4 / 2025-12-02 09:17:43

ZFP612 controls neuropathic pain through epigenetic repression of Il1rl1 within the silencer-promoter loop in primary sensory neurons

neurodegenerative disease, neuronal intrinsic immune response, 3D epigenomic, zinc finger proteins, silencer, epigenetic repressive complex

Peripheral nerve injury-induced intrinsic immune responses in primary sensory neurons are critical for neuropathic pain genesis. However, the key regulators driving these responses remain elusive. Here, we report that nerve injury-specific downregulation of zinc finger protein 612 (ZFP612) in injured sensory neurons contributes to the neuronal interleukin (IL) signaling activation and neuropathic pain in male mice, which is largely alleviated by interleukin 1 receptor-like 1 (Il1rl1) knockout. Mechanistically, an identified intronic cis-regulatory silencer represses the transcription of Il1rl1 via interaction with ZFP612. Mice lacking the silencer exhibit a loss of ZFP612 suppression on Il1rl1 transcription from its three alternative promoters (P1-P3) and impairment of ZFP612-mediated anti-nociception. Further, ZFP612 downregulation disrupts the ZFP612/HDAC1/HDAC2/SETDB1 epigenetic complex and eliminates the repressive modifications within the silencer-P3 loop, thereby facilitating transcriptional elongation from P1/P2 and initiation from P3 of Il1rl1 simultaneously. Thus, ZFP612 controls nociceptive hypersensitivity likely through silencer-based epigenetic silencing of Il1rl1, a key neuropathic pain player, in injured sensory neurons.