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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 regions in CFS.Distribution of hyper- and hypo-methylated CpG regions in CFS patients compared to healthy control subjects according to (a) genic location 1500 bp and 200 bp relative to the transcription start site (TSS), in the 5′ UTR, 3′ UTR, and within gene bodies and (b) location relative to CpG islands, including 2 kb upstream and downstream of CpG islands (N, S Shore respectively), and 2 kb upstream and downstream of CpG shores (N, S Shelf respectively). No significant differences were found within CpG islands.
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pone-0104757-g001: Distribution of differentially methylated regions in CFS.Distribution of hyper- and hypo-methylated CpG regions in CFS patients compared to healthy control subjects according to (a) genic location 1500 bp and 200 bp relative to the transcription start site (TSS), in the 5′ UTR, 3′ UTR, and within gene bodies and (b) location relative to CpG islands, including 2 kb upstream and downstream of CpG islands (N, S Shore respectively), and 2 kb upstream and downstream of CpG shores (N, S Shelf respectively). No significant differences were found within CpG islands.

Mentions: Region-level analysis was performed by grouping probes within their respective annotations, and comparing average methylation values for all CpG sites at each location between CFS patients and healthy controls using the IMA regionswrapper function. A total of 934 differentially methylated CpG sites were found within or proximal to genes (i.e., genic locations) and 448 differentially methylated CpG sites were mapped with respect to their location relative to CpG islands (i.e. CpG island locations). As shown in Figure 1A, within genic regions, 30% of differentially methylated regions were hypomethylated and 70% were hypermethylated overall (Table S3). Differential methylation was localized predominantly to regions 1500 bp and 200 bp proximal to transcription start sites (31% in TSS1500 and TSS200) and more broadly within gene regulatory elements (78% in TSS1500, TSS200, 5′UTR and 3′UTR). Gene bodies contained 22% of differential methylation. Hypomethylated regions consisted of 8% of TSS regions, 21% of gene regulatory elements and 9% of gene bodies. Hypermethylated regions consisted of 23% of TSS regions, 57% of gene regulatory elements and 13% of gene bodies. As shown in Figure 1B, proximal to CpG islands, 23% of differentially methylated regions were hypomethylated, and 77% were hypermethylated overall. 29% of differentially methylated CpGs were located 2 kb upstream and downstream of CpG islands (N, S Shores), and 71% of differentially methylated CpGs were located 2 kb upstream and downstream of CpG shores (N, S Shelves). Within these regions, 23% of shores and shelves were hypomethylated, while 77% of CpG island shores and shelves were hypermethylated. No significant enrichment of DNA methylation differences was observed within 1st exons or CpG islands.


DNA methylation modifications associated with chronic fatigue syndrome.

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

Distribution of differentially methylated regions in CFS.Distribution of hyper- and hypo-methylated CpG regions in CFS patients compared to healthy control subjects according to (a) genic location 1500 bp and 200 bp relative to the transcription start site (TSS), in the 5′ UTR, 3′ UTR, and within gene bodies and (b) location relative to CpG islands, including 2 kb upstream and downstream of CpG islands (N, S Shore respectively), and 2 kb upstream and downstream of CpG shores (N, S Shelf respectively). No significant differences were found within CpG islands.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104757-g001: Distribution of differentially methylated regions in CFS.Distribution of hyper- and hypo-methylated CpG regions in CFS patients compared to healthy control subjects according to (a) genic location 1500 bp and 200 bp relative to the transcription start site (TSS), in the 5′ UTR, 3′ UTR, and within gene bodies and (b) location relative to CpG islands, including 2 kb upstream and downstream of CpG islands (N, S Shore respectively), and 2 kb upstream and downstream of CpG shores (N, S Shelf respectively). No significant differences were found within CpG islands.
Mentions: Region-level analysis was performed by grouping probes within their respective annotations, and comparing average methylation values for all CpG sites at each location between CFS patients and healthy controls using the IMA regionswrapper function. A total of 934 differentially methylated CpG sites were found within or proximal to genes (i.e., genic locations) and 448 differentially methylated CpG sites were mapped with respect to their location relative to CpG islands (i.e. CpG island locations). As shown in Figure 1A, within genic regions, 30% of differentially methylated regions were hypomethylated and 70% were hypermethylated overall (Table S3). Differential methylation was localized predominantly to regions 1500 bp and 200 bp proximal to transcription start sites (31% in TSS1500 and TSS200) and more broadly within gene regulatory elements (78% in TSS1500, TSS200, 5′UTR and 3′UTR). Gene bodies contained 22% of differential methylation. Hypomethylated regions consisted of 8% of TSS regions, 21% of gene regulatory elements and 9% of gene bodies. Hypermethylated regions consisted of 23% of TSS regions, 57% of gene regulatory elements and 13% of gene bodies. As shown in Figure 1B, proximal to CpG islands, 23% of differentially methylated regions were hypomethylated, and 77% were hypermethylated overall. 29% of differentially methylated CpGs were located 2 kb upstream and downstream of CpG islands (N, S Shores), and 71% of differentially methylated CpGs were located 2 kb upstream and downstream of CpG shores (N, S Shelves). Within these regions, 23% of shores and shelves were hypomethylated, while 77% of CpG island shores and shelves were hypermethylated. No significant enrichment of DNA methylation differences was observed within 1st exons or CpG islands.

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