Identification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-associated DNA methylation patterns

Abstract

BackgroundMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition involving multiple organ systems and characterized by persistent/relapsing debilitating fatigue, immune dysfunction, neurological problems, and other symptoms not curable for at least 6 months. Disruption of DNA methylation patterns has been tied to various immune and neurological diseases; however, its status in ME/CFS remains uncertain. Our study aimed at identifying changes in the DNA methylation patterns that associate with ME/CFS.MethodsWe extracted genomic DNA from peripheral blood mononuclear cells from 13 ME/CFS study subjects and 12 healthy controls and measured global DNA methylation by ELISA-like method and site-specific methylation status using Illumina MethylationEPIC microarrays. Pyrosequencing validation included 33 ME/CFS cases and 31 controls from two geographically distant cohorts.ResultsGlobal DNA methylation levels of ME/CFS cases were similar to those of controls. However, microarray-based approach allowed detection of 17,296 differentially methylated CpG sites in 6,368 genes across regulatory elements and within coding regions of genes. Analysis of DNA methylation in promoter regions revealed 307 differentially methylated promoters. Ingenuity pathway analysis indicated that genes associated with differentially methylated promoters participated in at least 15 different pathways mostly related to cell signaling with a strong immune component.ConclusionsThis is the first study that has explored genome-wide epigenetic changes associated with ME/CFS using the advanced Illumina MethylationEPIC microarrays covering about 850,000 CpG sites in two geographically distant cohorts of ME/CFS cases and matched controls. Our results are aligned with previous studies that indicate a dysregulation of the immune system in ME/CFS. They also suggest a potential role of epigenetic de-regulation in the pathobiology of ME/CFS. We propose screening of larger cohorts of ME/CFS cases to determine the external validity of these epigenetic changes in order to implement them as possible diagnostic markers in clinical setting.

Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells and extracellular vesicles in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…GO pathway analysis and RT-qPCR results ( Fig. 9) points to potential epigenetic and signal transduction mechanisms associating with ME/CFS, in good agreement with the differential methylation patterns formerly detected in ME/CFS patients by our group 62 .…”

Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules

“…7,55e57 Unlike other biomarkers, TGF-b was the only biomarker elevated in a meta-analysis of data from ME/CFS studies. 7 Additionally, in a study conducted by Trivedi et al, 58 hypomethylation of a TGFBR1 promoter, implicating that the gene for the TGF-b receptor may be overexpressed. TGF-b elevation may be linked to "sickness behavior" or decreased motor activity, changes in energy intake, sleep abnormalities and cognitive deficits, 59 as well as fatigue 60 from immune system dysregulation.…”

Epigenetic Components of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Uncover Potential Transposable Element Activation

“…By contrast, a more recent study performed by our group using the improved Illumina MethylationEPIC microarrays covering 850,000 CpGs in 2 geographically distant cohorts of 33 ME/CFS cases and 31 matched control subjects yielded a striking predominant hypomethylation among DM promoters: 306 of them exhibited decreased methylation versus only 1 presenting with hypermethylation. 31 Clinical criteria applied for patient diagnosis and type of samples analyzed varied across these studies; the Fukuda/Centers for Disease Control and Prevention 1994 case definition in CD4 + cells was used for the first study 28 and both the Fukuda and Canadian criteria in PBMCs for the rest 29e32 (Table I). The discrepancy across epimethylome findings may involve additional variables.…”

“…To answer this question, we performed a second Dfam search for TEs associated with the 307 ME/ CFS DM promoters of the genome-wide study performed by our group that contained DM promoter data already classified in these 4 major transcript subgroups. 31 Before this analysis, DM promoter coordinates were converted to the updated GRCh38 human genome version (as described in the Materials and Methods section). As summarized in Supplemental Table III (in the online version at doi:10.1016/j.clinthera.2019.02.012), a total of 744 TEs were allocated within the 307 ME/CFS DM promoters.…”