Tet1 is critical for neuronal activity-regulated gene expression and memory extinction

Neuron. 2013 Sep 18;79(6):1109-1122. doi: 10.1016/j.neuron.2013.08.003.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Analysis of Variance
  • Animals
  • Anxiety / genetics
  • Anxiety / physiopathology
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cerebral Cortex / cytology
  • Conditioning, Classical / physiology
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / physiology*
  • Depression / genetics
  • Depression / metabolism
  • Disease Models, Animal
  • Exploratory Behavior / physiology
  • Extinction, Psychological / physiology*
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Hippocampus / cytology
  • In Vitro Techniques
  • Locomotion / genetics
  • Long-Term Synaptic Depression / genetics
  • Male
  • Maze Learning
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Tissue Proteins / metabolism
  • Neurons / physiology*
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / genetics
  • Synapsins / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • Nerve Tissue Proteins
  • Npas4 protein, mouse
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-fos
  • Receptors, N-Methyl-D-Aspartate
  • Synapsins
  • TET1 protein, mouse
  • Methoxyhydroxyphenylglycol
  • 3,4-dihydroxyphenylglycol