G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation.
G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation.
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DOI：
10.1523/jneurosci.0147-12.2012
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发表时间：
2012-04-18
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影响因子：
--
通讯作者：
Lubin FD
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文献类型：
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作者：
Gupta-Agarwal S;Franklin AV;Deramus T;Wheelock M;Davis RL;McMahon LL;Lubin FD
学习会触发大脑区域（如海马体和内嗅皮层（EC））中基因转录的改变，这是长期记忆（LTM）形成所必需的。在这里，我们确定了G9 a/GLP赖氨酸二甲基转移酶复合物和组蛋白H3赖氨酸9二甲基化（H3 K9 me 2）标志着它催化的一个重要作用，在大鼠海马CA 1区和EC记忆巩固过程中的基因转录调控。情境恐惧学习增加了CA 1区和EC中H3 K9 me 2的整体水平，在Zif 268，DNMT 3a，BDNF外显子IV和cFOS基因启动子处可观察到变化，这些变化与mRNA表达一致。在EC中抑制G9 a/GLP，但在海马中不抑制，相对于对照动物增强了背景恐惧条件反射。EC中G9 a/GLP的抑制诱导了几种组蛋白修饰，不仅包括甲基化，还包括乙酰化。令人惊讶的是，我们发现EC中G9 a/GLP活性的下调增强了CA 1区的H3 K9 me 2，导致海马中非记忆允许基因COMT的转录沉默。此外，在两个不同的EC-CA 1细胞通路的突触可塑性研究表明，G9 a/GLP活性是至关重要的，在EC中通过穿孔通路，但不是temporoammonic通路的海马依赖性的长时程增强。总之，这些数据表明，G9 a/GLP差异调节海马和EC在记忆巩固过程中的基因转录。此外，这些发现支持了G9 a/GLP在LTM形成期间调节这两个脑区域之间的细胞和分子串扰的可能性。
Learning triggers alterations in gene transcription in brain regions such as the hippocampus and the entorhinal cortex (EC) that are necessary for long-term memory (LTM) formation. Here, we identify an essential role for the G9a/GLP lysine dimethyltransferase complex and the histone H3 lysine 9 di-methylation (H3K9me2) marks it catalyzes, in the transcriptional regulation of genes in area CA1 of the rat hippocampus and the EC during memory consolidation. Contextual fear learning increased global levels of H3K9me2 in area CA1 and the EC, with observable changes at the Zif268, DNMT3a, BDNF exon IV, and cFOS gene promoters, which occurred in concert with mRNA expression. Inhibition of G9a/GLP in the EC, but not in the hippocampus, enhanced contextual fear conditioning relative to control animals. The inhibition of G9a/GLP in the EC induced several histone modifications that include not only methylation but also acetylation. Surprisingly, we found that down-regulation of G9a/GLP activity in the EC enhanced H3K9me2 in area CA1, resulting in transcriptional silencing of the non-memory permissive gene COMT in the hippocampus. In addition, synaptic plasticity studies at two distinct EC-CA1 cellular pathways revealed that G9a/GLP activity is critical for hippocampus-dependent long-term potentiation initiated in the EC via the perforant pathway, but not the temporoammonic pathway. Together, these data demonstrate that G9a/GLP differentially regulates gene transcription in the hippocampus and the EC during memory consolidation. Furthermore, these findings support the possibility of role for G9a/GLP in the regulation of cellular and molecular cross-talk between these two brain regions during LTM formation.