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Transcriptional reprogramming primes CD8+ T cells towards exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [RNA-seq]

ABSTRACT: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME) is a severe, debilitating disease, with mounting evidence pointing to immune dysregulation as a key contributor to pathophysiology. To characterize the gene regulatory state underlying dysregulation of T cells in ME, we performed multiomic analysis of distinct subsets by integrating single-cell RNA-seq, RNA-seq and ATAC-seq, and further analyzed CD8+ T cell subpopulations following symptom provocation. Certain subsets of CD8+ T cells, as well as certain innate lineages of T cells, displayed the most pronounced dysregulation in ME. We observed upregulation of key transcription factors associated with T cell exhaustion in CD8+ T cell effector memory subsets, as well as an altered chromatin landscape and metabolic reprogramming consistent with an exhausted immune cell state. To validate these observations, we analyzed expression of exhaustion markers using flow cytometry, detecting a higher frequency of exhaustion-associated transcription factors, and supporting a novel state of immune dysregulation in ME, which may ultimately provide a basis for future therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268212 | GEO | 2024/11/11

REPOSITORIES: GEO

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Transcriptional reprogramming primes CD8+ T cells towards exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [ATAC-seq]

Project description:Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME) is a severe, debilitating disease, with mounting evidence pointing to immune dysregulation as a key contributor to pathophysiology. To characterize the gene regulatory state underlying dysregulation of T cells in ME, we performed multiomic analysis of distinct subsets by integrating single-cell RNA-seq, RNA-seq and ATAC-seq, and further analyzed CD8+ T cell subpopulations following symptom provocation. Certain subsets of CD8+ T cells, as well as certain innate lineages of T cells, displayed the most pronounced dysregulation in ME. We observed upregulation of key transcription factors associated with T cell exhaustion in CD8+ T cell effector memory subsets, as well as an altered chromatin landscape and metabolic reprogramming consistent with an exhausted immune cell state. To validate these observations, we analyzed expression of exhaustion markers using flow cytometry, detecting a higher frequency of exhaustion-associated transcription factors, and supporting a novel state of immune dysregulation in ME, which may ultimately provide a basis for future therapies.

2024-11-11 | GSE268223 | GEO

Transcriptional reprogramming primes CD8+ T cells towards exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [RNA-seq]

Project description:Transcriptional reprogramming primes CD8+ T cells towards exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [RNA-seq]

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Transcriptional reprogramming primes CD8+ T cells towards exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [ATAC-seq]

Project description:Transcriptional reprogramming primes CD8+ T cells towards exhaustion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [ATAC-seq]

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Deep phenotyping of Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [Protein]

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Deep phenotyping of Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [Protein plasma]

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Deep phenotyping of Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [RNA-Seq]

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Deep phenotyping of Post-infectious Myalgic Encephalomyelitis/Chronic Fatigue Syndrome [PBMC RNA-Seq]

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

Project description: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.

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