Tag: chromatin

Beyond genes: EpiSwitch® and Orion platform-powered 3D genome architecture biomarkers reveal shared biology across ME/CFS, long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Long COVID (LC19), post-traumatic stress disorder (PTSD), rheumatoid arthritis (RA), and multiple sclerosis (MS) are clinically distinct disorders that share substantial symptom overlap, including persistent fatigue, cognitive impairment, autonomic dysfunction, and immune dysregulation. Although these conditions differ in diagnosis and clinical presentation, their underlying biological mechanisms remain poorly understood and may involve convergent regulatory pathways.

Methods: The EpiSwitch® 3D genomics platform and Orion knowledgebase were used to integrate chromosome conformation signatures with genome-wide association study (GWAS)-derived datasets across ME/CFS, LC19, PTSD, RA, and MS. Three-dimensional genomic anchors were mapped to coding genes and analysed using STRING protein-protein interaction networks and Cytoscape-based systems biology approaches. Disease-specific anchor datasets were generated and compared at both gene and network levels to identify shared biological processes and regulatory mechanisms.

Results: Analysis of the ME/CFS dataset identified 552 unique 3D genomic anchors mapped to 567 genes, with analogous disease-specific anchor sets generated for LC19, PTSD, RA, and MS. Direct overlap between disease-associated genes was limited; however, higher-order network analyses revealed substantial interconnectivity and convergence across conditions. Shared biological pathways included immune and cytokine signalling, interferon responses, mitochondrial function, metabolic regulation, and neuroendocrine processes. Highly connected hub genes included immune regulatory nodes such as LAG3 and components of the mTOR signalling pathway, implicating T-cell exhaustion, chronic immune activation, and immunometabolic dysregulation as common mechanisms underlying these disorders.

Conclusions: These findings support a systems-level model in which clinically overlapping fatigue-associated syndromes arise from perturbations of interconnected regulatory networks rather than discrete disease-specific pathways. Despite limited genetic overlap, substantial convergence at the network level suggests shared biological architecture across ME/CFS, LC19, PTSD, RA, and MS. The identification of common regulatory pathways provides a mechanistic framework for the development of cross-disease diagnostic and therapeutic strategies. By capturing dynamic regulatory states, 3D genomic biomarkers offer significant potential for objective blood-based diagnostics, patient stratification, and the identification of shared therapeutic targets across complex chronic disorders. These findings support the application of precision medicine approaches and may accelerate the development of novel interventions for fatigue-associated multisystem diseases.

Source: Hunter E, Alshaker H, Vugrinec D, Bautista S, Gebregzabhar A, Virdi A, Croxford J, Dring A, Powell R, Salter M, Kingdon C, Green J, Akoulitchev A, Pchejetski D. Beyond genes: EpiSwitch® and Orion platform-powered 3D genome architecture biomarkers reveal shared biology across ME/CFS, long COVID, PTSD, rheumatoid arthritis, and multiple sclerosis. J Transl Med. 2026 Aug 22;24(1):1134. doi: 10.1186/s12967-026-08874-9. PMID: 42693463. https://link.springer.com/article/10.1186/s12967-026-08874-9 (Full text)

Advocating the role of trained immunity in the pathogenesis of ME/CFS: a mini review

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic disease of which the underlying (molecular) mechanisms are mostly unknown. An estimated 0.89% of the global population is affected by ME/CFS. Most patients experience a multitude of symptoms that severely affect their lives. These symptoms include post-exertional malaise, chronic fatigue, sleep disorder, impaired cognitive functions, flu-like symptoms, and chronic immune activation. Therapy focusses on symptom management, as there are no drugs available. Approximately 60% of patients develop ME/CFS following an acute infection.

Such a preceding infection may induce a state of trained immunity; defined as acquired, nonspecific, immunological memory of innate immune cells. Trained immune cells undergo long term epigenetic reprogramming, which leads to changes in chromatin accessibility, metabolism, and results in a hyperresponsive phenotype. Initially, trained immunity has only been demonstrated in peripheral blood monocytes and macrophages. However, more recent findings indicate that hematopoietic stem cells in the bone marrow are required for long-term persistence of trained immunity. While trained immunity is beneficial to combat infections, a disproportionate response may cause disease.

We hypothesize that pronounced hyperresponsiveness of innate immune cells to stimuli could account for the aberrant activation of various immune pathways, thereby contributing to the pathophysiology of ME/CFS. In this mini review, we elaborate on the concept of trained immunity as a factor involved in the pathogenesis of ME/CFS by presenting evidence from other post-infectious diseases with symptoms that closely resemble those of ME/CFS.

Source: Humer B, Dik WA, Versnel MA. Advocating the role of trained immunity in the pathogenesis of ME/CFS: a mini review. Front Immunol. 2025 Mar 25;16:1483764. doi: 10.3389/fimmu.2025.1483764. PMID: 40201181; PMCID: PMC11975576. https://pmc.ncbi.nlm.nih.gov/articles/PMC11975576/ (Full text)

Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME) is a severe, debilitating disease, with substantial evidence pointing to immune dysregulation as a key contributor to pathophysiology. To characterize the gene regulatory state underlying T cell dysregulation in ME, we performed multiomic analysis across T cell subsets by integrating single-cell RNA-seq, RNA-seq, and ATAC-seq and further analyzed CD8+ T cell subpopulations following symptom provocation.

Specific subsets of CD8+ T cells, as well as certain innate 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 factors.

Together, these data identify T cell exhaustion as a component of ME, a finding which may provide a basis for future therapies, such as checkpoint blockade, metabolic interventions, or drugs that target chronic viral infections.

Source: Iu DS, Maya J, Vu LT, Fogarty EA, McNairn AJ, Ahmed F, Franconi CJ, Munn PR, Grenier JK, Hanson MR, Grimson A. Transcriptional reprogramming primes CD8+ T cells toward exhaustion in Myalgic encephalomyelitis/chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2024 Dec 10;121(50):e2415119121. doi: 10.1073/pnas.2415119121. Epub 2024 Dec 2. PMID: 39621903. https://www.pnas.org/doi/10.1073/pnas.2415119121 (Full text)