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

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.