PTPRN2 hypomethylation and PHB2-modulated miR-153-3p maturation reveal dual epigenetic mechanisms linked to symptom variability in Myalgic Encephalomyelitis

Methods

Saliva samples from 54 ME patients and 21 sedentary healthy controls were analyzed by DNA methylation array. Symptom assessment was conducted using validated questionnaires (SF-36, MFI-20, and DSQ). Results: A significant DNA hypomethylation at the CpG site cg19803194 (Bonferroni-corrected p=3x10-7) within the PTPRN2 gene body was identified.

This hypomethylation was associated with cognitive impairments in both sexes, such as difficulties expressing thoughts and comprehension, commonly known as "brain fog," and as well as respiratory issues in male patients. The hypomethylation also corresponded with reduced circulating levels of miR-153-3p, an intronic microRNA of PTPRN2, which was associated with impaired memory recall in both sexes. Interestingly, the mitochondrial protein Prohibitin 2 (PHB2) emerged as a negative regulator of miR-153-3p maturation, likely through its physical interaction with immature forms of miR-153 within cells, which was attenuated in female patients due to increased extracellular export of PHB2.

Conclusions: These findings propose a potential epigenetic mechanism in ME involving PTPRN2 body hypomethylation and PHB2-modulated miR-153-3p maturation. While the directionality between gene-body methylation and expression remains a biological hypothesis, these results shedding light on possible pathways contributing to symptom variability and sex differences in ME severity.