A Cartography of Differential Gene Methylation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Different Network Roles in the Protein-Protein Interactions Network Play Different, Biologically Relevant, Roles

Abstract

Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a debilitating illness characterised by severe fatigue and associated with immune dysfunction. Previous studies of DNA methylation (epigenetic changes that can affect the gene transcription) have found evidence of changes in immune cells for ME/CFS. However these studies have been limited by their small sample size, precluding the ability to detect changes to methylation of smaller magnitude. Therefore, to achieve a larger sample size and detect small changes to DNA methylation, we aggregate three comparable datasets and analyse them in unison. We find 10,824 differentially methylated genes, with a very small average change. We then turn our attention to the network structure of the Protein-Protein interaction, which we built from the currently known interactions of relevant proteins, and localising the network cartography framework, we identify 184 hub genes. A distinct structuring emerges, with different hub types playing differing, meaningful, biological roles. Supporting previous theories about ME/CFS, Gene ontology enrichment analysis of these hubs reveal that they are involved in immune system processes, including response to TGF-β and LPS, as well as mitochondrial functioning. We also show that dopaminergic signalling may potentially contribute to immune pathology in ME/CFS. Our results demonstrate the potentiality of network cartographic approaches in shedding light on the epigenetic contribution to the immune dysregulation of ME/CFS.

Perturbations in common and distinct inflammatory pathways associated with morning and evening fatigue in outpatients receiving chemotherapy

“… 39 clrs can activate NF‐κb signaling (morning fatigue) and pathways for T‐cell differentiation (both morning and evening fatigue). While not evaluated in patients undergoing chemotherapy, in a study of patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), 40 the C‐type lectin receptor signaling pathway was a member of a cluster of pathways enriched for differentially methylated genes associated with CFS severity. CRF and CFS/ME share gene expression patterns at a subset of genes 7 and may share underlying mechanisms.…”