Sex differences uncovered: baseline epigenetic patterns in human dorsal root ganglia

Aims: In this study, the Price group examined baseline sex differences in chromatin accessibility from human dorsal root ganglia (hDRG), which are crucial for nociceptive signaling. Their work aimed to interrogate underlying epigenetic differences that might lead to divergent gene expression patterns in men and women before the onset of pathological pain, potentially contributing to pain disparities.

Methods: Lumbar hDRG from adult donors without chronic pain were analysed using bulk and spatial ATAC-seq to map chromatin accessibility and identify sex-specific regulatory elements. RNA-seq and in situ hybridization complemented these approaches by linking chromatin accessibility to gene expression, offering a clearer understanding of the genetic and epigenetic factors at play.

Results: The study revealed significant sex-based differences in chromatin accessibility in the hDRG, with the X chromosome playing a major role in females, potentially due to reduced X inactivation or a readiness for gene expression changes. Hormone-responsive transcription factor motifs like EGR1/3 were prevalent in these regions. In males, differentially accessible regions were found on autosomal genes with enriched AP-1 factors such as JUN and FOS, suggesting higher cellular activation. Spatial ATAC-seq showed that females had increased accessibility in GABA-A and glutamatergic genes, while males exhibited open chromatin in calcium and potassium channels, reflecting diverse neuronal signaling pathways. Notably, spatial ATAC-seq also identified sex differences in TRPV3 gene accessibility within DRG neurons, involved in thermal heat transduction.

Conclusions: Together, this work highlights sex-specific chromatin accessibility in the hDRG, indicating unique mechanisms that contribute to differing pain experiences in men and women, with significant implications for clinical pain management.

Comments: This study delves into sex-specific epigenetic differences in the hDRG, highlighting implications for diabetic neuropathy. The findings show that females have increased chromatin accessibility in genes related to GABAergic, glutamatergic, and interferon pathways, which may explain their increased pain sensitivity. Conversely, in males, the prevalence of open chromatin in calcium and potassium channels suggests distinct neuronal signaling pathways. These results emphasize the need for tailored approaches in managing pain disorders like diabetic neuropathy, considering the foundational chromatin differences that drive sex-specific pain experiences. As the scientific community seeks to further understand the complexities of pain across sexes, this research paves the way for exploring dynamic epigenetic components in chronic pain conditions, potentially offering novel strategies for pain management in diabetic patients.

Stéphanie Eid

Reference: Franco-Enzástiga Ú, Inturi NN, Natarajan K, Mwirigi JM, Mazhar K, Schlachetzki JCM, Schumacher M, Price TJ. Epigenomic landscape of the human dorsal root ganglion: sex differences and transcriptional regulation of nociceptive genes. Pain. 2025 Mar 1;166(3):614-630. doi: 10.1097/j.pain.0000000000003508. Epub 2025 Jan 23. PMID: 39928726; PMCID: PMC11819886.

🔗 https://journals.lww.com/pain/fulltext/2025/03000/epigenomic_landscape_of_the_human_dorsal_root.16.aspx