Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice
Open accessAbstract
Many of the genes disrupted in autism are identified as histone-modifying enzymes and chromatin remodelers, most prominently those that mediate histone methylation/demethylation. However, the role of histone methylation enzymes in the pathophysiology and treatment of autism remains unknown. To address this, we used mouse models of haploinsufficiency of the Shank3 gene (a highly penetrant monogenic autism risk factor), which exhibits prominent autism-like social deficits. We found that histone methyltransferases EHMT1 and EHMT2, as well as histone lysine 9 dimethylation (specifically catalyzed by EHMT1/2), were selectively increased in the prefrontal cortex (PFC) of Shank3-deficient mice and autistic human postmortem brains. Treatment with the EHMT1/2 inhibitor UNC0642 or knockdown of EHMT1/2 in PFC induced a robust rescue of autism-like social deficits in Shank3-deficient mice, and restored NMDAR-mediated synaptic function. Activity-regulated cytoskeleton-associated protein (Arc) was identified as one of the causal factors underlying the rescuing effects of UNC0642 on NMDAR function and social behaviors in Shank3-deficient mice. UNC0642 treatment also restored a large set of genes involved in neural signaling in PFC of Shank3-deficient mice. These results suggest that targeting histone methylation enzymes to adjust gene expression and ameliorate synaptic defects could be a potential therapeutic strategy for autism.
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Repressive histone mark H3K9me2 and its catalyzing enzymes EHMT1/2 are selectively increased in PFC of Shank3-deficient mice and autistic human postmortem brains.
“Moreover, the repressive histone mark H3K9me2 and its catalyzing enzymes EHMT1/2 are selectively increased in the PFC of Shank3-deficient mice and autistic human postmortem brains 146.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [146]
Targeting epigenetic enzymes to adjust gene expression and ameliorate synaptic defects in PFC is a potential strategy to normalize behavioral phenotypes associated with autism.
“A recent series of studies have shown that targeting epigenetic enzymes to adjust gene expression and ameliorate synaptic defects in PFC is a potential strategy to normalize behavioral phenotypes associated with autism 144–147.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [146]
Inhibition of EHMT1/2 rescues social deficits and restores PFC NMDAR function in Shank3-deficient mice via restoring expression of plasticity gene Arc.
“Inhibition of EHMT1/2 rescues social deficits and restores PFC NMDAR function in Shank3-deficient mice via restoring the expression of plasticity gene Arc, which encodes the activity-regulated cytoskeleton-associated protein Arc 146.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [146]
β-catenin links loss of Shank3 in synapse to upregulation of HDAC2 and EHMT1/2 transcription in nucleus.
“The nucleocytoplasmic shuttle protein involved in both cell adhesion and transcriptional regulation, β-catenin, is found to link the loss of Shank3 in the synapse to the upregulation of HDAC2 and EHMT1/2 transcription in the nucleus 145,146 (Fig. 3).”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [146]
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The Role of Zinc and NMDA Receptors in Autism Spectrum Disorders
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Twenty years of discoveries emerging from mouse models of autism
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Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model
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Self-citationDormant state of quiescent neural stem cells links Shank3 mutation to autism development
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A convergent mechanism of high risk factors ADNP and POGZ in neurodevelopmental disorders
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SHANK family on stem cell fate and development
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Targeting epigenetic enzymes for autism treatment
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Self-citationEarly Chronic Memantine Treatment-Induced Transcriptomic Changes in Wild-Type and Shank2-Mutant Mice
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Retinoic Acid Supplementation Rescues the Social Deficits in Fmr1 Knockout Mice
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Inhibition of EHMT1/2 rescues synaptic damage and motor impairment in a PD mouse model
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Unravelling the role of SHANK3 mutations in targeted therapies for autism spectrum disorders
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IGF-1 Microinjection in the Prefrontal Cortex Attenuates Fentanyl-Seeking Behavior in Mice
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Self-citationInhibition of histone deacetylase 5 ameliorates abnormalities in 16p11.2 duplication mouse model
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Self-citationAn epigenetic mechanism of social isolation stress in adolescent female mice
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Self-citationSynaptic Deficits in Adnp‐ Mutant Mice Are Ameliorated by Histone Demethylase LSD1 Inhibition
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Clinical characteristics and genetic analysis of four pediatric patients with Kleefstra syndrome
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Epigenetic Mechanisms of Autism Spectrum Disorders
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Self-citationThe Use of Nutraceutical and Pharmacological Strategies in Murine Models of Autism Spectrum Disorder
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Epigenetic treatment of synaptic and behavioral deficits in Dyrk1a-mutant mice
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Self-citationHistone deacetylase 4 inhibition ameliorates the social deficits induced by Ephrin-B2 mutation
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Epigenetic Mechanisms of Autism Spectrum Disorders
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Self-citationTargeting Epigenetic Enzymes for Treatment of Autism Spectrum Disorders
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Self-citationDomain-specific and sex-dependent behavioral alterations in the BTBR mouse model of autism
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Epigenetic Hierarchies in Autism from Folate–SAM Metabolism to LSD1 and G9a
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Disrupted synaptic vacuolar H+-ATPase renders synaptic vulnerability to Alzheimer’s disease
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Self-citationTranslational Neuroscience of Autism Spectrum Disorder
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- Authors
- Wang, Z.-J., Zhong, P., Ma, K., Seo, J.-S., Yang, F., Hu, Z., Zhang, F., Lin, L., Wang, J., Liu, T., Matas, E., Greengard, P., & Yan, Z.
- Affiliations
- University at Buffalo, State University of New York (US)
- Rockefeller University (US)
- Corresponding author
- Yan, Zhen
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2019-01-18
- Volume
- 25
- Issue
- 10
- Pages
- 2517-2533
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC6639159
- OpenAlex
- W2908953418
- Cited by
- 82
- References
- 67
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 12 · 2023: 11 · 2022: 15 · 2021: 15 · 2020: 9 · 2019: 4
- FWCI
- 6.47
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-09-13)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Nancy Lurie Marks Family Foundation
- U.S. Department of Health & Human Services | National Institutes of Health (MH112237, MH108842)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- autism spectrum disorder, SHANK3, EHMT1, G9a, histone methyltransferase, UNC0642, social dysfunction, prefrontal cortex, NMDA receptor, synaptic function, Arc, histone methylation, therapeutic target, haploinsufficiency
- MeSH terms
- Animals, Autistic Disorder, Disease Models, Animal, Female, Histones, Male, Methylation, Microfilament Proteins, Nerve Tissue Proteins, Histone-Lysine N-Methyltransferase, Quinazolines, Prefrontal Cortex, Mice, Haploinsufficiency
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