetic research has ramped up.

Leading the way is Patrick McGowan at the University of Toronto, who has multiple ME epigenetic studies under his belt. The epigenetically modified genes identified in McGowan’s first study related to the immune response, cellular metabolism and kinase activity. These findings were encouraging, and track well with what researchers suspect is going on in ME.

With these promising results, the McGowan team attempted to determine if the epigenetic modifications they’d found mattered – did they actually affect functioning? Their 2017 study honed in on two longstanding subjects of interest in ME: the HPA axis and the immune system.

Once again, they found that genes associated with energy production (metabolic regulation) had been epigenetically modified in ME. Other epigenetic changes may have produced the increased oxidative stress found in an earlier ME Research UK-funded study at the University of Dundee.

The 2017 McGowan study also suggested that epigenetically modified HPA-axis genes could be contributing to increased glucocorticoid sensitivity in a subset of patients – a finding which could translate to increased inflammation. Finally, and perhaps most importantly, the study suggested that the epigenetic modifications were associated with a reduced quality of life.

The next McGowan study again found that epigenetic modifications had occurred in close proximity to genes associated with immune function and cellular metabolism. In 2018, the team produced a first when it used epigenetics to identify four patient subsets in ME/CFS. Remarkably, the most notable epigenetic changes occurred in genes involved in cellular energy production and metabolism – perhaps providing a direct link to post-exertional malaise.

Next week, Cort looks at some of the epigenetic research carried out by ME Research UK-funded scientists, and how this relates to the effects of exercise in people with ME/CFS. Read part 2 here.

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