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Control of Cognition and Adaptive Behavior by the GLP/G9a Epigenetic Suppressor Complex
Open accessAbstract
The genetic basis of cognition and behavioral adaptation to the environment remains poorly understood. Here we demonstrate that the histone methyltransferase complex GLP/G9a controls cognition and adaptive responses in a region-specific fashion in the adult brain. Using conditional mutagenesis in mice, we show that postnatal, neuron-specific deficiency of GLP/G9a leads to derepression of numerous nonneuronal and neuron progenitor genes in adult neurons. This transcriptional alteration is associated with complex behavioral abnormalities, including defects in learning, motivation, and environmental adaptation. The behavioral changes triggered by GLP/G9a deficiency are similar to key symptoms of the human 9q34 mental retardation syndrome that is associated with structural alterations of the GLP/EHMT1 gene. The likely causal role of GLP/G9a in mental retardation in mice and humans suggests a key role for the GLP/G9a-controlled histone H3K9 dimethylation in regulation of brain function through maintenance of the transcriptional homeostasis in adult neurons.
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“Researchers have reported that postnatal knockout of G9a reduced the anxiety phenotype in mice, while mutation or deletion of one copy of the GLP gene in humans leads to Kleefstra syndrome, characterized by social behavior impairment, impulsivity, aggression, and mental retardation (Schaefer et al., 2009).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Schaefer et al., 2009
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“The HMT complex G9a/G9a-like protein (GLP), composed of the HMT euchromatic histone-lysine N-methyltransferase 2 (EHMT2) or G9a and G9a-like protein (GLP or EHMT1), has been shown to be involved in the monomethylation and dimethylation of H3K9 (Schaefer et al., 2009).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Schaefer et al., 2009
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Researchers have reported that postnatal knockout of G9a reduced the anxiety phenotype in mice, while mutation or deletion of one copy of the GLP gene in humans leads to Kleefstra syndrome, characterized by social behavior impairment, impulsivity, aggression, and mental retardation (Schaefer et al., 2009).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Schaefer et al., 2009
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“Thus, G9a/GLP seems to exert temporal effects on developmental histone methylation.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Schaefer et al., 2009
Experimental — accuracy not yet measuredIn the citing paper
“No statistical methods were used to pre-determine sample sizes but our sample sizes are similar to those reported in previous publications19,31,95,99,108.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [95]
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Metadata
- Authors
- Schaefer, A., Sampath, S. C., Intrator, A., Min, A., Gertler, T. S., Surmeier, D. J., Tarakhovsky, A., & Greengard, P.
- Affiliations
- Rockefeller University (US)
- Northwestern University (US)
- Corresponding author
- Tarakhovsky, Alexander
- Greengard, Paul
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 64
- Issue
- 5
- Pages
- 678-691
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2814156
- OpenAlex
- W2065364505
- Cited by
- 317
- References
- 57
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 14 · 2023: 11 · 2022: 12 · 2021: 17 · 2020: 16 · 2019: 20 · 2018: 16 · 2017: 24 · 2016: 23 · 2015: 27 · 2014: 28 · 2013: 24 · 2012: 24
- FWCI
- 9.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG09464, P01AG009464)
- National Institute of Mental Health (MH-074866, F30MH082522, MH082522, P50MH074866)
- National Institute on Drug Abuse (R03DA025962, DA025962)
- National Institute of General Medical Sciences (GM 07739, R01GM112811, T32GM007739)
- National Institute of Allergy and Infectious Diseases (AI068058, R01AI068058)
- National Institute of Neurological Disorders and Stroke (P01NS013742)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- EHMT1, histone methyltransferase, epigenetic regulation, cognition, learning and memory, motivation, environmental adaptation, adult neurons
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Adaptation, Physiological, Central Nervous System Stimulants, Animals, Animals, Newborn, Behavior, Animal, Benzazepines, Body Weight, Caffeine, Cognition, Cognition Disorders, Conditioning, Classical, Exploratory Behavior, Fear, Food Preferences, Mice, Inbred DBA, Mice, Transgenic, Motor Activity, Histone-Lysine N-Methyltransferase, Mutagenesis, Dopamine Agonists, Maze Learning, Epigenesis, Genetic, Green Fluorescent Proteins, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Polycomb Repressive Complex 2
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