Tet1 对于神经元活动调节基因表达和记忆消除至关重要。
Tet1 is critical for neuronal activity-regulated gene expression and memory extinction.
机构信息
The Picower Institute for Learning and Memory, 77 Massachusetts Avenue, Cambridge, MA, 02139.
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139.
出版信息
Neuron. 2013 Sep 18;79(6):1109-1122. doi: 10.1016/j.neuron.2013.08.003.
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.
十 - 十一易位（Tet）家族的甲基胞嘧啶双加氧酶催化 5- 甲基胞嘧啶（5mC）氧化为 5- 羟甲基胞嘧啶（5hmC），并促进 DNA 去甲基化。尽管大脑中 5hmC 和 Tet 蛋白含量丰富，但神经元 Tet 酶的功能知之甚少。在这里，我们分析了 Tet1 敲除小鼠（Tet1KO），发现多种神经元活性调节基因下调，包括 Npas4、c-Fos 和 Arc。此外，Tet1KO 动物表现出异常的海马长时程抑制和记忆消退受损。对关键调节基因 Npas4 的分析表明，其启动子区域含有多个 CpG 二核苷酸，在未训练的 Tet1KO 小鼠和消退训练后均发生过度甲基化。这种过度甲基化可能导致 Npas4 自身及其下游靶基因的表达减少，从而破坏认知过程的转录程序。总之，我们表明神经元 Tet1 调节正常的 DNA 甲基化水平、活性调节基因的表达、突触可塑性和记忆消退。
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