Abstract
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 currentsĀ 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.
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Data availability
The RNAseq and ChIPseq data generated in this study have been deposited in the GEO public repository under accession code GSE193380.
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Acknowledgements
We thank Dr. Craig Powell at University of Alabama at Birmingham for kindly providing breeding pairs of Shank3E13 mice. We thank Dr. Mohamed Kabbaj at Florida State University for kindly providing Egr1 AAV and GFP AAV. We also thank Xiaoqing Chen for excellent technical support and Luciana R. Frick for taking some confocal images. This work was supported by: Nancy Lurie Marks Family Foundation (ZY), National Institutes of Health (MH112237, MH126443) (ZY), National Center for Advancing Translational Sciences of the National Institutes of Health (KL2TR001413) (MR), and National Institutes of Health (MH104341, MH117790) (SA).
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MR performed some behavioral, immunocytochemical, biochemical experiments, bioinformatic analyses, and wrote the draft. JW and FY performed bioinformatic analyses. KM performed behavioral experiments. PZ carried out electrophysiological experiments. RP and MK performed some behavioral and biochemical assays. LQ, BR, Z-JW carried out qPCR or immunocytochemical experiments. BK, BJ, and LC extracted neuronal nuclei for ChIPseq experiments. SA oversaw ChIPseq studies. ZY designed experiments, supervised the project and wrote the paper. None of the authors have the financial interest related to this work.
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Rapanelli, M., Williams, J.B., Ma, K. et al. Targeting histone demethylase LSD1 for treatment of deficits in autism mouse models. Mol Psychiatry 27, 3355ā3366 (2022). https://doi.org/10.1038/s41380-022-01508-8
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DOI: https://doi.org/10.1038/s41380-022-01508-8
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