TY - JOUR
T1 - Tet1 is critical for neuronal activity-regulated gene expression and memory extinction
AU - Rudenko, Andrii
AU - Dawlaty, Meelad M.
AU - Seo, Jinsoo
AU - Cheng, Albert W.
AU - Meng, Jia
AU - Le, Thuc
AU - Faull, Kym F.
AU - Jaenisch, Rudolf
AU - Tsai, Li Huei
N1 - Funding Information:
The authors would like to thank Dr. Tracy Petryshen and Dr. Mike Lewis for the valuable advice on behavioral assays; Dr. Yingxi Lin for providing Npas4 antibody; Lin laboratory members for discussion; Dr. Alison Mungenast and Dr. Alexi Nott for helpful comments on the manuscript; Dr. Susan C. Su for the help with histological preparations; and all members of Tsai and Jaenisch laboratories for advice and discussion. We would like to thank Mali Taylor, Ruth Flannery, and Kibibi Ganz for help with animal care, J. Kwon and J. Love from the Whitehead Genome Technology Core for help with microarrays, and A. Yoon for help with mass spectrometry. A.R is supported by NARSAD Young Investigator Award; M.M.D. is a Damon Runyon Postdoctoral Fellow; A.W.C is supported by a Croucher scholarship; T.L. is supported by a UCLA Molecular, Cellular and Neurobiology Training Grant, a UCLA Mental Retardation Training Grant, and a Eugene V. Cota-Robles Fellowship. Work in R.J. laboratory is supported by grants from National Institutes of Health (HD 045022 and R37CA084198) and the Simons Foundation. L.-H.T. is an investigator of the Howard Hughes Medical Institute. This work is partially supported by an NIH RO1 grant (NS078839) to L.H.-T.
PY - 2013/9/18
Y1 - 2013/9/18
N2 - 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
AB - 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
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U2 - 10.1016/j.neuron.2013.08.003
DO - 10.1016/j.neuron.2013.08.003
M3 - Article
C2 - 24050401
AN - SCOPUS:84884241288
SN - 0896-6273
VL - 79
SP - 1109
EP - 1122
JO - Neuron
JF - Neuron
IS - 6
ER -