Mixed lineage
leukemia 1 (MLL1)-mediated
histone H3 lysine 4 trimethylation (
H3K4me3) of a subset of genes has been linked to the transcriptional activation critical for synaptic plasticity, but its potential contribution to neuropathic
allodynia development remains poorly explored. Here, we show that MLL1, which is induced in dorsal horn neuron after spinal nerve
ligation (SNL), is responsible for
mechanical allodynia and increased
H3K4me3 at
metabotropic glutamate receptor subtype 5 (mGluR5) promoter. Moreover, SNL induced WD (Trp-Asp) repeat domain 5 subunit (WDR5) expression as well as the MLL1-WDR5 interaction accompany with
H3K4me3 enrichment and transcription of mGluR5 gene in the dorsal horn in neuropathic
allodynia progression. Conversely, WDR5-0103, a novel inhibitor of the MLL1-WDR5 interaction, reversed SNL-induced
allodynia and inhibited SNL-enhanced mGluR5 transcription/expression as well as MLL1, WDR5, and
H3K4me3 at the mGluR5 promoter in the dorsal horn. Furthermore, disrupting the expression of MLL1 or WDR5 using
small interfering RNA attenuated
mechanical allodynia and reversed
protein transcription/expression and complex localizing at mGluR5 promoter in the dorsal horn induced by SNL. This finding revealed that MLL1-WDR5 complex integrity regulates MLL1 and WDR5 recruitment to
H3K4me3 enrichment at mGluR5 promoter in the dorsal horn underlying neuropathic
allodynia. Collectively, our findings indicated that SNL enhances the MLL1-WDR5 complex, which facilitates MLL1 and WDR5 recruitment to
H3K4me3 enrichment at mGluR5 promoter in spinal plasticity contributing to neuropathic
allodynia pathogenesis.