Chromodomain Y-like Protein-Mediated Histone Crotonylation Regulates Stress-Induced Depressive Behaviors
Chromodomain Y-like Protein-Mediated Histone Crotonylation Regulates Stress-Induced Depressive Behaviors
复制标题
染色质结构域 Y 样蛋白介导的组蛋白巴豆酰化调节压力诱发的抑郁行为
DOI：
10.1016/j.biopsych.2018.11.025
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发表时间：
2019-04-15
影响因子：
10.6
通讯作者：
Huang, Zhuo
中科院分区：
文献类型：
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作者：
Liu, Yongqing;Li, Minghua;Huang, Zhuo
背景：重度抑郁症是现代社会中一种普遍存在且危及生命的疾病。重度抑郁症的易感性深受环境因素的影响，例如压力生活方式或创伤事件，这些因素可能通过表观遗传调控施加适应不良的转录程序。然而，潜在的分子机制仍然难以捉摸。在这里，我们研究了组蛋白巴豆酰化（一种新型组蛋白修饰）和染色质 Y 样蛋白 (CDYL)（一种巴豆酰辅酶 A 水合酶和组蛋白甲基赖氨酸读取器）在此过程中的作用。 方法：我们使用慢性社交失败压力和微失败压力来检查抑郁行为。此外，我们将诊断雄性小鼠行为策略的程序与组蛋白提取、病毒介导的 CDYL 操作、RNA 测序、染色质免疫沉淀、蛋白质印迹和信使 RNA 定量相结合。 结果：结果表明，应激敏感的啮齿类动物在内侧前额皮质中表现出较低水平的组蛋白巴豆酰化，同时 CDYL 选择性上调。 CDYL 在前额叶皮层（内侧前额叶皮层的一个子区域）中过度表达，会增加小鼠微失败诱导的社交回避行为和快感缺失。相反，前边缘皮质中 CDYL 的敲除可以防止慢性社交失败压力诱发的抑郁样行为。从机制上讲，我们表明CDYL主要通过神经肽VGF神经生长因子诱导的转录抑制来抑制结构突触可塑性，并且这种活性依赖于其对组蛋白巴豆酰化和VGF启动子上的H3K27三甲基化的双重作用。结论：我们的结果表明CDYL介导的组蛋白巴豆酰化在调节应激诱发的抑郁症中发挥着关键作用，为重度抑郁症提供了潜在的治疗靶点。
BACKGROUND: Major depressive disorder is a prevalent and life-threatening illness in modern society. The susceptibility to major depressive disorder is profoundly influenced by environmental factors, such as stressful lifestyle or traumatic events, which could impose maladaptive transcriptional program through epigenetic regulation. However, the underlying molecular mechanisms remain elusive. Here, we examined the role of histone crotonylation, a novel type of histone modification, and chromodomain Y-like protein (CDYL), a crotonyl-coenzyme A hydratase and histone methyllysine reader, in this process.METHODS: We used chronic social defeat stress and microdefeat stress to examine the depressive behaviors. In addition, we combined procedures that diagnose behavioral strategy in male mice with histone extraction, viralmediated CDYL manipulations, RNA sequencing, chromatin immunoprecipitation, Western blot, and messenger RNA quantification.RESULTS: The results indicate that stress-susceptible rodents exhibit lower levels of histone crotonylation in the medial prefrontal cortex concurrent with selective upregulation of CDYL. Overexpression of CDYL in the prelimbic cortex, a subregion of the medial prefrontal cortex, increases microdefeat-induced social avoidance behaviors and anhedonia in mice. Conversely, knockdown of CDYL in the prelimbic cortex prevents chronic social defeat stress- induced depression-like behaviors. Mechanistically, we show that CDYL inhibits structural synaptic plasticity mainly by transcriptional repression of neuropeptide VGF nerve growth factor inducible, and this activity is dependent on its dual effect on histone crotonylation and H3K27 trimethylation on the VGF promoter.CONCLUSIONS: Our results demonstrate that CDYL-mediated histone crotonylation plays a critical role in regulating stress-induced depression, providing a potential therapeutic target for major depressive disorder.