The epigenetics of Chronic Fatigue Syndrome?

"These data are consistent with evidence of multisystem dysregulation in CFS [Chronic Fatigue Syndrome] and implicate the involvement of DNA modifications in CFS pathology". So said the paper by Wilfred de Vega and colleagues [1] (open-access here) which, I think, represents a bit of a first for CFS with their examination of the possible role of epigenetic modifications in relation to the condition(s) [2].

Ladies first @ Wikipedia 

I have to say that I was really quite excited by the de Vega paper and the fact that someone has actually started to apply the science of epigenetics (see here) to CFS. Indeed, only a few months back I mentioned the dearth of research in this area (see here) on the back of some interesting if preliminary findings in relation to things like HERV expression (see here) in ME (myalgic encephalomyelitis) which may very well be linked to methylation issues [3].

A few details about the de Vega paper might be useful, bearing in mind it is open-access:

• This was a preliminary study which included 12 participants diagnosed with CFS and 12 asymptomatic controls, all women, and age- and BMI matched. Participants were recruited from the SolveCFS BioBank which also talks a little about this trial on their website (see here). Alongside the donation of a blood sample, participants completed the RAND-36, asking questions about health-related quality of life.  
• "Methylomes in PBMCs [peripheral blood mononucleated cells] were examined" looking for any differences in methylation patterns between the groups. CpG sites were the analytical target, which as has been discussed in previous posts (see here), are those islands of DNA which can be methylated. Oh, and I should at this point also say that methylation or hypermethylation of specific parts of genes normally means gene silencing [4]. 
• Alongside looking at any methylation differences between the groups, some analytical time was also devoted to gene ontology (GO) and network analysis with the aim to "identify major enriched biological themes". In other words, to look at the biological functions behind any differentially methylated DNA sites.
• Results: perhaps unsurprisingly, there were some differences between the groups: "1,192 CpG sites were identified as differentially methylated between CFS patients and healthy control subjects, corresponding to 826 genes". These differences were present "across promoters, gene regulatory elements and within coding regions of genes". Further: "within genic regions, 30% of differentially methylated regions were hypomethylated and 70% were hypermethylated overall".
• When it came to where in the genome differences were found and what functions might be impacted, well among other things, there was "an overrepresentation of terms related to immune cell regulation". With particular regard for gene regulatory elements, and bearing in mind: "Differential methylation of gene regulatory elements is classically associated with alterations in gene expression", the authors reported "a number" of differentially methylated CpGs in such elements related to the immune response. There is also some chatter about the de Vega data being "consistent with previous observations of a Th1- to Th2-mediated immune response shift in CFS".

As per my previous comment, this was quite a small-scale study which although valuable, only really dips it's toe into the epigenetic waters potentially associated with cases of CFS. The authors also note that their results "do not indicate whether these observed epigenetic differences are a cause or a consequence of CFS".

That being said, and knowing what we are starting to know about methylation and how we might be able to manipulate methylation patterns through for example, the use of DNA methyltransferase inhibitors [5], there may be some scope to explore whether a reversal or inhibition of hypermethylation for example, might exert some effect on the clinical signs and symptoms of at least some CFS. I say this without making any value judgements nor providing anything that looks, sounds or smells like clinical advice.

I'd like to think that the de Vega paper might stimulate further research into a possible role for epigenetics in relation to CFS. I say this acknowledging that genes and gene expression are likely to be only one part of the spectrum of presentations which fall under the CFS banner; not forgetting important areas such as the viral link to cases (see here), the growing emphasis on mitochondrial issues (see here) and even some potential role for those trillions of beasties which call our darkest recesses home (see here).

Music then, and Bill Haley and the Comets. Did you know he has an asteroid named after him?

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[1] de Vega WC. et al. DNA Methylation Modifications Associated with Chronic Fatigue Syndrome. PLoS One. 2014 Aug 11;9(8):e104757.

[2] Whiteley P. et al. Correlates of Overlapping Fatigue Syndromes. J Nutr Environ Med. 2004; 14: 247-259.

[3] Laska MJ. et al. (Some) cellular mechanisms influencing the transcription of human endogenous retrovirus, HERV-Fc1. PLoS One. 2013;8(1):e53895.

[4] Baylin SB. DNA methylation and gene silencing in cancer. Nature Clinical Practice Oncology. 2005; 2: S4-S11.

[5] Goffin J. & Eisenhauer E. DNA methyltransferase inhibitors-state of the art. Ann Oncol. 2002 Nov;13(11):1699-716.

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de Vega WC, Vernon SD, & McGowan PO (2014). DNA Methylation Modifications Associated with Chronic Fatigue Syndrome. PloS one, 9 (8) PMID: 25111603