JMJD1C: A critical suppressor in neuropathic pain via the SOCS3/JAK/STAT3 regulatory pathway
New study identifies super-enhancers associated with neuropathic pain
image: (A) Experimental validation of NP rat model by detecting PWT and NSF. (B) The expression levels of IL-6, TNF-α, and IL-1β were detected by ELISA in respective groups. (C) The counts of peak length by H3K27ac-based chromatin immunoprecipitation sequencing were calculated in both groups. (D) The landscape of the H3K27ac enrichment profile surrounding the transcription start site in SNI-NP and sham rat tissues. (E) The abundance of reads surrounding TSS and TES was calculated in SNI and sham rats. (F) Calculation and distribution of H3K27ac enriched reads in genome area. (G) Genomic distribution of differentially enriched peaks between SNI-NP and sham rats. The statistical results were presented as mean ± standard deviation. Student's t-test was used to determine the significance of the difference between the two groups. The asterisks indicate significance values (∗∗∗P < 0.001). NP, neuropathic pain; PWT, paw-withdrawal threshold; NSF, the number of spontaneous flinches; SNI, spared nerve injury; ELISA, enzyme‐linked immunosorbent assay; TSS, transcription start site; TES, transcription end sites.
Credit: Genes & Diseases
Neuropathic pain (NP), a chronic and debilitating condition caused by nerve damage, significantly impairs patients' quality of life. Super-enhancers (SEs), important cis-regulatory elements, have been implicated in various pathological processes; however, their specific role in NP remains unclear. This study explores the molecular mechanisms by which SEs contribute to NP progression and identifies potential therapeutic targets.
Published in Genes & Diseases, this new study by scientists at Shandong University and Tongji University investigates NP progression and examines the relevance of SE-associated epigenetic alterations in the regulation of pain behavior.
The researchers first established a spared nerve injury (SNI)-induced NP rat model and performed H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) and the corresponding RNA sequencing (RNA-seq) to characterize NP-related transcriptomic and epigenomic changes. Using ROSE (rank ordering of super-enhancers) analysis, the team identified several potential NP-related genes located near SE regions, including Rasal3, Lzts1, Metrnl, and Kcnk1. Additionally, integrative analyses of ChIP-seq, RNA-seq and and Gene Ontology (GO) data revealed Jmjd1c to be involved in the induction of pro-inflammatory factors.
Subsequent validation using quantitative PCR and double immunofluorescence staining confirmed a significant down-regulation of Jmjd1c mRNA and protein levels in the NP model. Further investigation using positional motif analysis demonstrated that the transcription factor KLF15 activates Jmjd1c transcription by binding to its SE regions. However, knockdown of KLF15 impaired this activation.
Functionally, Jmjd1c overexpression in NP rats inhibited the levels of inflammatory cytokines such as IL-6, TNF-α, and IL-1β, and mitigated the progression of NP. In contrast, Jmjd1c silencing aggravated the condition. Mechanistically, Jmjd1c promoted the transcriptional activity of suppressor of cytokine signaling 3 (Socs3) by promoting H3K9 demethylation at the Socs3 promoter, thereby modulating the JAK-STAT3 pathway and leading to an anti-NP effect. These findings highlight the Jmjd1c/Socs3/JAK/STAT3 axis as a critical downstream effector in NP pathology.
In conclusion, this study offers the first comprehensive landscape of SEs in NP rats and highlights Jmjd1c as a promising therapeutic target. Overall, the findings of this preclinical research enhance our understanding of NP progression and pave the way for the development of targeted interventions.
Reference
Title of Original Paper: Enhancer profiling uncovers Jmjd1c as an essential suppressor in neuropathic pain by targeting Socs3
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101545
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