A Cartography of Differential Gene Methylation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Different Network Roles i... (Wilberforce, 2021)

[Consul]

A Cartography of Differential Gene Methylation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Different Network Roles in the Protein-Protein Interactions Network Play Different, Biologically Relevant, Roles

Abstract
Myalgic Encephalomyelitis, or Chronic Fatigue Syndrome (ME/CFS), is characterised by severe fatigue and associated with immune dysfunction. Previous studies of DNA methylation have found evidence of changes in immune cells for ME/CFS. However these studies have been limited by their small sample size. Here, we aggregate three comparable datasets to achieve a larger sample size and detect small changes to DNA methylation. We find 10,824 differentially methylated genes, with a small average change. Next, from the currently known interactions of relevant proteins, we build a Protein-Protein interaction network and,localising the network cartography analysis, we identify 184 hub genes. We find that different hub types play different, and meaningful, biological roles. Finally, we perform Gene ontology enrichment analysis, and we find that these hubs are involved in immune system processes, including response to TGF-β and LPS, as well as mitochondrial functioning, supporting previous theories about ME/CFS. We also show that dopaminergic signalling may potentially contribute to immune pathology in ME/CFS, suggesting a possible interplay with Long Covid. Our results demonstrate the potentiality of network analysis in shedding light on the epigenetic contribution to the immune dysregulation of ME/CFS.

Conclusion
Our result suggest that small, widespread, changes in gene methylation may mediate some of the immune system pathology seen in ME/CFS. If Covid-19 does indeed lead to ME/CFS as Komaroff et al. (2021) are suggesting, then methylation profiling a large sample of patients would be beneficial in understanding its pathogenesis. Efforts to understand the cause of methylation changes in ME/CFS, and Long Covid if applicable, should also occur. Moreover, analysing relationships between the DMGs is necessary: few signalling pathways that activate key effectors, their receptors are probably present in the hubs of this study. If these proteins do exist, they may lead to the discovery of druggable targets for ME/CFS immune dysregulation.

Our results further support the presence of methylation changes contributing to the immune dysregulation that characterises ME/CFS. They also suggest that responses to LPS, cytokines, O&NS, and viruses function differently to what is seen in healthy controls, exacerbating immune abnormalities beyond what would be expected otherwise. Finally, signalling by multiple endogenous chemicals is also perturbed and may affect immune activation. Depending on whether Long Covid is related to ME/CFS, our findings may be of interest for consideration when studying treatment implications.

The study https://www.biorxiv.org/content/10.1101/2021.12.20.473375v2.full

 

[ljimbo423]

They also suggest that responses to LPS, cytokines, O&NS, and viruses function differently to what is seen in healthy controls, exacerbating immune abnormalities beyond what would be expected otherwise.

I think the above statement is very important to the cause of ME/CFS symptoms. ME/CFS doctor Sarah Myhill has also said that she thinks we have a "sensitized" immune response.

If that's true, even small amounts of LPS for example, from a minor leaky gut, could cause a significant immune system reaction. LPS are very well known to trigger the sickness response in the brain. Causing fatigue, malaise, aches and pains, brain fog, etc.

 

[Consul]

Throwing in a bit more here from the Dopamine section:

Dopaminergic processes were the only processes to feature in the results for the GO enrichment analysis of all hub types. The fatigue in ME/CFS seems likely to be partially dopaminergic centrally, considering the efficacy of multiple dopaminergic agents in ME/CFS (Blockmans et al., 2006; Blockmans and Persoons, 2016; Crosby et al., 2021; Goodnick et al., 1992; Kaiser, 2015), and in mouse models of ME/CFS (Song et al., 2021; Thakur et al., 2020). This would also fit with the high rates of Attention Deficit Hyperactivity Disorder (ADHD) in ME/CFS (Sáez-Francàs et al., 2012), and monoamine metabolite levels in cerebrospinal fluid (Demitrack et al., 1992). Moreover, levels of both general and mental fatigue in ME/CFS have been inversely correlated with basal ganglia activation as assessed by fMRI, potentially secondary to dopaminergic deficits (Miller et al., 2014). Numerous other neuroimaging studies also support this notion (see (Almutairi et al., 2020; Cook et al., 2017; Gay et al., 2016; Josev et al., 2019; Manca et al., 2021; Shan et al., 2020; Shan et al., 2018; Tanaka et al., 2006; Van Der Schaaf et al., 2018, 2017; Wortinger et al., 2017; Wortinger et al., 2016)). Furthermore, Carandini et al. (2021) found an inverse correlation between levels of mental fatigue and DA tract abnormalities in MS. Carandini et al. (2021) suggested that this is evidence of dopaminergic abnormalities underlying mental fatigue, as hypothesised by Dobryakova et al. (2015). Research in animals, and in patients given cytokine therapies, has demonstrated that peripheral inflammation can lead to central dopaminergic hypofunction (Anisman et al., 1996; Felger et al., 2013; Felger and Miller, 2012; Lee et al., 2021). Hence it can be postulated that the immune dysregulation and inflammation in the periphery may lead to central dopaminergic deficits, which then may lead to some of the experience of fatigue in ME/CFS. It is important to note that this does not dismiss the impact of other mediators, such as impaired mitochondrial functioning (Holden et al., 2020; Mandarano et al., 2020; Tomas et al., 2017). Dopaminergic hypo-functioning would simply make the fatigue caused by peripheral processes feel significantly worse for the patients involved.

 

[Pyrrhus]

Thanks so much @Consul for posting!

Previous studies of DNA methylation have found evidence of changes in immune cells for ME/CFS.

Related discussion:

Changes in DNA methylation profiles of [ME/CFS] patients reflect systemic dysfunctions (Helliwell et al. 2020)
https://forums.phoenixrising.me/thr...emic-dysfunctions-helliwell-et-al-2020.81953/

Finally, we perform Gene ontology enrichment analysis, and we find that these hubs are involved in immune system processes, including response to TGF-β and LPS, as well as mitochondrial functioning, supporting previous theories about ME/CFS.

Very interesting...

 

[Wishful]

If these are fairly minor differences, might they be due to the difference between healthy lifestyles and restricted lifestyles? Surely bedridden patients are going to have measurable differences in many aspects. I'm relatively healthy, but my changes in diet and activities probably make me noticeably different from how I would be if I ate and acted normally.