Family 12: Genomic and Epigenetic Regulation
Family overview. The epigenome — DNA methylation, histone modifications, chromatin remodelling, non-coding RNAs — determines which genes are expressed in response to environmental signals without changing the DNA sequence. Epigenetic dysregulation can stably alter cellular programs in response to transient triggers, providing a molecular mechanism for how infection produces durable disease.
Concrete mechanisms and ME/CFS evidence:
Genome-wide DNA methylation signatures. Multiple EWAS studies identify differentially methylated CpG sites in ME/CFS leukocytes — over 17,000 sites in 6,368 genes in the largest study, enriched in immune signalling pathways (Trivedi et al. 2018). Relapse episodes produce dynamic methylome changes that partially recover with remission (Helliwell et al. 2022).
Histone modification dysregulation. HDAC activity alterations reported; chromatin remodelling changes affect immune gene expression. Glucocorticoid receptor sensitivity is epigenetically reduced, contributing to HPA axis blunting (Roberts et al. 2017).
Telomere attrition. ME/CFS patients show telomeres shorter by 254–957 base pairs than age-matched controls, corresponding to 4–20 years of additional biological aging; effect strongest in women under 45. Chronic inflammation and oxidative stress drive accelerated attrition (Rajeevan et al. 2018).
Oxidative DNA damage. Elevated 8-OHdG as a marker of guanine oxidation; DNA repair pathway capacity (nucleotide excision repair, base excision repair) has not been directly assessed in ME/CFS.
Post-viral epigenetic persistence. EBV and SARS-CoV-2 infection leaves specific epigenetic marks in immune cells; these may perpetuate altered immune gene expression profiles long after active infection resolves, providing a mechanism for how a transient trigger produces durable ME/CFS.
MicroRNA and non-coding RNA dysregulation. Preliminary data suggests altered miRNA profiles in ME/CFS PBMCs; functional characterisation of downstream targets is incomplete.
Full discussion: Genetic and Epigenetic Factors.
Evidence status: Established (methylation findings in multiple independent cohorts); Preliminary (telomere — single study; needs replication).