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The SETDB2/KLF4/IDE/CGRP signaling axis in sensory neurons controls migraine [NTG]

ABSTRACT: The persistent headaches characteristic of chronic migraine may stem from the activation and sensitization of primary afferent neurons within the trigeminovascular pathway. The molecular basis for this pathophysiology, however, remains incompletely understood. In this study, we demonstrated that SETDB2, a histone methyltransferase expressed in trigeminal ganglion (TG) neurons, plays a pivotal role in facilitating migraine-associated pain behaviors. We modelled chronic headache with repeated administration of nitroglycerin (NTG, a well-recognized migraine trigger in migraineurs) and observed a notable upregulation of SETDB2 in mouse TG neurons following NTG treatment. A comparable increase was also identified in the cerebrospinal fluid of migraine sufferers. Reversing the NTG-induced SETDB2 upregulation abrogated the increased trimethylation of histone H3K9 (H3K9me3) and alleviated established migraine-associated pain behaviors. Conversely, mimicking the upregulation of SETDB2 in intact TG neurons was sufficient to induce pain hypersensitivity. Moreover, we found that SETDB2 upregulation induced by NTG prevented the binding of the transcription factor KLF4 to the promoter of the insulin-degrading enzyme (Ide) gene. This, in turn, inhibited IDE expression, and hindered the degradation of calcitonin- gene-related peptide (CGRP), a promising target for preventing migraine, in TG neurons. Targeting the sensory SETDB2-KLF4-IDE transcriptional axis may present novel therapeutic opportunities for treating migraine.

ORGANISM(S): Mus musculus

PROVIDER: GSE308023 | GEO | 2026/02/28

REPOSITORIES: GEO

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Project description:Background Vestibular migraine (VM) is a disorder characterized by recurrent episodes of dizziness or vertigo and is often accompanied by headache. The mechanisms underlying vestibular dysfunction and pain in VM remain unclear. Methods Chronic migraine (CM) and VM models were induced by NTG and kainic acid, respectively. Behavioral assessments were conducted to evaluate vestibular dysfunction and pain in the VM and CM models. Transmission electron microscopy (TEM) was used to examine peripheral receptor impairment. Immunofluorescence, including staining for Cellular Proto-oncogene (c-Fos), Neuronal Nuclei (NeuN), and calcitonin gene-related peptide (CGRP), identified activated brain regions such as the cortex, midbrain, and cerebellum. Multiplex immunohistochemistry and cholera toxin subunit B (CTB) tracing were performed to analyze nuclear heterogeneity and neural communication. Additionally, RNA sequencing (RNA-Seq) and Ionized calcium-binding adapter molecule 1 (IBA1) immunostaining were used to investigate ion channel expression in the spinal trigeminal nucleus caudalis (Sp5c). Results CM and VM-related behaviors, such as allodynia and balance disturbance, were successfully reproduced in mouse model. TEM revealed significant damage to peripheral sensory receptors, particularly in the trigeminal ganglion and cochlear cells. Distinct activation patterns of c-Fos and CGRP were observed in VMs and CMs. CTB tracing confirmed that signals are transmitted from the vestibulocerebellum (VbC) to the Sp5c via the vestibular nuclei (VN). Furthermore, RNA-Seq combined with coimmunostaining revealed an increased expression of transient receptor potential vanilloid 2 (TRPV2) ion channels in microglia within Sp5c, indicating their potential role in VM pathology. Conclusions This study preliminarily explored VbC-VN-Sp5c communication and identified TRPV2 ion channels in microglia as key players in neuron-glia crosstalk in VM. These findings provide new insights into the mechanisms underlying vestibular migraine and suggest potential therapeutic targets.

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The SETDB2/KLF4/IDE/CGRP signaling axis in sensory neurons controls migraine [NTG]

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