Dynamic Epigenetic Changes during a Relapse and Recovery Cycle in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

(242) Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease with variable severity throughout the ongoing illness. Patients experience relapses where symptoms increase in severity, leaving them with a marked reduction in quality of life. Previous work has investigated molecular differences between ME/CFS patients and healthy controls, but the dynamic changes specific to each individual patient are unknown. Precision medicine can determine how each patient responds individually during variations in their long-term illness. We apply precision medicine here to map genomic changes in two selected ME/CFS patients through a relapse recovery cycle. Results DNA was isolated from Peripheral Blood Mononuclear Cells (PBMCs) from two patients and a healthy age/gender matched control in a longitudinal study to capture a patient relapse. Reduced representation DNA methylation sequencing profiles were obtained from each time point spanning the relapse recovery cycle. Both patients throughout the time course showed a significantly larger methylome variability (10-20 fold) compared with the control. During the relapse changes in the methylome profiles of the two patients were detected in regulatory-active regions of the genome that were associated respectively with 157 and 127 downstream genes, indicating disturbed metabolic, immune and inflammatory functions occurring during the relapse. Conclusions Severe health relapses in ME/CFS patients result in functionally important changes in their DNA methylomes that, while differing among patients, lead to similar compromised physiology. DNA methylation that is a signature of disease variability in ongoing ME/CFS may have practical applications for strategies to decrease relapse frequency.

Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses

“…Critically, in mitochondria this can lead to compromised energy production that may have repercussions throughout all body systems and an ability to provide extra energy to manage stress. Our most recent study has followed individual patients through a “relapse/recovery cycle” and has indicated there is a stronger peripheral immune dysfunction and greater inflammatory response during relapse that we infer arises from increased neuroinflammation and, from the altered DNA methylation profiles, changes in the expression of critical genes that would likely mediate this peripheral response in the immune cells ( 49 ). These studies from our group are summarized in the following Sections: Changes in the Transcriptome of Immune Cells in ME/CFS Patients, Differentially Expressed Proteins in the Immune Cells of ME/CFS Patients Analyzed by Sequential Window All Theoretical Spectra Mass Spectrometry MS (SWATH-MS), and A Comparison Between the ME/CFS Patient Cohort and the Healthy Controls Showed Changes in the DNA Methylation Profiles That Reflect Systemic Dysfunctions That Become More Pronounced During a Relapse.…”

“…Datasets generated and analysed for Figure 3 of this study can be found in the GEO database NCBI (GSE166592), see also ( 49 ).…”

“…Our most recent study has examined how the immune cell DNA methylome changed in two ME/CFS patients over a year, capturing a serious relapse recovery cycle in each case, together with a control, who remained healthy through the whole period. Reduced representation DNA methylation sequencing profiles were generated from 5 different blood samples for each individual to capture the oncoming relapse and the recovery from it in each patient ( 49 ). As shown in Figure 3 , comparisons of the DNA methylation changes in each sample over the time course showed both patients had an ongoing methylome instability from sample to sample independent of the relapse, that was 10–20-fold greater than in the control.…”