• Neuron-specific WDR5 epigeneti...

*Result*: Neuron-specific WDR5 epigenetically upregulates ARID5B to impair GABAergic synaptic transmission and promotes epileptogenesis.

Title:
Neuron-specific WDR5 epigenetically upregulates ARID5B to impair GABAergic synaptic transmission and promotes epileptogenesis.
Authors:
Gu J; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical, Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China.; Department of Neurology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China.; Department of Anesthesiology, First Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China., Ke PY; Department of Neurology, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Neurology Key Laboratory of Chongqing Education Commission of China, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China., Zhang XY; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical, Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China., Liu C; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical, Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China., Yang Y; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical, Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China., Yu ML; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical, Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China., Xu ZZ; Department of Anesthesiology, First Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China., Zhang CX; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical, Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China., Dong W; Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical, Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China.
Source:
Theranostics [Theranostics] 2026 Jan 01; Vol. 16 (6), pp. 2721-2747. Date of Electronic Publication: 2026 Jan 01 (Print Publication: 2026).
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Ivyspring International Publisher Country of Publication: Australia NLM ID: 101552395 Publication Model: eCollection Cited Medium: Internet ISSN: 1838-7640 (Electronic) Linking ISSN: 18387640 NLM ISO Abbreviation: Theranostics Subsets: MEDLINE
Imprint Name(s):
Original Publication: Wyoming, N.S.W. : Ivyspring International Publisher, 2011-
MeSH Terms:
Histone-Lysine N-Methyltransferase*/metabolism , Histone-Lysine N-Methyltransferase*/genetics , Epilepsy, Temporal Lobe*/genetics , Epilepsy, Temporal Lobe*/metabolism , Synaptic Transmission*/genetics , Transcription Factors*/genetics , Transcription Factors*/metabolism , DNA-Binding Proteins*/genetics , DNA-Binding Proteins*/metabolism , Neurons*/metabolism , GABAergic Neurons*/metabolism , Epigenesis, Genetic*, Histones/metabolism ; Epilepsy/genetics ; Hippocampus/metabolism ; Animals ; Mice ; Up-Regulation ; Disease Models, Animal ; Male ; Rats ; Humans ; Mice, Inbred C57BL
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Contributed Indexing:
Keywords: ARID5B; GABAergic synaptic transmission; H3K4me3; WDR5; epilepsy
Substance Nomenclature:
EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
0 (Histones)
0 (Transcription Factors)
0 (DNA-Binding Proteins)
0 (histone H3 trimethyl Lys4)
Entry Date(s):
Date Created: 20260109 Date Completed: 20260109 Latest Revision: 20260111
Update Code:
20260130
PubMed Central ID:
PMC12775672
DOI:
10.7150/thno.122246
PMID:
41510154
Database:
MEDLINE

*Further Information*

*Rationale: Temporal lobe epilepsy (TLE) is a prevalent, drug-resistant neurological disorder that causes severe disability, highlighting the need to identify novel therapeutic targets. Emerging evidence reveals widespread transcriptional dysregulation during epileptogenesis, in which multiple dysregulated genes functionally contribute to disease progression. However, the epigenetic basis of these transcriptomic changes remains poorly characterized. Methods: We established experimental epilepsy models and systematically investigated the remodeling of major histone methylation modifications during epileptogenesis using integrated low-throughput molecular assays and epigenomic profiling. Through pharmacological and genetic interventions, combined with synchronized video-EEG monitoring, whole-cell patch-clamp recordings, multi-omics analyses, and in vivo/ex vivo molecular biology approaches, we mechanistically dissected the pathological role of elevated histone H3 lysine 4 trimethylation (H3K4me3) in epileptogenesis. Results: We demonstrated the dynamic increase in H3K4me3, an epigenetic marker of transcriptional activation, during TLE development. Both pharmacological inhibition of the WD repeat-containing protein 5 (WDR5)-lysine methyltransferase 2 (KMT2) methyltransferase complex and neuron-specific WDR5 knockdown consistently conferred anti-epileptogenic effects. Mechanistically, integrated ChIP-seq and RNA-seq analyses identified AT-rich interactive domain-containing protein 5B (ARID5B) as a key WDR5-targeted effector in hippocampal neurons. WDR5 enhances H3K4me3 deposition at the Arid5b promoter to drive its transcriptional upregulation. The upregulated ARID5B protein subsequently represses γ-aminobutyric acid type A receptor (GABA<subscript>A</subscript>R) subunit expression, impairing inhibitory synaptic transmission and facilitating epileptogenesis. In addition, the WDR5-H3K4me3 axis may directly or indirectly regulate genes involved in glutamatergic synaptic transmission. Conclusions: The neuronal WDR5-H3K4me3 axis is an important epigenetic driver in epileptogenesis, providing both mechanistic insights and promising therapeutic targets for early intervention.
(© The author(s).)*

*Competing Interests: The authors have declared that no competing interest exists.*