DNA Methylation Modifications Associated with CFS

[Sushi]

DNA Methylation Modifications Associated with Chronic Fatigue Syndrome

Wilfred C. de Vega, Suzanne D. Vernon, Patrick O. McGowan
Published: August 11, 2014 DOI: 10.1371/journal.pone.0104757

Abstract

Chronic Fatigue Syndrome (CFS), also known as myalgic encephalomyelitis, is a complex multifactorial disease that is characterized by the persistent presence of fatigue and other particular symptoms for a minimum of 6 months....Stable alterations in gene function in the immune system have been reported in several studies of CFS. Epigenetic modifications have been implicated in long-term effects on gene function, however, to our knowledge, genome-wide epigenetic modifications associated with CFS have not been explored.

We examined the DNA methylome in peripheral blood mononuclear cells isolated from CFS patients and healthy controls using the Illumina HumanMethylation450 BeadChip array, controlling for invariant probes and probes overlapping polymorphic sequences....We found an increased abundance of differentially methylated genes related to the immune response, cellular metabolism, and kinase activity.

Genes associated with immune cell regulation, the largest coordinated enrichment of differentially methylated pathways, showed hypomethylation within promoters and other gene regulatory elements in CFS. These data are consistent with evidence of multisystem dysregulation in CFS and implicate the involvement of DNA modifications in CFS pathology.

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104757

 

[adreno]

Rich Vank would have enjoyed seeing this.

 

[Helen]

Thanks @Sushi and agree @adreno . Finally methylation and CFS was studied. Many interesting results.

 

[Simon]

It's an interesting approach, but note the tiny sample size of just 12 patients and 12 controls

We recruited 231 volunteers from 4 clinical centers. For this exploratory study, we selected white female subjects, 52 years of age or younger, non-obese (BMI<30) and with no previous consumption of immunomodulatory medications and medications with known effects on epigenetic mechanisms (Table S1), to exclude factors associated with epigenetic differences and altered immune profiles [23]–[25]. All CFS subjects had an infectious phenotype where subjects reported the onset of flu-like illness prior to CFS diagnosis. After applying these exclusion criteria, 12 CFS patients and 12 healthy controls matched for age (within the range of 23–52 years old) and BMI (within the range of 18.6–29.8) were available for DNA methylation analysis.

As the authors acknowledge, this is a cross-sectional study and a longitudinal study (following patients over time, preferably from before they got ill) would be needed to demonstrate a causal relationship.

IT would have been nice to see more emphasis in the paper on the need for much bigger studies to confirm these findings. It's a start, but we shouldn't get too excited - hopefully the kind of large-scale replication that's needed to confirm these findings will follow soon.

 

[Countrygirl]

I have just stumbled across this and given my track record for double posting someone will probably tell me that there are already at least three threads discussing it, so I will start now to save time later. Just in case you haven't already debated it to death I will risk posting it now.

http://solvecfs.org/breaking-news-chemical-changes-in-immune-cell-dna-from-mecfs-patients/

We are pleased to announce the first study to report epigenetic modifications throughout the genome in female ME/CFS patients compared to a matched sample of healthy controls. This research conducted in partnership and funded by the Solve ME/CFS Initiative (SMCI) was published today in the high impact and open access journal PLOS ONE (http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104757).

The Solve ME/CFS Initiative launched our Research Institute Without Walls in 2010 and Dr. Patrick McGowan was one of our first grantees to use this innovative infrastructure. Together with his graduate student, Will de Vega and SMCI’s Scientific Director, Suzanne D. Vernon, they found evidence of distinct epigenetic profiles in immune and other physiologically relevant genes in a selected group of female ME/CFS patients. Will de Vega, who performed much of the work, is a PhD candidate in the department of Cell and Systems Biology at the University of Toronto. His thesis research concerns how environmental factors and ME/CFS impact immunological processes, and their effects on clinically relevant phenotypes.

Epigenetic modifications affect the way genes are turned on or off without changing the inherited gene sequences. “Knowledge about the epigenetics of ME/CFS could potentially lead to alternative treatment options for sufferers, from targeted lifestyle interventions to new pharmacological treatments”, notes McGowan. There were many epigenetic modifications in and around immune genes that affect the way these genes are regulated and expressed. These types of changes would be expected to affect immune cell function in ME/CFS patients. “This is the first in a series of exciting results coming from McGowan’s lab at the University of Toronto”, says Suzanne D. Vernon. “By understanding these epigenetic differences in the immune cells of ME/CFS patients, we can begin to decipher the molecular mechanisms of the immune dysfunction that we suspect is at the root of ME/CFS”.

