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

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

Rudenko A#1,2,3, Dawlaty MM#4, Seo J1,2,3, Cheng AW4,5, Meng J1, Le T6, Faull KF6, Jaenisch R4,7, Tsai LH1,2,3,8.

Author information

1
The Picower Institute for Learning and Memory, 77 Massachusetts Avenue, Cambridge, MA, 02139.
2
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139.
3
Howard Hughes Medical Institute, Cambridge, MA.
4
Whitehead Institute for Biomedical Research, Cambridge, MA.
5
Computational and Systems Biology Program, Cambridge, MA 02142, USA.
6
Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
7
Department of Biology Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
8
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA.
#
Contributed equally

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.

PMID:
24050401
PMCID:
PMC4543319
DOI:
10.1016/j.neuron.2013.08.003
[Indexed for MEDLINE]
Free PMC Article

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