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DNA methylation modifications associated with chronic fatigue syndrome.

de Vega WC, Vernon SD, McGowan PO - PLoS ONE (2014)

Bottom Line: Epigenetic modifications have been implicated in long-term effects on gene function, however, to our knowledge, genome-wide epigenetic modifications associated with CFS have not been explored.We found an increased abundance of differentially methylated genes related to the immune response, cellular metabolism, and kinase activity.Genes associated with immune cell regulation, the largest coordinated enrichment of differentially methylated pathways, showed hypomethylation within promoters and other gene regulatory elements in CFS.

View Article: PubMed Central - PubMed

Affiliation: Centre for Environmental Epigenetics and Development, University of Toronto, Scarborough, ON, Canada; Department of Biological Sciences, University of Toronto, Scarborough, ON, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada.

ABSTRACT
Chronic Fatigue Syndrome (CFS), also known as myalgic encephalomyelitis, is a complex multifactorial disease that is characterized by the persistent presence of fatigue and other particular symptoms for a minimum of 6 months. Symptoms fail to dissipate after sufficient rest and have major effects on the daily functioning of CFS sufferers. CFS is a multi-system disease with a heterogeneous patient population showing a wide variety of functional disabilities and its biological basis remains poorly understood. Stable alterations in gene function in the immune system have been reported in several studies of CFS. Epigenetic modifications have been implicated in long-term effects on gene function, however, to our knowledge, genome-wide epigenetic modifications associated with CFS have not been explored. We examined the DNA methylome in peripheral blood mononuclear cells isolated from CFS patients and healthy controls using the Illumina HumanMethylation450 BeadChip array, controlling for invariant probes and probes overlapping polymorphic sequences. Gene ontology (GO) and network analysis of differentially methylated genes was performed to determine potential biological pathways showing changes in DNA methylation in CFS. We found an increased abundance of differentially methylated genes related to the immune response, cellular metabolism, and kinase activity. Genes associated with immune cell regulation, the largest coordinated enrichment of differentially methylated pathways, showed hypomethylation within promoters and other gene regulatory elements in CFS. These data are consistent with evidence of multisystem dysregulation in CFS and implicate the involvement of DNA modifications in CFS pathology.

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Distribution of differentially methylated sites in CFS according to GO clusters and functional relevance.Relative proportions of hyper- and hypo-methylated CpG sites between CFS patients and healthy control subjects for genes associated with the immune cell regulation cluster group (immune GO) compared to all four GO term cluster groups (all GO). Results are shown for each genic region, consisting of promoter regions within 1500 bp and 200 bp of the transcription start sites (TSS), gene regulatory elements (regulatory: TSS1500, TSS200, 5′ UTR, 3′ UTR), the coding regions of genes (gene body), as well as all regions combined (total: regulatory, gene body). * = p<0.0125, Pearson Chi-Squared Test.
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pone-0104757-g004: Distribution of differentially methylated sites in CFS according to GO clusters and functional relevance.Relative proportions of hyper- and hypo-methylated CpG sites between CFS patients and healthy control subjects for genes associated with the immune cell regulation cluster group (immune GO) compared to all four GO term cluster groups (all GO). Results are shown for each genic region, consisting of promoter regions within 1500 bp and 200 bp of the transcription start sites (TSS), gene regulatory elements (regulatory: TSS1500, TSS200, 5′ UTR, 3′ UTR), the coding regions of genes (gene body), as well as all regions combined (total: regulatory, gene body). * = p<0.0125, Pearson Chi-Squared Test.

Mentions: Within the 4 cluster groups, 511 unique genes containing a total of 637 CpG sites were significantly hypermethylated among CFS patients compared to healthy controls, and 184 unique genes containing 237 CpGs were significantly hypomethylated. The full list of differentially methylated genes and their associated CpG sites is provided in Table S6. To examine the potential biological meaning of differentially methylated CpG sites, we determined the localization of differentially methylated CpGs in promoter regions within 1500 bp and 200 bp of transcription start sites (TSS: TSS1500, TSS200), in gene regulatory elements (regulatory: TSS1500, TSS200, 5′ UTR, 3′ UTR) and in gene coding regions (gene body). For hypermethylated genes, the proportion of differentially methylated CpGs in TSS, regulatory, and gene body regions was 73.05%, 70.83%, and 74.17%, respectively (Figure 4). For hypomethylated genes, the proportion found within each of these regions was 26.95% (TSS), 29.17% (regulatory), and 25.84% (gene body).


