NF-κB mediates Gadd45β expression and DNA demethylation in the hippocampus during fear memory formation.
NF-κB mediates Gadd45β expression and DNA demethylation in the hippocampus during fear memory formation.
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DOI：
10.3389/fnmol.2015.00054
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发表时间：
2015
影响因子：
4.8
通讯作者：
Lubin FD
中科院分区：
文献类型：
--
作者：
Jarome TJ;Butler AA;Nichols JN;Pacheco NL;Lubin FD
Gadd 45介导的DNA去甲基化机制与记忆形成过程有关。然而，参与记忆形成过程中Gadd 45基因表达调控的转录机制仍有待研究。NF-κB（活化B细胞的核因子κ轻链增强子）控制神经元中的基因转录，并且是突触可塑性和记忆形成的关键调节剂。计算机模拟分析显示Gadd 45 β基因启动子内存在多个NF-κB（p65/RelA和cRel）共有序列。NF-κB活性是否调节记忆形成过程中神经元中Gadd 45的表达和相关的DNA去甲基化尚不清楚。我们发现，在恐惧条件反射模式下学习增加了海马CA 1区Gadd 45 β基因表达和脑源性神经营养因子（BDNF）DNA去甲基化，这两种情况都可以通过抑制NF-κB活性来预防。进一步的实验发现，p65/RelA的条件性突变会损害恐惧记忆的形成，但不会改变Gadd 45 β表达的变化。c-rel基因敲除小鼠CA 1区Gadd 45 β mRNA水平的升高、Gadd 45 β与BDNF基因的结合以及BDNF DNA去甲基化均被阻断。此外，siRNA介导的CA 1区c-rel基因敲低可阻止恐惧条件化诱导的Gadd 45 β表达增加和BDNF DNA去甲基化，提示含c-rel的NF-κB转录因子复合物参与了记忆形成过程中Gadd 45 β的调控。这些结果共同支持了NF-κB在恐惧记忆过程中调节海马神经元Gadd 45 β表达和DNA去甲基化的新的转录作用。
Gadd45-mediated DNA demethylation mechanisms have been implicated in the process of memory formation. However, the transcriptional mechanisms involved in the regulation of Gadd45 gene expression during memory formation remain unexplored. NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) controls transcription of genes in neurons and is a critical regulator of synaptic plasticity and memory formation. In silico analysis revealed several NF-κB (p65/RelA and cRel) consensus sequences within the Gadd45β gene promoter. Whether NF-κB activity regulates Gadd45 expression and associated DNA demethylation in neurons during memory formation is unknown. Here, we found that learning in a fear conditioning paradigm increased Gadd45β gene expression and brain-derivedneurotrophic factor (BDNF) DNA demethylation in area CA1 of the hippocampus, both of which were prevented with pharmacological inhibition of NF-κB activity. Further experiments found that conditional mutations in p65/RelA impaired fear memory formation but did not alter changes in Gadd45β expression. The learning-induced increases in Gadd45β mRNA levels, Gadd45β binding at the BDNF gene and BDNF DNA demethylation were blocked in area CA1 of the c-rel knockout mice. Additionally, local siRNA-mediated knockdown of c-rel in area CA1 prevented fear conditioning-induced increases in Gadd45β expression and BDNF DNA demethylation, suggesting that c-Rel containing NF-κB transcription factor complex is responsible for Gadd45β regulation during memory formation. Together, these results support a novel transcriptional role for NF-κB in regulation of Gadd45β expression and DNA demethylation in hippocampal neurons during fear memory.