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

Andrii Rudenko, Meelad M. Dawlaty, Jinsoo Seo, AlbertW Cheng, Jia Meng, Thuc Le, KymF Faull, Rudolf Jaenisch, Li Huei Tsai

Research output: Contribution to journalArticle

240 Citations (Scopus)

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

Original languageEnglish (US)
Pages (from-to)1109-1122
Number of pages14
JournalNeuron
Volume79
Issue number6
DOIs
StatePublished - Sep 18 2013
Externally publishedYes

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Knockout Mice
Gene Expression
5-Methylcytosine
Dioxygenases
Neuronal Plasticity
Protein Transport
DNA Methylation
Regulator Genes
Genetic Promoter Regions
Genes
Down-Regulation
Depression
DNA
Brain
Enzymes
Psychological Extinction
5-hydroxymethylcytosine

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. / Rudenko, Andrii; Dawlaty, Meelad M.; Seo, Jinsoo; Cheng, AlbertW; Meng, Jia; Le, Thuc; Faull, KymF; Jaenisch, Rudolf; Tsai, Li Huei.

In: Neuron, Vol. 79, No. 6, 18.09.2013, p. 1109-1122.

Research output: Contribution to journalArticle

Rudenko, A, Dawlaty, MM, Seo, J, Cheng, A, Meng, J, Le, T, Faull, K, Jaenisch, R & Tsai, LH 2013, 'Tet1 is critical for neuronal activity-regulated gene expression and memory extinction', Neuron, vol. 79, no. 6, pp. 1109-1122. https://doi.org/10.1016/j.neuron.2013.08.003
Rudenko, Andrii ; Dawlaty, Meelad M. ; Seo, Jinsoo ; Cheng, AlbertW ; Meng, Jia ; Le, Thuc ; Faull, KymF ; Jaenisch, Rudolf ; Tsai, Li Huei. / Tet1 is critical for neuronal activity-regulated gene expression and memory extinction. In: Neuron. 2013 ; Vol. 79, No. 6. pp. 1109-1122.
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AU - Le, Thuc

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