State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Beijing, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Beijing, China.
Biol Psychiatry. 2019 Apr 15;85(8):635-649. doi: 10.1016/j.biopsych.2018.11.025. Epub 2018 Dec 5.
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.
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, viral-mediated CDYL manipulations, RNA sequencing, chromatin immunoprecipitation, Western blot, and messenger RNA quantification.
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.
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.
重度抑郁症是现代社会中一种普遍且危及生命的疾病。环境因素，如压力生活方式或创伤事件，对重度抑郁症的易感性有深远影响，它们可以通过表观遗传调控施加适应性转录程序。然而，其潜在的分子机制仍不清楚。在这里，我们研究了组蛋白巴豆酰化（一种新型组蛋白修饰）和色氨酸结构域 Y 样蛋白（CDYL），即巴豆酰辅酶 A 水解酶和组蛋白甲基赖氨酸阅读器，在这一过程中的作用。
我们使用慢性社交挫败应激和微挫败应激来检查抑郁行为。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、Western blot 和信使 RNA 定量相结合。
结果表明，应激易感啮齿动物的内侧前额叶皮质中的组蛋白巴豆酰化水平较低，同时 CDYL 选择性地上调。CDYL 在内侧前额叶皮质的一个亚区——前额叶皮层中的过表达会增加微挫败诱导的社交回避行为和小鼠的快感缺失。相反，CDYL 在前额叶皮层中的敲低可防止慢性社交挫败应激引起的抑郁样行为。从机制上讲，我们表明 CDYL 通过抑制神经肽 VGF 神经生长因子诱导的结构突触可塑性主要发挥作用，并且该活性依赖于其对 VGF 启动子上组蛋白巴豆酰化和 H3K27 三甲基化的双重作用。
我们的结果表明，CDYL 介导的组蛋白巴豆酰化在调节应激诱导的抑郁中起着关键作用，为重度抑郁症提供了一个潜在的治疗靶点。
