Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory.
Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory.
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DOI：
10.1523/jneurosci.1786-08.2008
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发表时间：
2008-10-15
期刊：
影响因子：
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通讯作者：
Sweatt JD
中科院分区：
文献类型：
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作者：
Lubin FD;Roth TL;Sweatt JD
长期记忆的形成需要基因表达的选择性改变。在此，我们确定了染色质重塑对成年海马体中脑源性神经营养因子（bdnf）基因表达的学习诱导性改变的作用。情境恐惧学习诱导了外显子特异性bdnf mRNA（I、IV、VI、IX）的差异调节，这与bdnf DNA甲基化的改变以及局部染色质结构的改变有关。注入泽布拉林（一种DNA甲基转移酶抑制剂）显著改变了bdnf DNA甲基化，并引发了外显子特异性bdnf mRNA水平的变化，这表明DNA甲基化的改变足以驱动海马体中bdnf转录本的差异调节。此外，N -甲基 - D -天冬氨酸（NMDA）受体阻断阻止了bdnf DNA甲基化中与记忆相关的改变，导致海马体中bdnf基因表达改变受阻以及记忆形成缺陷。这些结果表明，bdnf基因的表观遗传修饰是记忆巩固过程中异构体特异性基因表达的一种机制。
Long-term memory formation requires selective changes in gene expression. Here, we determined the contribution of chromatin remodeling to learning-induced changes in brain-derived neurotrophic factor (bdnf) gene expression in the adult hippocampus. Contextual fear learning induced differential regulation of exon-specific bdnf mRNAs (I, IV, VI, IX) that was associated with changes in bdnf DNA methylation and altered local chromatin structure. Infusions of Zebularine (a DNA methyltransferase inhibitor) significantly altered bdnf DNA methylation, and triggered changes in exon-specific bdnf mRNA levels, indicating that altered DNA methylation is sufficient to drive differential bdnf transcript regulation in the hippocampus. In addition, N-methyl-D-aspartic acid (NMDA) receptor blockade prevented memory-associated alterations in bdnf DNA methylation, resulting in a block of altered bdnf gene expression in hippocampus and a deficit in memory formation. These results suggest epigenetic modification of the bdnf gene as a mechanism for isoform-specific gene readout during memory consolidation.