McGowan started this ME/CFS epigenetic research in 2012. His quick success is a testament to the power of patient-centered research approach used by the Solve ME/CFS Initiative. “Our study would not have been possible without the funding provided by the Solve ME/CFS Initiative, patient samples from the SolveCFS BioBank, and the collaborative support of the Initiative’s scientific director Dr. Suzanne D. Vernon” says McGowan.

The Solve ME/CFS Initiative will continue to partner with McGowan and his team at the University of Toronto to further this exciting work of epigenetics and ME/CFS. This field of research holds promise for identification of diagnostic biomarkers and potential treatment and interventions for ME/CFS. For right now it is further demonstration of the indisputable biological basis of ME/CFS.

__________

Learn More about McGowan’s work and results through our Webinar Series
Investigator Report: Epigenetics of ME/CFS
Thursday, August 21, 2014
2-3:00pm Eastern (1pm Central/Noon Mountain/11am Pacific)

Space is limited – RSVP to Reserve Your Slot - Click HERE

Patrick O. McGowan, Ph.D., is one of the Solve ME/CFS Initiative 2011 funded investigators. McGowan is an assistant professor in the Department of Biological Sciences, University of Toronto at Scarborough. He will talk about his latest results from our grant funding. McGowan used blood samples from the SolveCFS BioBank to identify the chemical modifications (e.g., methylation) to the DNA that is different in ME/CFS patients compared to healthy people. This type of research will help explain the immune dysfunction of ME/CFS.

 

[Helen]

@Simon I think you are right about the need for further studies of different kinds, but could we definitely say that n=12 (with matched controls) are too few for drawing any conclusions without having evaluated the inclusion criterias, studied parameters and the choosen statistical method-s ? And maybe a causal relationship never will be confirmed, only a connection - that would be of value to know about too.

 

[Bob]

I have just stumbled across this and given my track record for double posting someone will probably tell me that there are already at least three threads discussing it, so I will start now to save time later. Just in case you haven't already debated it to death I will risk posting it now.

lol

http://forums.phoenixrising.me/inde...tion-modifications-associated-with-cfs.31960/

 

[Valentijn]

To clarify, this study isn't looking at the prevalence of the genes involved in the methylation cycle (MTHFR, MTRR, BHMT, etc). Rather it's looking at how methylated various genes are. Some are hypermethylated and some are hypomethylated, which would seem to suggest that the problem is in the regulation of the methylation cycle from an outside factor, rather than a strictly genetic issue in those methylation genes themselves.

Hypermethylated genes: ATG7 BCL10 CD83 FCER2 HLA-H IL19 IL1RL1 LAIR1 TNFSF13B TREM2
Hypomethylated genes: CD3D CD3E CD3G CD96 FASLG HLA-E ICOS LAX1 LCK LY9

Maybe this would also mean that supplements and vitamins encouraging methylation might be somewhat helpful for ME/CFS patients, regardless of methylation cycle mutations?

 

[DanME]

Interesting study. Though the sample and matched control sizes (n=12) are quite small, the patients were carefully selected out of a bigger sample (n=231).

Volunteers with HIV and HepC were excluded. They selected specifically 12 white female subjects, 52 years or younger, non-obese, with no previous consumption of immunmodulators and only with a sudden viral onset. Furthermore, PEM > 24h, cognitive impairment, a low vitality, low social and/or physical functioning were required.

The authors themselfs say, though the sample size for this study was small, it was carefully selected and likely representative of sudden onset CFS. I cannot say anything about their statistical analyses (maybe we have an expert around?).

They found different DNA Methylation in overall 826 genes in four clusters, cellular processes, positive metabolic regulation, kinase activity and mostly in the the immune response. The majority were hypermethylated (> 60%), so inactivated in comparison to controls.

In my understanding this study has nothing to do with RichvanK's work. Methylation of the DNA activates or inactivates certain gens and their expression in relation to other bodily processes (like autoimmunity) and environmental factors (like an infection or stress). It is not about the methylation process itself.

Here some quotes, I found interesting.

"Differentially methylated genes related to immune cell regulation showed an increased proportion of hypomethylated CpG sites among CFS patients, particularly in promoters and in gene regulatory elements."

"Hypomethylated CpG sites were significantly enriched in promoters and gene regulatory elements of genes related to immune signaling. It is possible that these immune genes may show increased transcript abundance or increased transcriptional potential, at least among the CFS group selected in this study, as promoter hypomethylation is generally associated with an increase in gene expression."

"Nevertheless, our data provide evidence that epigenetic variation in CFS may be distinct, at least in part, from related disorders with an immunological component. For example, epigenomic analysis of whole blood in fibromyalgia (FM) patients indicated differential methylation in genes associated with structural and nervous system development and neuron differentiation [72]."

"Although the immune system showed most changes in DNA methylation, we also found an enrichment in gene sets linked to cellular components, kinase activity, and positive metabolic activity, supporting previous data indicating differences in the expression of genes associated with cellular metabolism and oxidative stress in PBMCs from CFS patients [48,51,52]."

