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

Longfei Ma (), Yangyuxin Huang, Meiling Han, Bing Wang, Xinying Guo, Zanbin Wang, Fan Zhang, Yuqiong Xie, Jinxuan Ren, Junwu Wang, Xiaotian Ma, Jia Dan, Yanni He, Yutao Deng, Mingzhe Yin, Hongming Wu, Hao Hu, Qin Ouyang, Na Sun, Jianing Wu, Xiaotong Li, Jingkai Wang, Wenkan Zhang, Zhi-Qiang Pan, Lina Yu (), Bao-Chun Jiang (), Yuan-Xiang Tao () and Min Yan ()
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Longfei Ma: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Yangyuxin Huang: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Meiling Han: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Bing Wang: New Jersey Medical School, Rutgers, The State University of New Jersey, Department of Anesthesiology
Xinying Guo: Guangdong Provincial Clinical Research Center for Child Health, Department of Anesthesiology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University
Zanbin Wang: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Fan Zhang: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Yuqiong Xie: Second Affiliated Hospital of Zhejiang University School of Medicine, Center for Basic and Translational Research
Jinxuan Ren: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Junwu Wang: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Xiaotian Ma: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Jia Dan: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Yanni He: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Yutao Deng: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Mingzhe Yin: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Hongming Wu: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Hao Hu: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Qin Ouyang: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Na Sun: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Jianing Wu: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Xiaotong Li: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Jingkai Wang: Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province
Wenkan Zhang: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Plastic Surgery
Zhi-Qiang Pan: Xuzhou Medical University, Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs
Lina Yu: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Bao-Chun Jiang: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology
Yuan-Xiang Tao: New Jersey Medical School, Rutgers, The State University of New Jersey, Department of Anesthesiology
Min Yan: Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Anesthesiology

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-65935-1

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