DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation.
DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation.
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DOI：
10.3390/ijms21238995
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发表时间：
2020-11-26
影响因子：
5.6
通讯作者：
Jarome TJ
中科院分区：
文献类型：
--
作者：
Navabpour S;Rogers J;McFadden T;Jarome TJ
许多研究表明，在检索之后，先前巩固的记忆需要增加转录调控才能重新巩固。以前，有报道说，组蛋白H3赖氨酸-4三甲基化（H3 K4 me 3），一个活跃的转录标记物，在海马中增加后，检索的上下文恐惧记忆。然而，目前尚不清楚这种表观遗传标记在再巩固过程中如何调节。此外，尽管最近的证据表明神经元活动会触发一些早期反应基因中的DNA双链断裂（DSB），但目前尚不清楚DSB是否有助于提取后记忆的重新巩固。在这里，使用染色质免疫沉淀（ChIP）分析，我们报告了一个显着的重叠DSB和H3 K4 me 3在CA 1区的海马在再巩固过程中。我们发现，组蛋白H2A.X在丝氨酸139（H2A.XpS139），DSB的标志物，在Npas 4，而不是c-fos，启动子区域的磷酸化增加检索后5分钟，这与增加H3 K4 me 3水平，这表明这两个表观遗传标记可能在再巩固过程中协同工作。与此一致，在体内siRNA介导的拓扑异构酶II β（负责DSB的酶）的敲低，在恢复之前，降低了Npas 4启动子特异性H2A.XpS139和H3 K4 me 3水平，并损害了长期记忆，表明DSB在记忆再巩固过程中不可或缺的作用。总的来说，我们的数据提出了一种新的机制，通过增加表观遗传介导的转录控制，通过DNA双链断裂的记忆再巩固。
Numerous studies have shown that following retrieval, a previously consolidated memory requires increased transcriptional regulation in order to be reconsolidated. Previously, it was reported that histone H3 lysine-4 trimethylation (H3K4me3), a marker of active transcription, is increased in the hippocampus after the retrieval of contextual fear memory. However, it is currently unknown how this epigenetic mark is regulated during the reconsolidation process. Furthermore, though recent evidence suggests that neuronal activity triggers DNA double-strand breaks (DSBs) in some early-response genes, it is currently unknown if DSBs contribute to the reconsolidation of a memory following retrieval. Here, using chromatin immunoprecipitation (ChIP) analyses, we report a significant overlap between DSBs and H3K4me3 in area CA1 of the hippocampus during the reconsolidation process. We found an increase in phosphorylation of histone H2A.X at serine 139 (H2A.XpS139), a marker of DSB, in the Npas4, but not c-fos, promoter region 5 min after retrieval, which correlated with increased H3K4me3 levels, suggesting that the two epigenetic marks may work in concert during the reconsolidation process. Consistent with this, in vivo siRNA-mediated knockdown of topoisomerase II β, the enzyme responsible for DSB, prior to retrieval, reduced Npas4 promoter-specific H2A.XpS139 and H3K4me3 levels and impaired long-term memory, indicating an indispensable role of DSBs in the memory reconsolidation process. Collectively, our data propose a novel mechanism for memory reconsolidation through increases in epigenetic-mediated transcriptional control via DNA double-strand breaks.
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影响因子：
2.7
作者：
Jarome, Timothy J.;Lubin, Farah D.
通讯作者：
Lubin, Farah D.
影响因子：
16.6
作者：
Husain A;Begum NA;Taniguchi T;Taniguchi H;Kobayashi M;Honjo T
通讯作者：
Honjo T
影响因子：
4.8
作者：
Jarome TJ;Butler AA;Nichols JN;Pacheco NL;Lubin FD
通讯作者：
Lubin FD
影响因子：
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作者：
Bae, Sunhee;Lesch, Bluma J.
通讯作者：
Lesch, Bluma J.
影响因子：
11.4
作者：
Durand-Dubief, Mickael;Persson, Jenna;Ekwall, Karl
通讯作者：
Ekwall, Karl