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

ABSTRACT: Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition that involves multiple organ systems and is characterized by an abrupt or delayed onset of persistent/relapsing symptomatology such as 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, the status of this epigenetic mark in ME/CFS remains uncertain. This study aimed at identifying changes in the DNA methylation patterns that are causative of changes in the regulation of gene expression in ME/CSF patients. Such changes may be also used for diagnostic purposes and be indicative of potential therapeutic targets. Methods: Peripheral blood mononuclear cells (PBMCs) from 13 ME/CFS patients and 12 healthy controls (HC) were used to extract genomic DNA and measure global DNA methylation, and the methylation status at 850,000 CpG sites was assessed using Illumina MethylationEPIC microarrays. Results: Global DNA methylation levels of ME/CFS patients were similar to those of HC. However, microarray-based genome-wide technology allowed detection of 17,296 differentially methylated CpG sites in 6,368 genes across promoters, gene regulatory elements and within coding regions of genes. Analysis of DNA methylation in promoter regions found 307 differentially methylated promoters (DMP); genes associated with DMP participate in at least 15 different pathways mostly related to cell signaling with a strong immune component. Conclusions: This is the first study that has explored genome-wide epigenetic changes associated with ME/CFS using the new MethylationEPIC microarrays covering about 850,000 CpG sites. Our results are consistent with dysregulation of the immune system in ME/CFS and suggest a role of this epigenetic modification on the DNA pathobiology of ME/CFS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE111183 | GEO | 2018/07/23

REPOSITORIES: GEO

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Project description:Gulf War Illness (GWI) is a complex condition that involves multiple organ systems and is characterized by an abrupt or delayed onset of persistent/relapsing symptomatology such as memory and other neurological problems, muscle and joint pain, gastrointestinal issues, hormonal imbalance, immune dysfunction and debilitating fatigue. Currently, treatment of the condition relies solely on management of symptomatology and improvement in quality of life due to a lack of knowledgeof the underlying mechanisms of disease onset and progression. An improved understanding of the key mechanisms of GWI and dysfunction within regulatory systems will lead to more objective diagnosis methods and adequate management of patients by providing targeted approaches to treatment. Disruption of DNA methylation patterns has been tied to various immune, neurological and endocrine disease states; however, the status of this epigenetic mark in GWI remains uncertain. This study aimed at identifying biomarkers of GWI by gaining knowledge on DNA methylation patterns of GWI in an effort to determine therapeutic targets of disease activity and provide insight into disease onset and progression. Methods: Genomic DNA from 10 GWI patients and 10 healthy controls [HC] (“experimental cohort”) prepared from PBMCs was analyzed with ELISA-based DNA methylation assays and Illumina MethylationEPIC microarrays. These arrays allow measuring the methylation status at 850,000 CpG sites. Methylation changes in promoter regions were separately analyzed and used as input data in ingenuity pathway analysis software to identify altered functional pathways. Relevant differentially methylated CpG sites (DMS) were validated by pyrosequencing. Results: Global DNA methylation levels using the ELISA-based assay on the DNA isolated from PBMCs of GWI patients were similar to those of HC. However, deeper evaluation using microarray-based genome-wide technology allowed detection of DMS in GWI patients with respect to HC. As an overall 10,767 CpG sites presented with differential DNA methylation levels across promoters, gene regulatory elements and within coding regions of genes. Majority of these DMS were hypermethylated in GWI patients as compared to the HC, and more than half of these sites localized to promoters and gene regulatory elements, relative to distribution of DMSin the network as a whole, indicating gene regulatory potential. Functional pathway analysis of the 776 genes with differentially methylated promoters (DMPs) fulfilling FDR≤0.2 criteriafollowing a genomic region-based approachlinks GWI to defects in at least 15 different pathways mostly related to cell signaling with a strong immune component. Conclusions: This is the first study that has explored genome-wide epigenetic changes associated with GWI using the new MethylationEPIC microarrays covering about 850,000 CpG sites; which builds on previous methylation preliminary reports. The data obtained are consistent with previous evidence for dysregulation of the immune system in GWI and suggests a role of this epigenetic modification on the DNA pathobiology of GWI. They are also consistent with previous reports showing a Th1- to Th2-mediated immune response shift in GWI in addition to altered immune system function. Future validation studies in larger cohorts of GWI patients and evaluation of the effects of these methylation patterns on gene expression regulation are granted.

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

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