2. Academic Validation
  3. SETDB2-mediated transcriptional repression of IDE in sensory neurons promotes migraine-like pain behaviors in mice

SETDB2-mediated transcriptional repression of IDE in sensory neurons promotes migraine-like pain behaviors in mice

  • Cell Rep. 2026 Mar 24;45(4):117201. doi: 10.1016/j.celrep.2026.117201.
Yunmei Zhang 1,  Zitong Huang 2,  Yufang Sun 2,  Shoupeng Wang 2,  Yu Tao 2,  Weiwei Lu 2,  Yaqun Zhang 2,  Dongsheng Jiang 3,  Junzhe Ge 4,  Gang Chen 5,  Xiaohong Jin 6,  Fuhai Ji 7,  Yonggang Wang 8,  Yafeng Yu 9,  Yuan Zhang 10,  Jin Tao 11
Affiliations

Affiliations

  • 1 Department of Otolaryngology, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China; The First Affiliated Hospital of Soochow University, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, P.R. China.
  • 2 The First Affiliated Hospital of Soochow University, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, P.R. China.
  • 3 Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, P.R. China.
  • 4 St. Catharine's College, Cambridge University, Cambridge CB2 1RL, UK.
  • 5 The First Affiliated Hospital of Soochow University, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, P.R. China; Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, Center for Ion Channelopathy, Soochow University, Suzhou 215123, P.R. China.
  • 6 Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China.
  • 7 Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China; Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, Center for Ion Channelopathy, Soochow University, Suzhou 215123, P.R. China.
  • 8 Headache Center, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, P.R. China.
  • 9 Department of Otolaryngology, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China. Electronic address: [email protected].
  • 10 Clinical Research Center of Neurological Disease, Department of Geriatrics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, P.R. China. Electronic address: [email protected].
  • 11 Department of Otolaryngology, The First Affiliated Hospital of Soochow University, Suzhou 215006, P.R. China; The First Affiliated Hospital of Soochow University, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, P.R. China; Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, Center for Ion Channelopathy, Soochow University, Suzhou 215123, P.R. China; MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou 215123, P.R. China. Electronic address: [email protected].
PMID: 41880325 DOI: 10.1016/j.celrep.2026.117201
Abstract

The persistent headaches characteristic of chronic migraine may stem from the activation and sensitization of primary afferent neurons within the trigeminovascular pathway. However, the underlying molecular mechanisms remain unclear. This study shows a SET-domain bifurcated histone lysine methyltransferase, SETDB2, in trigeminal ganglion (TG) neurons as a key mediator of migraine-like pain. In a mouse model of chronic migraine induced by nitroglycerin (NTG), SETDB2 is significantly upregulated in TG neurons, a finding mirrored in cerebrospinal fluid from patients with migraine. Reversing this upregulation reduces levels of the repressive histone MARK H3K9me3 and alleviates migraine-like pain behaviors in mice, whereas mimicking it induces hypersensitivity. Mechanistically, SETDB2 upregulation impedes transcription factor KLF4 from binding to the promoter of the insulin-degrading enzyme (IDE) gene, thereby suppressing IDE expression and impairing degradation of calcitonin-gene-related peptide (CGRP) in TG neurons. Targeting the sensory SETDB2-KLF4-IDE transcriptional axis may present therapeutic opportunities for treating migraine.

Keywords

CP: molecular biology; CP: neuroscience; SETDB2; calcitonin-gene-related peptide; insulin-degrading enzyme; migraine; trigeminal ganglion neurons.

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