Coordinated Regulation of Dendrite Arborization by Epigenetic Factors CDYL and EZH2
Coordinated Regulation of Dendrite Arborization by Epigenetic Factors CDYL and EZH2
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表观遗传因子CDYL和EZH2对树突分枝的协调调控
DOI：
10.1523/jneurosci.3647-13.2014
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发表时间：
2014-03-26
影响因子：
5.3
通讯作者：
Liang, Jing
中科院分区：
文献类型：
--
作者：
Qi, Cai;Liu, Shumeng;Liang, Jing
树突分枝是神经元信息处理精确回路的关键决定因素之一。了解树突状细胞形态发生的分子机制对于理解神经元连接的建立至关重要。在这里，我们使用获得和功能丧失的方法，定义了在体外和体内的大鼠/小鼠海马神经元中，染色域蛋白和转录辅助抑制物染色域Y样蛋白(CDYL)是树突形态发生的负调控因子。CDYL的过度表达降低了原代培养大鼠神经元树突的复杂性，而敲除CDYL则增加了树突状细胞的复杂性。高通量DNA芯片筛选鉴定出CDYL下游的一些靶基因，包括脑源性神经营养因子(BDNF)。CDYL在神经细胞中的表达下调导致BDNF表达增加，这是CDYL对树突模式产生影响的主要原因。在机制上，CDYL直接与多梳抑制复合体2(PRC2)的催化亚单位EZH2相互作用，并将H(3)K27甲基转移酶的活性招募到BDNF基因的启动子区域。在这样做的过程中，CDYL和EZH2以相互依赖的方式协调地限制树突的形态发生。最后，我们发现神经活动通过降解CDYL蛋白来释放其对BDNF的抑制而增加了树突状细胞的复杂性。这些结果首次将表观遗传调控因子CDYL和EZH2与树突形态发生联系起来，并可能为我们理解神经发育的调控提供新的线索。
Dendritic arborization is one of the key determinants of precise circuits for information processing in neurons. Unraveling the molecular mechanisms underlying dendrite morphogenesis is critical to understanding the establishment of neuronal connections. Here, using gain- and loss-of-function approaches, we defined the chromodomain protein and transcription corepressor chromodomain Y-like (CDYL) protein as a negative regulator of dendrite morphogenesis in rat/mouse hippocampal neurons both in vitro and in vivo. Overexpressing CDYL decreased, whereas knocking it down increased, the dendritic complexity of the primary cultured rat neurons. High through put DNA microarray screening identified a number of CDYL downstream target genes, including the brain-derived neurotrophic factor (BDNF). Knock-down of CDYL in neuronal cells led to increased expression of BDNF, which is primarily responsible for CDYL's effects on dendrite patterns. Mechanistically, CDYL interacts with EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), directly and recruits the H(3)K27 methyltransferase activity to the promoter region of the BDNF gene. In doing so, CDYL and EZH2 coordinately restrict dendrite morphogenesis in an interdependent manner. Finally, we found that neural activity increased dendritic complexity through degradation of CDYL protein to unleash its inhibition on BDNF. These results link, for the first time, the epigenetic regulators CDYL and EZH2 to dendrite morphogenesis and might shed new light on our understanding of the regulation of the neurodevelopment.