Genome-Epigenome Interactions Associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Herrera, Santiago; Vega, Wilfred C. de; Ashbrook, David G.; Vernon, Suzanne D.; McGowan, Patrick O.

doi:10.1101/237958

Cited by 6 publications

(23 citation statements)

References 77 publications

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“…The addition of methyl groups at promoters is consistent with a hypometabolic state where the expression of genes involved in metabolic pathways is down regulated. Differential methylation in ME/CFS has been found in close proximity to genes involved in immune function and cellular metabolism, linked with the ME/CFS phenotype [43,44,45]. Overall, these ndings align with recent ME/CFS ndings pointing towards impairment in cellular energy production and immune dysfunction in the patient population.…”

Section: Histone Methylation and Proteasome Activation; Dampened Platsupporting

confidence: 75%

“…In recent years ME/CFS research has shifted its focus from attempting to identify a universal 'causative agent' for the illness, to instead ascertaining the key affected physiology and biological pathways behind the ME/CFS symptom complex. High-throughput molecular analyses including cytokine production [12], metabolomics [13][14][15][16], the microbiome [17][18][19], epigenetics [20][21][22][23], transcriptome [24][25][26] and proteome investigations [27][28][29][30][31][32] have provided substantial evidence of immune/in ammation involvement, and, signi cantly, suggest there are de cits in energy metabolism and mitochondrial function in ME/CFS. While there have been inconsistencies in the evidence for mitochondrial dysfunction, a growing number of research papers are supportive of this hypothesis.…”

Section: Introductionmentioning

confidence: 99%

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A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction

Sweetman

Kleffmann²,

Edgar³

et al. 2020

Preprint

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Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and ‘post-exertional malaise’, exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology.Methods: To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group. Results: A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < -0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation. Conclusions: The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.

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Section: Histone Methylation and Proteasome Activation; Dampened Platsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction

Sweetman

Kleffmann²,

Edgar³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The addition of methyl groups at promoters is consistent with a hypometabolic state where the expression of genes involved in metabolic pathways is down regulated. Differential methylation in ME/CFS has been found in close proximity to genes involved in immune function and cellular metabolism, linked with the ME/CFS phenotype [ 21 , 22 , 42 ]. Overall, these findings align with recent ME/CFS findings pointing towards impairment in cellular energy production and immune dysfunction in the patient population.…”

Section: Discussionmentioning

confidence: 99%

A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction

et al. 2020

View full text Add to dashboard Cite

Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a serious and complex physical illness that affects all body systems with a multiplicity of symptoms, but key hallmarks of the disease are pervasive fatigue and ‘post-exertional malaise’, exacerbation after physical and/or mental activity of the intrinsic fatigue and other symptoms that can be highly debilitating and last from days to months. Although the disease can vary widely between individuals, common symptoms also include pain, cognitive deficits, sleep dysfunction, as well as immune, neurological and autonomic symptoms. Typically, it is a very isolating illness socially, carrying a stigma because of the lack of understanding of the cause and pathophysiology. Methods To gain insight into the pathophysiology of ME/CFS, we examined the proteomes of peripheral blood mononuclear cells (PBMCs) by SWATH-MS analysis in a small well-characterised group of patients and matched controls. A principal component analysis (PCA) was used to stratify groups based on protein abundance patterns, which clearly segregated the majority of the ME/CFS patients (9/11) from the controls. This majority subgroup of ME/CFS patients was then further compared to the control group. Results A total of 60 proteins in the ME/CFS patients were differentially expressed (P < 0.01, Log10 (Fold Change) > 0.2 and < −0.2). Comparison of the PCA selected subgroup of ME/CFS patients (9/11) with controls increased the number of proteins differentially expressed to 99. Of particular relevance to the core symptoms of fatigue and post-exertional malaise experienced in ME/CFS, a proportion of the identified proteins in the ME/CFS groups were involved in mitochondrial function, oxidative phosphorylation, electron transport chain complexes, and redox regulation. A significant number were also involved in previously implicated disturbances in ME/CFS, such as the immune inflammatory response, DNA methylation, apoptosis and proteasome activation. Conclusions The results from this study support a model of deficient ATP production in ME/CFS, compensated for by upregulation of immediate pathways upstream of Complex V that would suggest an elevation of oxidative stress. This study and others have found evidence of a distinct pathology in ME/CFS that holds promise for developing diagnostic biomarkers.

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“…A number of environmental factors such as exposure to toxins/chemicals, stressful life events and especially viral infections have been frequency reported in association with the onset and progression of ME/CFS [ 3 ]. As environmental factors such as these have been observed to cause changes to an individual’s DNA methylation, this has prompted investigations into whether there are specific epigenetic changes linked to the disease [ 6 – 10 ]. DNA methylation is the best understood epigenetic modification where the addition of a methyl group to the cytosine base of DNA is associated with changes in gene expression without altering the genomic code itself [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…A small number of studies [ 6 – 10 ] have utilised array-based technology to interrogate DNA methylation in ME/CFS patients at a large number of sites across the genome. There are strengths in array-based genome scale investigation since the targeted probes result in low experimental variability, but they do have a restricted CpG coverage as they are designed to target regions that capture RefSeq genes and promoter CpG islands.…”

Section: Introductionmentioning

confidence: 99%

Changes in DNA methylation profiles of myalgic encephalomyelitis/chronic fatigue syndrome patients reflect systemic dysfunctions

et al. 2020

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Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a lifelong debilitating disease with a complex pathology not yet clearly defined. Susceptibility to ME/CFS involves genetic predisposition and exposure to environmental factors, suggesting an epigenetic association. Epigenetic studies with other ME/CFS cohorts have used array-based technology to identify differentially methylated individual sites. Changes in RNA quantities and protein abundance have been documented in our previous investigations with the same ME/CFS cohort used for this study. Results DNA from a well-characterised New Zealand cohort of 10 ME/CFS patients and 10 age-/sex-matched healthy controls was isolated from peripheral blood mononuclear (PBMC) cells, and used to generate reduced genome-scale DNA methylation maps using reduced representation bisulphite sequencing (RRBS). The sequencing data were analysed utilising the DMAP analysis pipeline to identify differentially methylated fragments, and the MethylKit pipeline was used to quantify methylation differences at individual CpG sites. DMAP identified 76 differentially methylated fragments and Methylkit identified 394 differentially methylated cytosines that included both hyper- and hypo-methylation. Four clusters were identified where differentially methylated DNA fragments overlapped with or were within close proximity to multiple differentially methylated individual cytosines. These clusters identified regulatory regions for 17 protein encoding genes related to metabolic and immune activity. Analysis of differentially methylated gene bodies (exons/introns) identified 122 unique genes. Comparison with other studies on PBMCs from ME/CFS patients and controls with array technology showed 59% of the genes identified in this study were also found in one or more of these studies. Functional pathway enrichment analysis identified 30 associated pathways. These included immune, metabolic and neurological-related functions differentially regulated in ME/CFS patients compared to the matched healthy controls. Conclusions Major differences were identified in the DNA methylation patterns of ME/CFS patients that clearly distinguished them from the healthy controls. Over half found in gene bodies with RRBS in this study had been identified in other ME/CFS studies using the same cells but with array technology. Within the enriched functional immune, metabolic and neurological pathways, a number of enriched neurotransmitter and neuropeptide reactome pathways highlighted a disturbed neurological pathophysiology within the patient group.

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Genome-Epigenome Interactions Associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Cited by 6 publications

References 77 publications

A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction

A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction

A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction

Changes in DNA methylation profiles of myalgic encephalomyelitis/chronic fatigue syndrome patients reflect systemic dysfunctions

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