Tet1 Is Critical for Neuronal Activity-Regulated Gene Expression and Memory Extinction
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Author(s)
Rudenko, Andrii
Dawlaty, Meelad M.
Seo, Jinsoo
Cheng, Albert W.
Meng, Jia
Le, Thuc
Faull, Kym F.
Jaenisch, Rudolf
Tsai, Li-Huei
Date Issued
September 2013
Journal
Neuron
Publisher
Elsevier
Citation
Rudenko, Andrii, Meelad M. Dawlaty, Jinsoo Seo, Albert W. Cheng, Jia Meng, Thuc Le, Kym F. Faull, Rudolf Jaenisch, and Li-Huei Tsai. “Tet1 Is Critical for Neuronal Activity-Regulated Gene Expression and Memory Extinction.” Neuron 79, no. 6 (September 2013): 1109–22.
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Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.1016/j.neuron.2013.08.003
