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Epigenetics

Resetting ME/CFS with epigenetics? https://www.meresearch.org.uk/resetting-me-cfs-with-epigenetics-part-1 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 epigenetics study conducted by Prof. Jo Nijs and colleagues at Vrije Universiteit Brussel in Belgium. The latest in a programme of research on this topic, the study found increased levels of brain-derived neurotropic factor (BDNF) in people with ME/CFS. BDNF has been linked with pain in fibromyalgia several times, but it is also particularly interesting in diseases such as ME because BDNF levels are elevated by ME’s own brand of kryptonite: exercise. Those increased BDNF levels in patients were associated with increased symptoms at rest. However, the real twist was the finding of low levels of DNA methylation (an epigenetic modification). That led the authors – piggybacking on findings from another study – to suggest that an infectious event had altered BDNF’s epigenetics, causing BDNF to become overly activated during exercise in ME/CFS. High levels of BDNF may then be sensitising pain pathways, leading to post-exertional malaise (PEM). That promising result set up a new study, recently funded by ME Research UK, and led by Prof. Nijs as well as Prof. Lode Godderis from the University of Leuven, looking at the role of epigenetic modification of BDNF in pain and PEM in ME/CFS. First, the study will assess a most interesting question: could exercise be sending BDNF levels into the stratosphere in ME/CFS? If it is, then a direct link between exercise and the pain it causes in the disease may have been found. If low BDNF methylation rates are again found, the study may also point to a potentially modifiable reason for the high BDNF levels. The study will also examine another exercise-triggered factor – enzymes called histone de-acetylases (HDACs) that usually decline during exercise, but have never previously been studied in ME/CFS. They are also associated with increased pain. We don’t yet fully understand what role epigenetics plays in ME/CFS, but the findings so far – increased levels of epigenetic changes in metabolic, immune and nerve factors – make perfect sense given what we know about the illness. Plus, this new epigenetics study from Belgium is aimed right at very heart of ME/CFS: exercise. The factors involved – an infection-triggered epigenetic change possibly associated with exercise and pain – all add up very enticingly. Time will tell, of course. All we can do is look, but this effort has the potential to provide something rare: a specific epigenetic target linked to PEM, which could potentially be used to reset at least part of ME/CFS 

 

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