ZNF382 controls mouse neuropathic pain via silencer-based epigenetic inhibition of Cxcl13 in DRG neurons

Author:

Ma Longfei1ORCID,Yu Lina1ORCID,Jiang Bao-Chun2ORCID,Wang Jingkai3ORCID,Guo Xinying4ORCID,Huang Yangyuxin1ORCID,Ren Jinxuan1ORCID,Sun Na1ORCID,Gao Dave Schwinn1ORCID,Ding Hao1ORCID,Lu Jianan5ORCID,Zhou Hang5ORCID,Zou Lijing1ORCID,Gao Yibo1ORCID,Wang Lieju1ORCID,Sun Kai1ORCID,Ming Yue1ORCID,Meng Zhipeng1ORCID,Tao Yuan-Xiang6ORCID,Yan Min1ORCID

Affiliation:

1. Department of Anesthesiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

2. Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Jiangsu, China

3. Department of Orthopedics, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

4. Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute and Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA

5. Department of Neurosurgery, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

6. Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ

Abstract

Nerve injury–induced changes of gene expression in dorsal root ganglion (DRG) are critical for neuropathic pain genesis. However, how these changes occur remains elusive. Here we report the down-regulation of zinc finger protein 382 (ZNF382) in injured DRG neurons after nerve injury. Rescuing this down-regulation attenuates nociceptive hypersensitivity. Conversely, mimicking this down-regulation produces neuropathic pain symptoms, which are alleviated by C-X-C motif chemokine 13 (CXCL13) knockdown or its receptor CXCR5 knockout. Mechanistically, an identified cis-acting silencer at distal upstream of the Cxcl13 promoter suppresses Cxcl13 transcription via binding to ZNF382. Blocking this binding or genetically deleting this silencer abolishes the ZNF382 suppression on Cxcl13 transcription and impairs ZNF382-induced antinociception. Moreover, ZNF382 down-regulation disrupts the repressive epigenetic complex containing histone deacetylase 1 and SET domain bifurcated 1 at the silencer-promoter loop, resulting in Cxcl13 transcriptional activation. Thus, ZNF382 down-regulation is required for neuropathic pain likely through silencer-based epigenetic disinhibition of CXCL13, a key neuropathic pain player, in DRG neurons.

Funder

National Natural Science Foundation of China

Zhejiang Provincial Natural Science Foundation of China

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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