Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus
Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus
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DOI：
10.1074/jbc.m511767200
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发表时间：
2006-06-09
影响因子：
4.8
通讯作者：
Sweatt, J. David
中科院分区：
文献类型：
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作者：
Levenson, Jonathan M.;Roth, Tania L.;Sweatt, J. David
DNA(胞嘧啶-5)甲基化是最广泛使用的持久细胞记忆机制之一。DNA甲基化的稳定模式是在发育过程中建立的，导致产生持久的细胞表型。越来越多的证据表明，神经系统在发育过程中使用了许多细胞机制来辅助长期记忆的形成。在这项研究中，我们研究了DNA(胞嘧啶-5)甲基转移酶(DNMT)活性在调节突触可塑性诱导中可能发挥的作用。我们发现，当DNMT活性被抑制时，Reelin和脑源性神经营养因子启动子内的DNA，这两个与成年海马突触可塑性有关的基因，在胞嘧啶甲基化方面显示出快速而戏剧性的变化。此外，DNMT活性的抑制剂ZeBularine和5-aza-2-deoxcytidine阻断了Schaffer侧支突触长时程增强的诱导。海马区蛋白激酶C的激活降低了reelin启动子的甲基化，增加了DNMT3A基因的表达。有趣的是，DNMT活性是蛋白激酶C诱导的组蛋白H3乙酰化增加所必需的。综上所述，这些结果表明，DNMT活性在成人神经系统中是动态调节的，DNMT可能在调节成熟中枢神经系统突触可塑性的诱导中发挥作用。
DNA (cytosine-5) methylation represents one of the most widely used mechanisms of enduring cellular memory. Stable patterns of DNA methylation are established during development, resulting in creation of persisting cellular phenotypes. There is growing evidence that the nervous system has co-opted a number of cellular mechanisms used during development to subserve the formation of long term memory. In this study, we examined the role DNA (cytosine-5) methyltransferase (DNMT) activity might play in regulating the induction of synaptic plasticity. We found that the DNA within promoters for reelin and brain-derived neurotrophic factor, genes implicated in the induction of synaptic plasticity in the adult hippocampus, exhibited rapid and dramatic changes in cytosine methylation when DNMT activity was inhibited. Moreover, zebularine and 5-aza-2-deoxycytidine, inhibitors of DNMT activity, blocked the induction of long term potentiation at Schaffer collateral synapses. Activation of protein kinase C in the hippocampus decreased reelin promoter methylation and increased DNMT3A gene expression. Interestingly, DNMT activity is required for protein kinase C-induced increases in histone H3 acetylation. Considered together, these results suggest that DNMT activity is dynamically regulated in the adult nervous system and that DNMT may play a role in regulating the induction of synaptic plasticity in the mature CNS.