Neuronal activity controls Bdnf expression via Polycomb de-repression and CREB/CBP/JMJD3 activation in mature neurons.
Neuronal activity controls Bdnf expression via Polycomb de-repression and CREB/CBP/JMJD3 activation in mature neurons.
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神经元活动通过成熟神经元中的 Polycomb 去抑制和 CREB/CBP/JMJD3 激活来控制 Bdnf 表达。
DOI：
10.1038/ncomms11081
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发表时间：
2016-03-24
影响因子：
16.6
通讯作者：
Martin MG
中科院分区：
文献类型：
--
作者：
Palomer E;Carretero J;Benvegnù S;Dotti CG;Martin MG
最近的研究表明，在胚胎干细胞中，一些重要的发育调控基因的表达受到抑制，但在适当的刺激下会迅速激活。在这项工作中，我们表明，BDNF启动子被抑制的Polycomb复合物2在成熟的海马神经元，和基础的表达是保证与激活组蛋白标记共存。由N-甲基-D-天冬氨酸应用触发的神经元刺激通过丝氨酸28处的H3 K27 Me 3去甲基化和H3 K27 Me 3磷酸化诱导这些启动子的转录，从而导致多梳阻遏复合物2的催化亚基EZH 2的置换。我们的数据表明，神经元刺激后，BDNF启动子II和VI的快速瞬时表达依赖于CREB-p/CBP对组蛋白H3 K27的乙酰化。因此，在发育过程中建立的调节机制似乎仍然在分化后控制由不同刺激诱导的基因，就像成熟神经元中的早期记忆基因一样。 在神经元中，脑源性神经营养因子（BDNF）的转录被突触活动激活，部分是通过其启动子区域的表观遗传调节。在这里，作者描述了响应于NMDA处理的组蛋白修饰，其导致Bdnf从其不同启动子区域激活的不同动力学。
It has been recently described that in embryonic stem cells, the expression of some important developmentally regulated genes is repressed, but poised for fast activation under the appropriate stimuli. In this work we show that Bdnf promoters are repressed by Polycomb Complex 2 in mature hippocampal neurons, and basal expression is guaranteed by the coexistence with activating histone marks. Neuronal stimulation triggered by N-methyl-D-aspartate application induces the transcription of these promoters by H3K27Me3 demethylation and H3K27Me3 phosphorylation at Serine 28 leading to displacement of EZH2, the catalytic subunit of Polycomb Repressor Complex 2. Our data show that the fast transient expression of Bdnf promoters II and VI after neuronal stimulation is dependent on acetylation of histone H3K27 by CREB-p/CBP. Thus, regulatory mechanisms established during development seem to remain after differentiation controlling genes induced by different stimuli, as would be the case of early memory genes in mature neurons. In neurons, brain-derived neurotrophic factor (BDNF) transcription is activated by synaptic activity, in part by epigenetic regulation of its promoter regions. Here the authors characterize histone modifications in response to NMDA treatment that result in different kinetics of Bdnf activation from its different promoter regions.