Inhibiting MLL1-WDR5 interaction ameliorates neuropathic allodynia by attenuating histone H3 lysine 4 trimethylation-dependent spinal mGluR5 transcription

doi:10.1097/j.pain.0000000000001898

中山醫學大學機構典藏 CSMUIR > 中山醫學大學研究成果 > 期刊論文 > Item 310902500/24716

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/24716

Title:	Inhibiting MLL1-WDR5 interaction ameliorates neuropathic allodynia by attenuating histone H3 lysine 4 trimethylation-dependent spinal mGluR5 transcription
Authors:	Lin, TB;Lai, CY;Hsieh, MC;Ho, YC;Wang, HH;Yang, PS;Cheng, JK;Chen, GD;Ng, SC;Peng, HY
Keywords:	MLL1;WDR5;mGluR5;Neuropathic allodynia
Date:	2020
Issue Date:	2022-08-09T08:06:52Z (UTC)
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
ISSN:	0304-3959
Abstract:	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.
URI:	http://dx.doi.org/10.1097/j.pain.0000000000001898 https://www.webofscience.com/wos/woscc/full-record/WOS:000571186100008 https://ir.csmu.edu.tw:8080/handle/310902500/24716
Relation:	PAIN ,2020 ,v161 ,issue 9 ,p1995-2009
Appears in Collections:	[中山醫學大學研究成果] 期刊論文

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