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SP1 recruits TET1 to mediate Kif1a demethylation and synaptic remodeling in a mouse model of chronic migraine
Wei Jiang1, Peng Yu2, Guo-Hua Liang3
1Department of Neurology and Neuroscience Center, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, 130021, China.
Background:
Chronic migraine (CM) involves persistent trigeminal sensitization and synaptic remodeling in the spinal trigeminal nucleus caudalis (SP5C), but the epigenetic mechanisms remain unclear. Kinesin family member 1 A (KIF1A), a synaptic vesicle motor protein, is regulated by transcription factors (TFs) and ten-eleven translocation methylcytosine dioxygenase 1 (TET1), yet its role in CM-related structural synaptic plasticity is unknown.
Methods:
TFs potentially regulating KIF1A were predicted using the HOMER and JASPAR databases, identifying specificity protein 1 (SP1) as a candidate regulator. A CM model was induced in male mice by repeated nitroglycerin (NTG) administration. The expression levels of SP1, TET1, KIF1A, and synaptic remodeling-related markers in the SP5C were evaluated using a combination of qPCR, Western blotting, and immunofluorescence. SP1, TET1, and KIF1A were manipulated in vitro/in vivo, and mechanisms were probed by co-immunoprecipitation (Co-IP), dual-luciferase assays, and sequential chromatin immunoprecipitation (Re-ChIP). Synaptic ultrastructure and dendritic morphology were examined by transmission electron microscopy and Golgi-Cox staining.
Results:
Repeated NTG increased SP1, TET1, and KIF1A expression in the SP5C, along with synaptic markers. Co-IP/ luciferase reporter and Re-ChIP demonstrated SP1-TET1 cooperation and co-occupancy at the Kif1a promoter, associated with promoter demethylation. Inhibition of SP1 or knockdown of TET1 reduced KIF1A expression and synaptic protein levels, whereas TET1 overexpression in vitro partially mitigated the effects of SP1 inhibition. Notably, KIF1A overexpression both in vitro and in vivo reversed the synaptic impairments induced by SP1 inhibition. Ultrastructural analyses further revealed marked changes in synaptic architecture and dendritic morphology following modulation of this pathway.
Conclusions:
CM activates an SP1-TET1 epigenetic regulatory module that demethylates and activates the Kif1a promoter, thereby linking TF-guided DNA demethylation to synaptic remodeling in the SP5C and promoting the structural changes associated with central sensitization. This pathway provides mechanistic insight into the epigenetic regulation of synaptic dysfunction in CM.
