Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis

ScottTriGuy

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De Vega presented his findings at the ME Conference in October...

"Conclusions


Our results indicate DNA methylation modifications in cellular metabolism in ME/CFS despite a heterogeneous patient population, implicating these processes in immune and HPA axis dysfunction in ME/CFS. Modifications to epigenetic loci associated with differences in glucocorticoid sensitivity may be important as biomarkers for future clinical testing. Overall, these findings align with recent ME/CFS work that point towards impairment in cellular energy production in this patient population.
"

https://bmcmedgenomics.biomedcentral.com/articles/10.1186/s12920-017-0248-3
 

Kati

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Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating idiopathic disease characterized by unexplained fatigue that fails to resolve with sufficient rest. Diagnosis is based on a list of symptoms and exclusion of other fatigue-related health conditions. Despite a heterogeneous patient population, immune and hypothalamic-pituitary-adrenal (HPA) axis function differences, such as enhanced negative feedback to glucocorticoids, are recurring findings in ME/CFS studies. Epigenetic modifications, such as CpG methylation, are known to regulate long-term phenotypic differences and previous work by our group found DNA methylome differences in ME/CFS, however the relationship between DNA methylome modifications, clinical and functional characteristics associated with ME/CFS has not been examined.

Methods
We examined the DNA methylome in peripheral blood mononuclear cells (PBMCs) of a larger cohort of female ME/CFS patients using the Illumina HumanMethylation450 BeadChip Array. In parallel to the DNA methylome analysis, we investigated in vitro glucocorticoid sensitivity differences by stimulating PBMCs with phytohaemagglutinin and suppressed growth with dexamethasone. We explored DNA methylation differences using bisulfite pyrosequencing and statistical permutation. Linear regression was implemented to discover epigenomic regions associated with self-reported quality of life and network analysis of gene ontology terms to biologically contextualize results.

Results
We detected 12,608 differentially methylated sites between ME/CFS patients and healthy controls predominantly localized to cellular metabolism genes, some of which were also related to self-reported quality of life health scores. Among ME/CFS patients, glucocorticoid sensitivity was associated with differential methylation at 13 loci.

Conclusions
Our results indicate DNA methylation modifications in cellular metabolism in ME/CFS despite a heterogeneous patient population, implicating these processes in immune and HPA axis dysfunction in ME/CFS. Modifications to epigenetic loci associated with differences in glucocorticoid sensitivity may be important as biomarkers for future clinical testing. Overall, these findings align with recent ME/CFS work that point towards impairment in cellular energy production in this patient population.
 

A.B.

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So what does this study tell us? Aside from there being a glucocorticoid sensitive subgroup which is probably not news but more confirmation.

That cellular energy metabolism is profoundly altered?
 

anciendaze

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I get the feeling that DNA methylation is a bit complex of a biomarker, even in terms of research (rather than in a clinical setting).
I think the research answer is to concentrate on RNA transcripts without worrying about how transcription of genes is controlled. All protein sequences are previously expressed as RNA sequences, while some start as DNA sequences in chromosomes, and others in DNA episomes inserted by DNA viruses. Most RNA viruses, except retroviruses and some hepatotropic viruses, bypass DNA.

Unfortunately, this is where a great deal of tricky natural sequence manipulation takes place. You can't even assume the sequence is linear, as there are some clear examples of circular RNA reordering sequences seen in DNA. It is hard to investigate pathological states when we are generally ignorant about why this doesn't routinely happen in DNA to RNA to peptide transcription.

This looks like an unpromising mess to most researchers, but this is an area where investigation not tied to a specific disease would likely yield insights with broad implications.
 
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AndyPR

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Can anybody do a layperson's summary/translation?
From https://batemanhornecenter.org/differences-so-clear/
“Epi” means above and epigenetics implies “above the DNA” of our genes. These are the chemical changes that occur to our DNA – such as the addition of sticky methyl groups – that change how our genes are expressed. In other words, the function of the gene is changed without changing the underlying DNA sequence. Lots of methylation can silence gene expression and no methylation means gene expression is turned on. This team found that almost half of the 12,608 methylation sites were located in protein coding genes. There was more hypermethylation of the DNA in ME/CFS patients (71.6% versus 28.4% hypomethylated) compared to controls. A full 1,600 differentially methylated genes were associated with physical impairment in ME/CFS. Notably many of these genes are involved in cell energy production, metabolism and immune signaling.

de Vega tested to see whether these differences could affect immune function. He took blood cells from ME/CFS patients and healthy controls and used a specific assay to activate the immune cells (to simulate an immune response) and then turn off the response using a synthetic cortisol. (Remember, cortisol calms the immune response). The blood cells from a subgroup of ME/CFS patients were hypersensitive to the cortisol meaning that the amount needed to calm healthy immune cells caused the ME/CFS immune cells to shut down. There were 13 differentially methylated genes associated with this hypersensitivity to cortisol in the ME/CFS subgroup.

These are big numbers of differences precisely mapped to genes in ME/CFS patients that clearly affect immune cell function and physical function. We don’t yet know is what causes these epigenetic differences. Innovative research being conducted by young investigators like Dr. Patrick McGowan and his team puts us hot on the trail to track that down.

If anyone still doubts the biological basis of ME/CFS, I would ask them to read this paper, then ask… How could it be more clear?
 

ScottTriGuy

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Here is a video interview Millions Missing Canada did with Will De Vega in October and now that his paper is published we can post the interview...where he uses more plain language to describe his findings.