DNA methylation modifications associated with chronic fatigue syndrome.

de Vega WC, Vernon SD, McGowan PO - PLoS ONE (2014)

Distribution of differentially methylated sites in CFS according to GO clusters and functional relevance.Relative proportions of hyper- and hypo-methylated CpG sites between CFS patients and healthy control subjects for genes associated with the immune cell regulation cluster group (immune GO) compared to all four GO term cluster groups (all GO). Results are shown for each genic region, consisting of promoter regions within 1500 bp and 200 bp of the transcription start sites (TSS), gene regulatory elements (regulatory: TSS1500, TSS200, 5′ UTR, 3′ UTR), the coding regions of genes (gene body), as well as all regions combined (total: regulatory, gene body). * = p<0.0125, Pearson Chi-Squared Test.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4128721&req=5

pone-0104757-g004: Distribution of differentially methylated sites in CFS according to GO clusters and functional relevance.Relative proportions of hyper- and hypo-methylated CpG sites between CFS patients and healthy control subjects for genes associated with the immune cell regulation cluster group (immune GO) compared to all four GO term cluster groups (all GO). Results are shown for each genic region, consisting of promoter regions within 1500 bp and 200 bp of the transcription start sites (TSS), gene regulatory elements (regulatory: TSS1500, TSS200, 5′ UTR, 3′ UTR), the coding regions of genes (gene body), as well as all regions combined (total: regulatory, gene body). * = p<0.0125, Pearson Chi-Squared Test.
Mentions: Within the 4 cluster groups, 511 unique genes containing a total of 637 CpG sites were significantly hypermethylated among CFS patients compared to healthy controls, and 184 unique genes containing 237 CpGs were significantly hypomethylated. The full list of differentially methylated genes and their associated CpG sites is provided in Table S6. To examine the potential biological meaning of differentially methylated CpG sites, we determined the localization of differentially methylated CpGs in promoter regions within 1500 bp and 200 bp of transcription start sites (TSS: TSS1500, TSS200), in gene regulatory elements (regulatory: TSS1500, TSS200, 5′ UTR, 3′ UTR) and in gene coding regions (gene body). For hypermethylated genes, the proportion of differentially methylated CpGs in TSS, regulatory, and gene body regions was 73.05%, 70.83%, and 74.17%, respectively (Figure 4). For hypomethylated genes, the proportion found within each of these regions was 26.95% (TSS), 29.17% (regulatory), and 25.84% (gene body).

Bottom Line: Epigenetic modifications have been implicated in long-term effects on gene function, however, to our knowledge, genome-wide epigenetic modifications associated with CFS have not been explored.We found an increased abundance of differentially methylated genes related to the immune response, cellular metabolism, and kinase activity.Genes associated with immune cell regulation, the largest coordinated enrichment of differentially methylated pathways, showed hypomethylation within promoters and other gene regulatory elements in CFS.

View Article: PubMed Central - PubMed

Affiliation: Centre for Environmental Epigenetics and Development, University of Toronto, Scarborough, ON, Canada; Department of Biological Sciences, University of Toronto, Scarborough, ON, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada.

ABSTRACT
Chronic Fatigue Syndrome (CFS), also known as myalgic encephalomyelitis, is a complex multifactorial disease that is characterized by the persistent presence of fatigue and other particular symptoms for a minimum of 6 months. Symptoms fail to dissipate after sufficient rest and have major effects on the daily functioning of CFS sufferers. CFS is a multi-system disease with a heterogeneous patient population showing a wide variety of functional disabilities and its biological basis remains poorly understood. Stable alterations in gene function in the immune system have been reported in several studies of CFS. Epigenetic modifications have been implicated in long-term effects on gene function, however, to our knowledge, genome-wide epigenetic modifications associated with CFS have not been explored. We examined the DNA methylome in peripheral blood mononuclear cells isolated from CFS patients and healthy controls using the Illumina HumanMethylation450 BeadChip array, controlling for invariant probes and probes overlapping polymorphic sequences. Gene ontology (GO) and network analysis of differentially methylated genes was performed to determine potential biological pathways showing changes in DNA methylation in CFS. We found an increased abundance of differentially methylated genes related to the immune response, cellular metabolism, and kinase activity. Genes associated with immune cell regulation, the largest coordinated enrichment of differentially methylated pathways, showed hypomethylation within promoters and other gene regulatory elements in CFS. These data are consistent with evidence of multisystem dysregulation in CFS and implicate the involvement of DNA modifications in CFS pathology.

Show MeSH
Related in: MedlinePlus