Enhancer profiling uncovers Jmjd1c as an essential suppressor in neuropathic pain by targeting Socs3

Neuropathic pain (NP) is a chronic debilitating disease caused by nerve damage or various diseases, significantly impairs patients’ quality of life. Super-enhancers (SEs) are important cis-regulatory elements, but how they affect NP remains elusive. Therefore, we aim to explore the molecular mechanism by which SEs are involved in NP progression and identify potential drug candidate targets. We first established a NP model in rats, and subsequently performed H3K27ac ChIP-Seq and RNA-Seq on their spinal cord tissues to analyze the active enhancers. By integrated analysis of ChIP-seq data and RNA-seq data, we clarified a series of SE-associated genes involved in NP progression. qPCR and double immunofluorescence staining results suggested that Jmjd1c mRNA and protein levels were significantly down-regulated in the NP model. In addition, a dual-luciferase reporter assay showed that KLF15 could activate Jmjd1c transcription by binding to the SE of Jmjd1c. Functionally, enhanced Jmjd1c can inhibit the levels of inflammatory cytokines such as IL-6, TNF-α, IL-1β, and inhibited the progression of NP, whereas silencing Jmjd1c had the opposite effect. Mechanistic exploration identified Jmjd1c exerted its anti-NP effect via positively regulating Socs3 expression by increasing the activity of H3K9 demethylation, and the Jmjd1c/Socs3/JAK/STAT3 regulatory pathway was finally validated as downstream effectors. In conclusion, our study suggests that SE-associated Jmjd1c was suppressed during NP progression due to the decreased recruitment of KLF15. The reduction of Jmjd1c downregulated Socs3 through the demethylation of H3K9 at Socs3 promoter region, leading to NP progression.