Will's mention of Rituximab as treatment is interesting...could it be that ME patients that have a hyper response to glucocorticoids may be good candidates for Rituximab?

https://www.facebook.com/MillionsMissingCanada/videos/396615247366870/
 

justy

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I don't respond well to steroids - my GP was freaked out because they do the opposite of what they do in most people - I don't feel lots of energy and really great on highish doses I feel really really tired and more ill and far from having an enormous appetitie I cant eat at all. Horrible things. I also have had lot of problems with high dose inhaled steroids for asthma and MCAS which again no Dr can believe. And this even though my 24hr cortisol is in my boots.
 
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Will's mention of Rituximab as treatment is interesting...could it be that ME patients that have a hyper response to glucocorticoids may be good candidates for Rituximab?
Is there any specific reason to assume that a hyper respons to glucocorticoids could be connected to rtx respons? Couldn't it just as well be the opposite way?
 
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I don't know what to make of this, the number of results they have is too much and probably much of it is noise.

The raw data isn't available until 15th of March, but there might be something interesting there if you want to test a priori hypotheses or use much more strict statistical thresholds.
 

ScottTriGuy

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Can anybody do a layperson's summary/translation?
I asked Will De Vega for a plain language version, and now that he's back from traveling he sent this:

ME has previously been associated with impaired neuroendocrine and immune response. Our study examined epigenetic changes in immune cells of healthy and ME women and their subsequent immune response to the drug dexamethasone, a synthetic version of cortisol known for its anti-inflammatory properties.

Epigenetics is an emerging field in biology that describes processes that modify the activity of genes that do not involve genetic mutations. The epigenome is known to be sensitive to environmental factors and modifications of the epigenome are potentially reversible, which has wide implications for medical treatment.

We investigated the association between the epigenome and immune responses, to determine the genes involved and their relationship with symptoms of ME. We found 12,608 sites in the genome that showed epigenetic differences in ME patients, which were predominantly associated with the regulation of cellular and metabolic processes.

In addition, we observed two subgroups of ME patients according to their response to synthetic cortisol after triggering an immune response. Immune cells (specifically T-cells) from one group of ME patients showed typical sensitivity, while cells from the other subgroup of patients showed a hypersensitivity to the synthetic cortisol, meaning that this ME subgroup had an abnormal cellular immune response.

Interestingly, there were 13 sites in the epigenome that differentiated the hypersensitive ME patients from both healthy controls and the other ME subgroup. These sites could represent biomarkers indicative of ME patients that have cortisol hypersensitivity.

While additional work needs to be performed in order to better understand this relationship, the results of our study provide evidence that modifications of the epigenome are associated with neuroendocrine and immune response impairments in ME.
 

bertiedog

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I guess that the above explanation explains why somebody like @justy has the complete opposite experience from me where glucocorticoids are concerned. She has had awful experiences from them whereas I benefit every day I take my 6 mg Prednisolone with increased wellbeing and ability to exercise. Sometimes I even wonder if I have ME/CFS because I can feel so well. However my energy always runs out when doing physical stuff and I suffer with frequent viruses in the winter which bring back the ME/CFS symptoms immediately so undoubtedly I do have ME/CFS.

On the other hand I have never taken more than 6 mg Pred plus 2.5 hydrocortisone on a daily basis. Only ever gone to 10 mg with an infection for a couple of days before going back down to the sort of dose one's own body could produce.

Pam
 

justy

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I asked Will De Vega for a plain language version, and now that he's back from traveling he sent this:

ME has previously been associated with impaired neuroendocrine and immune response. Our study examined epigenetic changes in immune cells of healthy and ME women and their subsequent immune response to the drug dexamethasone, a synthetic version of cortisol known for its anti-inflammatory properties.

Epigenetics is an emerging field in biology that describes processes that modify the activity of genes that do not involve genetic mutations. The epigenome is known to be sensitive to environmental factors and modifications of the epigenome are potentially reversible, which has wide implications for medical treatment.

We investigated the association between the epigenome and immune responses, to determine the genes involved and their relationship with symptoms of ME. We found 12,608 sites in the genome that showed epigenetic differences in ME patients, which were predominantly associated with the regulation of cellular and metabolic processes.

In addition, we observed two subgroups of ME patients according to their response to synthetic cortisol after triggering an immune response. Immune cells (specifically T-cells) from one group of ME patients showed typical sensitivity, while cells from the other subgroup of patients showed a hypersensitivity to the synthetic cortisol, meaning that this ME subgroup had an abnormal cellular immune response.

Interestingly, there were 13 sites in the epigenome that differentiated the hypersensitive ME patients from both healthy controls and the other ME subgroup. These sites could represent biomarkers indicative of ME patients that have cortisol hypersensitivity.

While additional work needs to be performed in order to better understand this relationship, the results of our study provide evidence that modifications of the epigenome are associated with neuroendocrine and immune response impairments in ME.
Thank you so much for this - what a wonderful explanation.
 

ukxmrv

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That's really interesting Scott. Thanks for asking Dr De Vega and then posting the reply.

The use of dexamethasone caught my eye. I've used Dexamethasone and also Prednisolone.

Dexamethosone makes me feel "poisoned". My energy (little that it is plummets) and I become bed bound quite quickly. Prednisolone on the other hand returns an energy boost.
 

dangermouse

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I've had a two week reducing dose of prednisolone (for reducing inflammation) and as much as it did ease pain/inflammation I didn't tolerate it well.