Targeting histone demethylase LSD1 for treatment of deficits in autism mouse models.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
06
05
2021
accepted:
23
02
2022
revised:
16
02
2022
pubmed:
18
3
2022
medline:
2
12
2022
entrez:
17
3
2022
Statut:
ppublish
Résumé
Large-scale genetic studies have revealed that the most prominent genes disrupted in autism are chromatin regulators mediating histone methylation/demethylation, suggesting the central role of epigenetic dysfunction in this disorder. Here, we show that histone lysine 4 dimethylation (H3K4me2), a histone mark linked to gene activation, is significantly decreased in the prefrontal cortex (PFC) of autistic human patients and mutant mice with the deficiency of top-ranking autism risk factor Shank3 or Cul3. A brief treatment of the autism models with highly potent and selective inhibitors of the H3K4me2 demethylase LSD1 (KDM1A) leads to the robust rescue of core symptoms of autism, including social deficits and repetitive behaviors. Concomitantly, LSD1 inhibition restores NMDA receptor function in PFC and AMPA receptor-mediated currents in striatum of Shank3-deficient mice. Genome-wide RNAseq and ChIPseq reveal that treatment of Shank3-deficient mice with the LSD1 inhibitor restores the expression and H3K4me2 occupancy of downregulated genes enriched in synaptic signaling and developmental processes. The immediate early gene tightly linked to neuronal plasticity, Egr1, is on the top list of rescued genes. The diminished transcription of Egr1 is recapitulated in PFC of autistic human patients. Overexpression of Egr1 in PFC of Shank3-deficient mice ameliorates social preference deficits. These results have for the first time revealed an important role of H3K4me2 abnormality in ASD pathophysiology, and the therapeutic potential of targeting H3K4me2 demethylase LSD1 or the downstream molecule Egr1 for ASD.
Identifiants
pubmed: 35296809
doi: 10.1038/s41380-022-01508-8
pii: 10.1038/s41380-022-01508-8
pmc: PMC9477974
mid: NIHMS1783735
doi:
Substances chimiques
Histones
0
Histone Demethylases
EC 1.14.11.-
Chromatin
0
KDM1A protein, human
EC 1.5.-
Shank3 protein, mouse
0
Microfilament Proteins
0
Nerve Tissue Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3355-3366Subventions
Organisme : NINDS NIH HHS
ID : R01 NS127728
Pays : United States
Organisme : NIMH NIH HHS
ID : R41 MH112237
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH126443
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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