Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex.
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.
Schaefer
Anne
A
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Sampath
Srihari C
SC
Intrator
Adam
A
Min
Alice
A
Gertler
Tracy S
TS
Surmeier
D James
DJ
Tarakhovsky
Alexander
A
Greengard
Paul
P
D000222:Adaptation, Physiological / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology*; D001552:Benzazepines / Q000494:pharmacology; D001835:Body Weight / Q000235:genetics; D002110:Caffeine / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000235:genetics; D003214:Conditioning, Classical / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000502:physiology; D005518:Food Preferences / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D016296:Mutagenesis / Q000502:physiology; D063151:Polycomb Repressive Complex 2
D001552:Benzazepines; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D049452:Green Fluorescent Proteins; D002110:Caffeine; C067113:SK&F 81297; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; C533711:G9a protein, mouse; C513479:GLP protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse