DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity
DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity
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DOI：
10.1016/j.nlm.2007.07.016
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发表时间：
2008-05-01
影响因子：
2.7
通讯作者：
Sweatt, J. David
中科院分区：
文献类型：
--
作者：
Miller, Courtney A.;Campbell, Susan L.;Sweatt, J. David
一个清晰的理解是发展有关转录依赖的长期记忆形成的表观遗传相关的分子机制的重要性。染色质修饰，特别是历史乙酰化，与转录激活相关，并且组蛋白3（H3）的乙酰化在背景恐惧条件训练后发生在海马体的CA1区。相反，DNA甲基化与转录抑制相关，但也在训练后在区域CA1中动态调节。我们最近报道了抑制成年大鼠海马中负责DNA甲基化的酶DNA甲基转移酶（DNMT）会阻断行为记忆的形成。在这里，我们报告说，DNMT抑制也阻止伴随的记忆相关的H3乙酰化，而不影响其上游调节，细胞外信号调节激酶（ERK）的磷酸化。有趣的是，DNMT抑制剂诱导的记忆巩固缺陷，沿着长时程增强缺陷，可以通过在DNMT抑制剂抑制前显著增加组蛋白乙酰化水平来挽救。这些观察结果表明，DNMT活性不仅是记忆和可塑性所必需的，而且DNA甲基化可能与历史修饰协同作用，以调节成年大鼠海马的可塑性和记忆形成。(C)2007年爱思唯尔公司All rights reserved.
A clear understanding is developing concerning the importance of epigenetic-related molecular mechanisms in transcription-dependent long-term memory formation. Chromatin modification, in particular historic acetylation, is associated with transcriptional activation, and acetylation of histone 3 (H3) occurs in Area CAl of the hippocampus following contextual fear conditioning training. Conversely, DNA methylation is associated with transcriptional repression, but is also dynamically regulated in Area CAl following training. We recently reported that inhibition of the enzyme responsible for DNA methylation, DNA methyltransferase (DNMT), in the adult rat hippocampus blocks behavioral memory formation. Here, we report that DNMT inhibition also blocks the concomitant memory-associated H3 acetylation, without affecting phosphorylation of its upstream regulator, extracellular signal-regulated kinase (ERK). Interestingly, the DNMT inhibitor-induced deficit in memory consolidation, along with deficits in long-term potentiation, can be rescued by pharmacologically increasing levels of histone acetylation prior to DNMT inhibition. These observations suggest that DNMT activity is not only necessary for memory and plasticity, but that DNA methylation may work in concert with historic modifications to regulate plasticity and memory formation in the adult rat hippocampus. (C) 2007 Elsevier Inc. All rights reserved.