"The results of this study do not indicate whether these observed epigenetic differences are a cause or a consequence of CFS. However, we provide evidence suggesting a potential role for epigenetic alterations in the pathophysiology of CFS."

I would like to see the same study before and after excersise.

 

[lauluce]

this is quite interesting, seems to support the idea that immunological abnormalities are present in CFS and could help pinpoint exactly which they are. Also could provide good disease markers. Exiting...

 

[Countrygirl]

http://forums.phoenixrising.me/inde...tion-modifications-associated-with-cfs.31960/[/quote]


Ahhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

 

[Bob]

@Countrygirl, lol

 

[Sushi]

Threads merged

@Countrygirl, the one you found is a layman's version, so it is a good addition.

 

[Countrygirl]

http://forums.phoenixrising.me/inde...tion-modifications-associated-with-cfs.31960/

Ahhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!![/quote]


Edited to say that if anyone is completely bewildered by my apparently bizarre response above and is tempted to question my mental health status this is what can happen when two threads are merged.

 

[RYO]

To clarify, this study isn't looking at the prevalence of the genes involved in the methylation cycle (MTHFR, MTRR, BHMT, etc). Rather it's looking at how methylated various genes are. Some are hypermethylated and some are hypomethylated, which would seem to suggest that the problem is in the regulation of the methylation cycle from an outside factor, rather than a strictly genetic issue in those methylation genes themselves.

Hypermethylated genes: ATG7 BCL10 CD83 FCER2 HLA-H IL19 IL1RL1 LAIR1 TNFSF13B TREM2
Hypomethylated genes: CD3D CD3E CD3G CD96 FASLG HLA-E ICOS LAX1 LCK LY9

Maybe this would also mean that supplements and vitamins encouraging methylation might be somewhat helpful for ME/CFS patients, regardless of methylation cycle mutations?

My understanding is that we can describe phenotype expression when certain genes become methylated. However, we don't understand what triggered that process (environmental toxins, diet, viral insult) nor do we understand how to reprogram methylation process.

I am not ruling out that dietary changes or supplements may have some effect but I personally have yet to find a supplement combination to alter disease state.

I did try fasting for 2 1/2 days. It resulted in mild improvement in intensity of my leg pains. I found fasting difficult. I would not suggest fasting to patients with POTS, low body weight, renal insufficiency or those on multiple medications.

My personal theory is that for many of us, the viral illness is what "pushes us over the methylation cliff". Wouldn't it be ironic if someone found a way to use a viral vector to fix methylation alterations in ME/CFS.

Thanks to the author of this thread. Hopefully more research will continue in this area.

 

[Little Bluestem]

I would not suggest fasting to patients with POTS, low body weight, renal insufficiency or those on multiple medications.

Add hypoglycemia to that.

 

[ukxmrv]

Is this important at all?

"DNA methylation suppresses the expression of endogenous retroviral genes and other harmful stretches of DNA that have been incorporated into the host genome over time. "

http://en.wikipedia.org/wiki/DNA_methylation

 

[RYO]

Is this important at all?

"DNA methylation suppresses the expression of endogenous retroviral genes and other harmful stretches of DNA that have been incorporated into the host genome over time. "

http://en.wikipedia.org/wiki/DNA_methylation

Yes, DNA methylation suppresses the expression of genes. But as previous comments mention, some areas appear hypomethylated.

What I would like to know is how a severe viral illness potentially affects long term intracellular function. Does virus alter methylation of genetic sequences that alter immune, mitochondrial, or function of membrane channels. Is it a "hit and run" phenomenon or are there residual viral proteins that linger and alter cellular function long term.

 

[lansbergen]

What I would like to know is how a severe viral illness potentially affects long term intracellular function. Does virus alter methylation of genetic sequences that alter immune, mitochondrial, or function of membrane channels. Is it a "hit and run" phenomenon or are there residual viral proteins that linger and alter cellular function long term.

The cell danger response will go on and on as long as the danger is not eliminated.

An article
http://www.sciencedirect.com/science/article/pii/S1567724913002390

 

[RYO]

The cell danger response will go on and on as long as the danger is not eliminated.

An article
http://www.sciencedirect.com/science/article/pii/S1567724913002390

I reached out to Robert K. Naviaux, MD, PhD. Unfortunately, he didn't think he could help but sent me copy of his paper.

I am currently ruling out metabolic myopathy with Dr Dwight Koeberl.

In the meantime, I am trying to achieve "mitocellular hormesis" through diet, mito cocktail, limited exercise, and intermittent fasting. I have yet to find alusive "reboot" button. I suspect biologic systems much more complicated. Studying and taking care of patients with sepsis syndrome is a good example.