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Tet1 Is Critical for Neuronal Activity-Regulated Gene Expression and Memory Extinction
- Source :
- PMC
- Publication Year :
- 2013
- Publisher :
- Elsevier, 2013.
-
Abstract
- The ten-eleven translocation (Tet) family of methylcytosine dioxygenases catalyze oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and promote DNA demethylation. Despite the abundance of 5hmC and Tet proteins in the brain, little is known about the functions of the neuronal Tet enzymes. Here, we analyzed Tet1 knockout mice (Tet1KO) and found downregulation of multiple neuronal activity-regulated genes, including Npas4, c-Fos, and Arc. Furthermore, Tet1KO animals exhibited abnormal hippocampal long-term depression and impaired memory extinction. Analysis of the key regulatory gene, Npas4, indicated that its promoter region, containing multiple CpG dinucleotides, is hypermethylated in both naive Tet1KO mice and after extinction training. Such hypermethylation may account for the diminished expression of Npas4 itself and its downstream targets, impairing transcriptional programs underlying cognitive processes. In summary, we show that neuronal Tet1 regulates normal DNA methylation levels, expression of activity-regulated genes, synaptic plasticity, and memory extinction.<br />Brain & Behavior Research Foundation (Young Investigator Award)<br />National Institutes of Health (U.S.) (Grant RO1 NS078839)
- Subjects :
- Male
Conditioning, Classical
Anxiety
Hippocampus
Extinction, Psychological
Methoxyhydroxyphenylglycol
Mice
0302 clinical medicine
Gene expression
Basic Helix-Loop-Helix Transcription Factors
Oligonucleotide Array Sequence Analysis
Regulator gene
Cerebral Cortex
Mice, Knockout
Neurons
Regulation of gene expression
0303 health sciences
Arc (protein)
Depression
General Neuroscience
Age Factors
DNA-Binding Proteins
DNA methylation
Knockout mouse
Proto-Oncogene Proteins c-fos
Locomotion
Neuroscience(all)
Nerve Tissue Proteins
In Vitro Techniques
Biology
Receptors, N-Methyl-D-Aspartate
Article
03 medical and health sciences
Proto-Oncogene Proteins
Animals
Maze Learning
030304 developmental biology
Analysis of Variance
Gene Expression Profiling
Long-Term Synaptic Depression
Synapsins
Molecular biology
Mice, Inbred C57BL
Gene expression profiling
Disease Models, Animal
DNA demethylation
Gene Expression Regulation
Synapses
Exploratory Behavior
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- PMC
- Accession number :
- edsair.doi.dedup.....a2a68149fcaf651b27cab97fcd078b9c