Whole-genome methylation sequencing reveals persistent changes in DNA methylation and hydroxymethylation in female mouse prefrontal cortex following recovery from neuropathic pain: a proof-of-concept study

Source abstract

Chronic pain is associated with long-lasting neuroplasticity in cortical brain regions involved in affective and cognitive regulation. While persistent epigenetic alterations in the cortex have been described in models of chronic neuropathic pain, it is unknown if transient pain experiences leave persistent signatures after recovery. We investigated genome-wide cytosine modification patterns in the prefrontal cortex of adult female mice following recovery from sciatic nerve crush injury, a model of peripheral neuropathic pain. Mice exhibited mechanical and cold hypersensitivity and depression-like behaviors that normalized by six weeks post-injury. Prefrontal cortex tissue was profiled using whole-genome long-read Oxford Nanopore sequencing, enabling direct detection of cytosine modifications. Analysis identified 114 differentially methylated and 51 differentially hydroxymethylated regions. Pathway analysis revealed differentially methylated regions were linked to regulatory processes including stress response, development, and metabolic pathways. Differentially methylated regions localized to genomic regions associated with active transcriptional machinery and Polycomb-related chromatin regulators and were enriched for transcription factor motifs involved in developmental and stimulus-responsive gene regulation. These findings indicate provide proof-of-concept evidence for persistent epigenetic alterations in the cortex despite behavioral recovery, and suggest that prior pain exposure leaves a latent regulatory imprint relevant to future neural and behavioral responses.