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

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.