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, or Chronic Fatigue Syndrome (ME/CFS), is characterised by severe fatigue and associated with immune dysfunction. Previous studies of DNA methylation have found evidence of changes in immune cells for ME/CFS. However these studies have been limited by their small sample size. Here, we aggregate three comparable datasets to achieve a larger sample size and detect small changes to DNA methylation. We find 10,824 differentially methylated genes, with a small average change. Next, from the currently known interactions of relevant proteins, we build a Protein-Protein interaction network and,localising the network cartography analysis, we identify 184 hub genes. We find that different hub types play different, and meaningful, biological roles. Finally, we perform Gene ontology enrichment analysis, and we find that these hubs are involved in immune system processes, including response to TGF-{beta} and LPS, as well as mitochondrial functioning, supporting previous theories about ME/CFS. We also show that dopaminergic signalling may potentially contribute to immune pathology in ME/CFS, suggesting a possible interplay with Long Covid. Our results demonstrate the potentiality of network analysis in shedding light on the epigenetic contribution to the immune dysregulation of ME/CFS.